NAMPT target protein-based protein degradation compounds and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, and uses thereof. The present disclosure also relates to pharmaceutical compositions comprising a compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as an active ingredient, and uses thereof. The present disclosure contemplates a series of compounds synthesized to effectively prevent and / or treat diseases or disorders associated with NAMPT.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a protein degradation compound of Formula (I) or a salt, enantiomer, stereoisomer, solvate, prodrug or polymorph thereof designed based on a target protein of nicotinamide phosphoribosyltransferase (NMPRTase; NAMPT), and its use in treating or preventing a disease or disorder associated with NAMPT.

[0002] BACKGROUND

[0003] Nicotinamide adenine dinucleotide (NAD + ) is a coenzyme that transfers hydrogen ions and is involved in energy synthesis, cell material metabolism, DNA repair and other physiological functions [1] , and as an important small molecule metabolite, it is widely involved in a series of biochemical reactions in cell energy metabolism such as oxidative phosphorylation, glycolysis and fatty acid oxidation, so NAD + is essential for human health [2] .

[0004] NAD + has three biosynthetic pathways in common [3] :

[0005] 1. De novo synthesis pathway. The de novo synthesis pathway is initiated by indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), which converts tryptophan to N-formylkynurenine. Then through formamidase (KFase), N-formylkynurenine is converted to kynurenine, and a hydroxyl group is added to it through kynurenine 3-hydroxylase (K3H). The product 3-hydroxy-kynurenine is converted to 3-hydroxy-anthranilic acid, and then through kynureninase (Kyase) and 3-hydroxy-anthranilic acid ester-3,4-dioxygenase to 2-amino-3-carboxymuconate semialdehyde (ACMS) [4] . Then ACMS is cyclized to form quinolinic acid (QA), and participates in NAMN biosynthesis with quinolinate phosphoribosyltransferase (QPRT) ,6] .

[0006] 2. Preiss-Handler pathway (nicotinic acid salvage pathway). This pathway begins after NA is converted to nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT) [7] , and NAMN is used for the biosynthesis of nicotinic acid adenine dinucleotide (NAAD) by nicotinamide / nicotinic acid mononucleotide adenylyltransferase (NMNAT). Finally, NAD+ Synthetase (NADS) converts NAAD into NAD via the action of ammonia and ATP +[8,9] .

[0007] 3. Salvage pathway. Most NAD + Rather than being produced de novo, it is recycled from NAM, NR, and NMN in the salvage pathway to maintain cellular NAD + level. Therefore, the salvage pathway is the NAD + The main source of NAD. + Consumption reactions (including NAD + NAM can be converted to NMN through the NAMPT cycle, catalyzing the rate-limiting reaction in the recycling pathway.

[10] The precursor NR is converted into NMN by NRK1 / 2, and NMN is adenylated by NMNAT to eventually produce NAD. +[2] .

[0008] Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that catalyzes the conversion of nicotinamide adenine dinucleotide (NAD + ) is the rate-limiting enzyme in its synthesis.

[0009] Cancer cells have altered metabolic requirements, requiring less nicotinamide adenine dinucleotide (NAD + ) Cycle speed increases

[11] Therefore, the salvage pathway is crucial for cancer cells. In fact, many types of cancer cells have been shown to highly express NAMPT, which reflects the fact that NAD + High utilization of, and in some cases, other key NAD + Loss of expression of biosynthetic enzymes potentially increases reliance on this pathway [12-15] Cancer types reported to have high NAMPT expression include, but are not limited to, colorectal cancer, breast cancer, osteosarcoma, chondrosarcoma, pancreatic ductal adenocarcinoma, oral squamous cell carcinoma, prostate cancer, rhabdomyosarcoma, leiomyosarcoma, esophagogastric junction adenocarcinoma, thyroid cancer, leukemia, lymphoma, ovarian cancer, and some renal cancers. In many of these cancers, higher NAMPT expression is associated with a poorer prognosis. [16-32] NMN can also be produced from nicotinamide riboside by nicotinamide riboside kinase

[13] However, NAMPT is currently the only NAD that is clinically targeted. + Producing enzymes.

[0010] NAMPT exists in mammals in two forms, intracellular NAMPT (iNAMPT) in the cytoplasm and nucleus and extracellular NAMPT (eNAMPT) in the plasma or extracellular space.

[0011] NAMPT is overexpressed in several human malignancies, including colorectal cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, endometrial cancer, melanoma, multiple myeloma, astrocytoma, hepatocarcinoma, thyroid cancer, malignant lymphoma, etc., in combination with its promotion of many aspects of malignant phenotype, suggesting that inhibition of NAMPT can play an anticancer role. NAMPT inhibition also leads to ATP depletion, reduces PARP-1 and SirT1 activity, and ultimately leads to cell death [34-36] . Due to the increase in NAD + and ATP catabolism, tumor cells are more sensitive to iNAMPT inhibition than normal cells

[37] . The highly specific NAMPT inhibitor FK866 can induce apoptosis in human hepatocarcinoma cells HepG2, which involves the depletion of NAD + , which can be partially reversed by adding NAM or nicotinic acid

[33] . NAMPT inhibitors can be used to treat triple-negative breast cancer, hepatocarcinoma, gastric cancer, non-small cell lung cancer with epidermal growth factor receptor gene mutation, glioblastoma, melanoma, etc.

[0012] eNAMPT can be released by multiple types of cells and acts on multiple cells as a cytokine. It can activate downstream pathways in cells by stimulating the subsequent release of other cytokines.

[0013] Plasma eNAMPT is elevated in a variety of human malignancies, including astrocytoma, myeloma, and male oral squamous cell carcinoma, gastric cancer, endometrial cancer, hepatocellular carcinoma, colorectal cancer, and invasive breast cancer, etc. [38-46] . In astrocytoma, plasma eNAMPT increases with the increase of astrocytoma grade, which is considered a prognostic marker. Similarly, in male oral squamous cell carcinoma, hepatocellular carcinoma, endometrial carcinoma and invasive breast cancer, eNAMPT is elevated when the tumor is high stage. In patients with endometrial cancer, higher eNAMPT levels are associated with endometrial invasion and shorter patient survival. Higher eNAMPT levels in invasive breast cancer are associated with lymph node metastasis and loss of estrogen and progesterone receptors. Mouse heart-specific eNAMPT overexpression leads to cardiac and cardiomyocyte hypertrophy by activating JNK1, p38 and ERK kinases, and cardiomyocytes cultured with H2O2 or serum starvation will secrete eNAMPT

[47] Pre-treatment of human chondrocytes with eNAMPT inhibited IGF-1-stimulated proteoglycan synthesis and AKT and insulin receptor substrate-1 phosphorylation, while activating ERK

[48] The researchers found that eNAMPT treatment rapidly induced IL-6 production in mouse macrophages, followed by IL-6-mediated STAT3 activation. Interestingly, IL-1β, TNF-α and IL-6 can induce the expression of eNAMPT in macrophages [49-51] These data suggest that plasma eNAMPT may contribute to carcinogenesis and tumor growth.

[0014] NAMPT is also closely related to the occurrence and development of many diseases.

[0015] Diabetic nephropathy is one of the most serious microvascular complications of diabetes and is one of the risk factors for death in diabetic patients, seriously threatening human health. The pathogenesis of diabetic nephropathy is complex and diverse, and inflammation-fibrosis of the kidney is the most important cause. Studies have shown that the inflammation-fibrosis process of the kidney is closely related to NAMPT. 1. In mesangial cells, NAMPT can mediate intracellular glucose transport by promoting the expression and translocation of GLUT-1 on the cell membrane, thereby increasing body glucose metabolism and increasing extracellular matrix synthesis, causing renal parenchyma damage [52,53] . 2. Diabetic patients are in a state of obvious oxidative stress imbalance. By detecting the patient's serum, it was found that NAMPT was positively correlated with lipid peroxidation metabolites and negatively correlated with antioxidant enzyme SOD, suggesting that NAMPT is closely related to oxidative stress in the body

[54] Both of them interact together to promote the occurrence of diabetic nephropathy.

[0016] NAMPT is closely related to the occurrence and development of cardiovascular and cerebrovascular diseases. NAMPT expression is significantly increased in the carotid artery plaque of patients with unstable atherosclerosis and the ruptured plaque of patients with acute myocardial infarction [55,56] Studies have found that NAMPT can enhance the enzyme activity of MMP-2 and MMP-9, and MMP can degrade extracellular matrix, making the fibrous cap thin and leading to plaque rupture, suggesting that NAMPT plays an important role in the instability of atherosclerotic plaques 57 NAMPT inhibitors can reduce myocardial infarction area, neutrophil infiltration and reactive oxygen species production in a mouse model of myocardial ischemia-reperfusion injury

[58] Therefore, NAMPT pharmacological inhibitors can reduce oxidative-mediated tissue damage in myocardial infarction as an effective therapeutic drug.

[0017] NAMPT is highly expressed in placental tissue of pregnant women with pregnancy-induced hypertension syndrome, and the expression levels of the two are positively correlated, suggesting that it is closely related to gestational hypertension.

[0018] Clinical studies have shown that NAMPT concentrations are significantly increased in chronic inflammatory diseases. As a pro-inflammatory adipokine, NAMPT promotes the expression of monocyte chemoattractant factor-1 and intercellular adhesion molecule-1 proteins.

[59] NAMPT can induce CD14 + Monocytes produce inflammatory factors such as interleukin-1β, tumor necrosis factor-α, and interleukin-6, and increase the surface expression of costimulatory molecules CD54, CD40, and CD80

[60] eNAMPT can activate NF-κB, leading to upregulation of inducible nitric oxide synthase expression and promoting inflammatory responses

[61] .

[0019] NAMPT also acts as an immunomodulatory cytokine. The development and function of T lymphocytes and B lymphocytes are almost completely dependent on NAMPT. Conditional knockout of the NAMPT gene in lymphocytes leads to a significant decrease in the number of thymocytes and an almost complete loss of peripheral blood T lymphocytes and B lymphocytes.

[62] High levels of NAMPT can be detected in the serum of patients with autoimmune diseases such as rheumatoid arthritis and autoimmune encephalitis. [63,64] .

[0020] High levels of NAMPT expressed in the blood and gastric adipose tissue are positively correlated with overweight or obesity. NAMPT is an essential factor for overweight or obesity, and if NAMPT is downregulated in adipose tissue, it will help improve obesity.

[65] .

[0021] Currently in clinical trials, the NAMPT inhibitor FK866 has anti-tumor effects in both cell and animal models, especially in hematological tumors. FK866 eliminates tumor cells to levels below detectable, resulting in long-term survival of 80% of mice.

[66] However, FK866 has some problems. Clinical trial results show that FK866 treatment can cause dose-limiting toxic thrombocytopenia and gastrointestinal reactions such as diarrhea and constipation.

[67] This is also the reason why FK866 has been stagnant since its Phase II clinical trial. In addition, NAMPT exists in both enzymatic and non-enzymatic forms. As an enzymatic inhibitor, FK866 cannot inhibit plasma and extracellular non-enzymatic NAMPT (eNAMPT). eNAMPT has been shown to contribute to carcinogenesis and tumor growth, which affects the therapeutic effect of FK866. Therefore, it is necessary to improve existing inhibitors or develop new drugs to overcome the shortcomings of existing inhibitors.

[0022] Designing proteolysis targeting agents with targeting specific proteins is a new model for drug development. We use the proteolysis targeting drug (PROTAD) technology platform and apply it to the development of anti-tumor drugs. PROTAD can mark target proteins for "degradation" through specially designed bispecific protein modulators, and can activate the intracellular protein degradation pathway to degrade target proteins. Therefore, we hope to use the protein degradation technology platform to develop protein modulators that can degrade disease-related pathogenic proteins, so as to treat and prolong the survival of tumor patients.

[0023] Therefore, there is an urgent need for a series of novel protein degradation agents designed based on NAMPT target proteins for the treatment and / or prevention of diseases or disorders associated with NAMPT. SUMMARY

[0024] The present disclosure provides a series of novel protein degradation compounds or salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers based on NAMPT target protein design, which can target and degrade NAMPT proteins, thereby effectively treating and / or preventing diseases or disorders associated with NAMPT. Diseases or disorders associated with NAMPT include, but are not limited to, tumors, autoimmune diseases, inflammatory diseases, pregnancy-induced hypertension syndrome, cardiovascular and cerebrovascular diseases, obesity, and diabetic nephropathy.

[0025] In some embodiments, the present disclosure provides a compound of formula (I) or a salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomers), or mixture of stereoisomers thereof:

[0026]

[0027] wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linking moiety, the remainder of the molecule of formula (I) is a nicotinamide phosphoribosyltransferase (NAMPT) ligand, and ULM is covalently linked to the NAMPT ligand via LIN;

[0028] wherein ring A is the following group:

[0029]

[0030] (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R a is independently hydroxyl, amino, halogen, or cyano, and m1 represents an integer of 0, 1, 2, 3, 4, or 5;

[0031] R 1 and R 2 are the same or different and independently of each other H, cyano or methyl;

[0032] L1represents a substituted or unsubstituted straight-chain C 3-6 alkylene group, or a substituted or unsubstituted straight-chain C 3-6 alkenylene group, optional substituents of the straight-chain C 3-6 alkylene and straight-chain C 3-6 alkenylene groups are selected from the group consisting of C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof;

[0033] Ring B is a 5- to 11-membered heterocyclylidene, (R b ) m2 denotes that ring B is optionally substituted by m2R b groups, each R b is independently C 1-3 alkyl, hydroxyl, amino, mercapto, halogen, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m2 denotes an integer 0, 1, 2, 3, 4 or 5;

[0034] Ring C is a 5- to 10-membered heteroarylidene, or a 6-membered ary lidene, (R c ) m3 denotes that ring C is optionally substituted by m3R c groups, each R c is independently C 1-3 alkyl, C 3-5 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m3 denotes an integer 0, 1, 2, 3, 4 or 5;

[0035] m denotes an integer 0 or 1 ; and

[0036] Y represents -N(R 3 )-, wherein R 3 is hydrogen or C 1-3 alkyl; or

[0037] Y represents -O-; or

[0038] Y is n contiguous rings D represented by the following structural formula:

[0039]

[0040] Each ring D is independently a 5- to 11-membered heterocyclyl, (R d ) m4 represents each ring D is optionally independently substituted with m4 R d groups, each R d is independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m4 represents an integer 0, 1, 2, 3, 4 or 5;

[0041] n is an integer 0, 1, 2 or 3, wherein when n represents an integer 2 or 3, each ring D can be the same or different, and

[0042] wherein m and n are not simultaneously 0;

[0043] with the proviso that the following compounds are excluded:

[0044] The nicotinamide phosphoribosyltransferase (NAMPT) ligand represents the following structure:

[0045]

[0046] and ULM represents the structure of formula (IV):

[0047]

[0048] wherein Z1 represents C(O) or Z1 represents a bond, and Z2 represents H or CH3.

[0049] In some embodiments, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.

[0050] In some embodiments, the present disclosure provides a kit or pharmaceutical pack comprising the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure.

[0051] In some embodiments, the present disclosure provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, for use as a medicament.

[0052] In some embodiments, the present disclosure further provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure, for use in the treatment or prevention of a disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT).

[0053] In some embodiments, the present disclosure provides the use of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure, for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT).

[0054] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT) in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0055] Figure 1 The degradation activity of the compounds of the present application SIAIS630120 and SIAIS630121 on NAMPT protein in SW620, HT29 cell lines is shown.

[0056] Figure 2 The degradation activity of the inventive compounds SIAIS630120 and SIAIS630121 on NAMPT protein in MCF-7 cell line is shown.

[0057] Figure 3 The degradation activity of the inventive compounds SIAIS630120 and SIAIS630121 on NAMPT protein in BEL7404 cell line is shown.

[0058] Figure 4 The degradation activity of the inventive compounds SIAIS630120 and SIAIS630121 on NAMPT protein in MOLT4, Jurkat, HL60 cell lines is shown.

[0059] Figure 5 The degradation activity of the inventive compounds SIAIS630120 and SIAIS630121 and the parent inhibitor FK866 on eNAMPT protein in HL60, MOLT4 cell lines is shown.

[0060] Figures 6-7 The in vitro killing effect of the inventive compounds SIAIS630120 and SIAIS630121 and the parent inhibitor FK866 on HL60, MOLT4 cell lines is shown. DETAILED DESCRIPTION

[0061] The following detailed description is provided as exemplary specific embodiments to assist in a thorough understanding of the disclosure. It should be recognized that such description is not intended as limiting and that modifications can be employed apart from the specific embodiments described without departing from the spirit and scope of the disclosure.

[0062] I. Compounds

[0063] The present disclosure provides a compound of Formula (I) or a salt (including a pharmaceutically acceptable salt), solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof:

[0064]

[0065] wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linking moiety, the remainder of the molecule of Formula (I) is a nicotinamide phosphoribosyltransferase (NAMPT) ligand, and ULM is covalently linked to the NAMPT ligand through LIN;

[0066] wherein ring A is a group:

[0067]

[0068] (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R a is independently hydroxyl, amino, halogen or cyano, and m1 represents an integer 0, 1, 2, 3, 4 or 5;

[0069] R 1 and R 2 are the same or different and independently of each other H, cyano or methyl;

[0070] L1represents a substituted or unsubstituted straight-chain C 3-6 alkylene, or a substituted or unsubstituted straight-chain C 3-6 alkenylene, the optional substituents of the straight-chain C 3-6 alkylene and straight-chain C 3-6 alkenylene are selected from the group consisting of C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof;

[0071] ring B is a 5- to 11-membered heterocyclylene, (R b ) m2 represents that ring B is optionally substituted with m2 R b groups, each R b is independently C 1-3 alkyl, hydroxyl, amino, mercapto, halogen, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m2 represents an integer 0, 1, 2, 3, 4 or 5;

[0072] ring C is a 5- to 10-membered heteroarylene, or a 6-membered arylene, (R c ) m3 represents that ring C is optionally substituted with m3 R c groups, each R c is independently C 1-3 alkyl, C 3-5 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1-3 alkoxy, C1-3 Alkylamino, halogenated C 1-3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m3 represents an integer of 0, 1, 2, 3, 4 or 5;

[0073] m represents an integer 0 or 1; and

[0074] Y represents -N(R 3 )-, where R 3 is hydrogen or C 1-3 alkyl; or

[0075] Y represents -O-; or

[0076] Y is n connected rings D represented by the following structural formula:

[0077]

[0078] Each ring D is independently a 5- to 11-membered heterocyclylene group, (R d ) m4 Indicates that each ring D can be optionally and independently replaced by m4 R d Group substitution, each R d Independently C 1-3 Alkyl, C 3-6 Cycloalkyl, hydroxyl, amino, mercapto, halogen, oxo, C 1-3 Alkoxy, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m4 represents an integer of 0, 1, 2, 3, 4 or 5;

[0079] n is an integer of 0, 1, 2 or 3, wherein when n represents an integer of 2 or 3, each ring D may be the same or different, and

[0080] Where m and n are not 0 at the same time;

[0081] Provided that the following compounds are not included:

[0082] The nicotinamide phosphoribosyltransferase (NAMPT) ligand represents the following structure:

[0083]

[0084] And ULM represents the structure of formula (IV):

[0085]

[0086] wherein Z1represents C(O) or Z1represents a bond, and Z2represents H or CH3.

[0087] In some embodiments, L1represents a substituted or unsubstituted straight chain C 3-6 alkylene. Exemplary examples of straight chain C 3-6 alkylene include, but are not limited to, propylene, butylene, pentylene, and hexylene. The straight chain C 3-6 alkylene is optionally further substituted with one or more substituents selected from C 1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halogenated C 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), C 1-3 alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. The number of substituents is in principle not limited by any or automatically by the size of the building block.

[0088] In some embodiments, L1represents a substituted or unsubstituted straight chain C 3-6 alkylene. Exemplary examples of straight chain C 3-6 alkylene include, but are not limited to, propylene, butylene, pentylene, and hexylene. The straight chain C In some embodiments, L1represents a substituted or unsubstituted straight chain C 3-6 alkylene. Exemplary examples of straight chain C 1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halogenated C 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), C 1-3alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. The number of substituents is in principle not limited by any or automatically by the size of the building block.

[0089] In some embodiments, ring B is a 5- to 11-membered heterocyclylidene group containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, ring B is a 5- to 11-membered heterocyclylidene group containing 1 nitrogen atom and optionally further containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments, exemplary instances of ring B include, but are not limited to, the following groups: piperidinylidene, piperazinylidene, morpholinylidene, azetidinylidene, oxetanyliden, pyrrolidinylidene, imidazolidinylidene, pyrazolidinylidene, tetrahydrofuranyliden, tetrahydropyranyliden, tetrahydrothiophenyliden, tetrahydrothiopyranyliden, oxazolidinyliden, thiazolidinyliden, sulfomorpholinyliden, dioxanyliden, diazepanyliden, or C 7-11 spiroheterocyclylidene.

[0092] In some embodiments, when ring B represents C 7-11 spiroheterocyclylidene, the C 7-11 spiroheterocyclylidene can be the following group:

[0093]

[0094] wherein the symbol * represents the point of attachment to the group L1 (which can be any ring atom of the spiroheterocyclyl group that can be attached to the group L1), X represents O, N(R e ), S, or CH2, or X represents a bond, R e represents hydrogen or methyl, and n1, n2, and n3 are each independently an integer of 1 or 2.

[0095] In the present text, the expression “X represents a bond” means that it is a bond linker (i.e. that it is not present). For example, the expression “X represents a bond” means that X is a bond linker. In other words, when X is a bond, the two carbon atoms adjacent to X on either side are directly connected to each other.

[0096] In some embodiments, when ring B represents C 7-11 spiroheterocyclylidene, the C 7-11 spiroheterocyclylidene can be the following group:

[0097]

[0098] wherein the symbol * indicates the point of attachment to the group L1.

[0099] In some embodiments, ring B is optionally further substituted with m2R b groups, wherein m2represents an integer 0, 1, 2, 3, 4, or 5, and each R b independently C 1-3 alkyl (e.g., methyl, ethyl, or propyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkyl NH-, e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, - CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene-, e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)-(e.g., CH3-NHC(O)-, CH3CH2- NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH-(e.g., CH3-C(O)NH-, CH3CH2- C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano.

[0100] In some embodiments, Exemplary examples include, but are not limited to, the following groups:

[0101]

[0102] wherein the symbol * indicates the point of attachment to the group L1.

[0103] In some embodiments, ring C is a 5- to 10-membered heteroarylene, or a 6-membered arylene. Illustrative examples of ring C include, but are not limited to, the following groups: phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, 1,2,4-triazinylene, 1,3,5-triazinylene, triazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazylyene, benzo[1,2,3]thiadiazylyene, quinolylene, isoquinolylene, naphthidylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, or imidazo[2,1-b]thiazolylene.

[0104] In some embodiments, ring C is optionally further substituted with m3R c groups, wherein m3 represents an integer of 0, 1, 2, 3, 4, or 5, and each R c is independently C 1-3 alkyl (e.g., methyl, ethyl, or propyl), C 3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkyl NH-, e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene-, e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano. 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano.

[0105] In some embodiments, Exemplary instances of include, but are not limited to, the following groups:

[0106]

[0107] wherein the symbol *** represents a point of attachment to the group Y, or the symbol *** represents a point of attachment to the carbonyl group.

[0108] In some embodiments, Y represents -N(R 3 )-, wherein R 3 is hydrogen or C 1-3 alkyl.

[0109] In some embodiments, Y represents -O-.

[0110] In some embodiments, Y is n contiguous rings D represented by the following structural formula:

[0111]

[0112] wherein n is an integer of 0, 1, 2, or 3, wherein when n represents an integer of 2 or 3, each ring D can be the same or different, each ring D is independently a 5- to 11-membered heterocyclyl, (R d ) m4 represents each ring D is optionally independently substituted with m4 R d groups, m4 represents an integer of 0, 1, 2, 3, 4, or 5, and each R d is independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, haloC 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano.

[0113] In some embodiments, exemplary instances of ring D include, but are not limited to, the following groups: piperidinylene, piperazinylene, morpholinylene, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, sulfomorpholinylene, dioxanylene, diazepanylene, or C 7-11 spiro heterocyclylidene.

[0114] In some embodiments, when ring D represents C 7-11 spiro heterocyclylidene, the C 7-11 spiro heterocyclylidene can be the following groups:

[0115]

[0116] wherein the symbol ** represents the point of attachment to ring C, X represents O, N(R e ), S, or CH2, or X represents a bond, wherein R e represents hydrogen or methyl, and each of n1, n2, and n3 is independently an integer of 1 or 2.

[0117] In some embodiments, when ring D represents C 7-11 spiro heterocyclylidene, the C 7-11 spiro heterocyclylidene can be the following groups:

[0118]

[0119] wherein the symbol ** represents the point of attachment to ring C.

[0120] In some embodiments, ring D is optionally further substituted with m4 R d groups, wherein m4 represents an integer of 0, 1, 2, 3, 4, or 5, and each R d is independently C 1-3 alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), oxo, C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkyl NH-, such as CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), halogenated C 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C1-3 alkylene(NH2-C 1-3 alkylene-, such as NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)-(such as CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH-(such as CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano.

[0121] In some embodiments, exemplary instances of which include, but are not limited to, the following groups:

[0122]

[0123] wherein the symbol ** indicates a point of attachment to ring C. Alternatively, in some embodiments, the symbol ** in the group can also indicate a point of attachment to the group LIN.

[0124] In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In some embodiments, m is 0 and n is 3. In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m is 1 and n is 2. In some embodiments, m is 1 and n is 3.

[0125] In some embodiments, exemplary instances of which include, but are not limited to, the following groups:

[0126]

[0127] wherein the symbol ## indicates a point of attachment to the group LIN.

[0128] In some embodiments, ULMrepresents a structure of formula (III):

[0129]

[0130] wherein R represents O, N(R 4 ), S, alkynylene, alkenylene, or optionally substituted triazolylene, wherein R 4 represents H or C 1-3 alkyl, or R represents a bond, and W represents optionally substituted phenylene or W represents a bond, wherein when R represents a bond, W represents a bond; and

[0131] (R f ) m5The phenyl ring of formula (III) is optionally substituted with m5 R f each R f is independently halo, m5 represents an integer of 0, 1, 2, or 3; and

[0132] Z represents C(O) or CH2.

[0133] In some embodiments, the structure of formula (III) can also be a structure of the following formula:

[0134]

[0135] wherein Z represents CH2or C(O);

[0136] (R f ) m5 The phenyl ring of formula (III) is optionally substituted with m5 R f each R f is independently halo, m5 represents an integer of 0, 1, 2, or 3; and

[0137] R represents O, N(R 4 ), S, alkynylene, alkenylene, or optionally substituted triazolylene, wherein R 4 represents H or C 1-3 alkyl, or R represents a bond, and W represents optionally substituted phenylene or W represents a bond, wherein when R represents a bond, W represents a bond.

[0138] In some embodiments, Z represents C(O).

[0139] In some embodiments, Z represents CH2.

[0140] In some embodiments, R represents O.

[0141] In some embodiments, R represents N(R 4 ), wherein R 4 represents H or C 1-3 alkyl (e.g., methyl, ethyl, or propyl).

[0142] In some embodiments, R represents a bond. In some embodiments, when R represents a bond, W represents a bond.

[0143] In some embodiments, R represents alkynylene, e.g., ethynylene or butynylene

[0144]

[0145] In some embodiments, R represents alkenylene, e.g., ethenylene

[0146] In some embodiments, R represents S.

[0147] In some embodiments, R represents triazolylene.

[0148] In some embodiments, W represents optionally substituted phenylene, exemplary substituents including but not limited to halogen (e.g., fluorine, chlorine, bromine, or iodine). The number of substituents can be 0, 1, 2, or 3.

[0149] In some embodiments, W represents a bond.

[0150] In some embodiments, ULM represents a structure of the following formula:

[0151]

[0152]

[0153] wherein R 4 represents H or C 1-3 alkyl (e.g., methyl, ethyl, or propyl); (R f ) m5 represents the phenyl ring is optionally substituted with m5 R f groups, each R f is independently halogen (e.g., fluorine, chlorine, bromine, or iodine), and m5 represents an integer of 0, 1, 2, or 3.

[0154] In some embodiments, ULM represents a structure of formula (IV):

[0155]

[0156] wherein Z1 represents C(O) or Z1 represents a bond, and Z2 represents H or CH3.

[0157] In some embodiments, ULM represents a structure of the following formula:

[0158]

[0159] wherein Z1 represents C(O) or Z1 represents a bond.

[0160] In some embodiments, LIN represents the following formula:

[0161] #-U-alkylene,

[0162] wherein U represents C(O) or U represents a bond, and the symbol # represents a point of attachment to the group Y; and

[0163] the alkylene is substituted or unsubstituted methylene, or substituted or unsubstituted straight chain or branched chain C 2-60alkylene, wherein the straight-chain or branched C 2-60 alkylene is optionally interrupted by one or more groups R 5 and / or one or more groups R 6 or one or more groups R 5 in any combination with R 6 . In other words, when the straight-chain or branched C 2-60 alkylene is interrupted by one or more groups R 5 and / or one or more groups R 6 or one or more groups R 5 in any combination with R 6 , the groups R 5 , R 6 or a combination of groups R 5 and R 6 interrupt a carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain. In some embodiments, each group R 5 is independently selected from O, N(R 7 ), C(O), C(O)O, OC(O), C(O)N(R 7 ), N(R 7 )C(O), or N(R 7 )C(O)N(R 7 ), wherein each R 7 independently represents H or C 1-3 alkyl (e.g., methyl, ethyl, or propyl), and when the straight-chain or branched C 2-60 alkylene is interrupted by more than two groups R 5 , each group R 5 is not directly attached to each other. In some embodiments, each group R 6 is independently selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene (e.g., ethynylene or butynylene ), alkenylene (e.g., ethenylene ), or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently optionally further substituted with one or more groups selected from C 1-3 alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3alkylNH-, such as CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC 1-3 alkyl (such as -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene (such as NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)- (such as CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (such as CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. In some sub-embodiments, the main carbon chain of the alkylene chain (such as substituted or unsubstituted straight-chained or branched C 2-60 one or more (such as 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 one or more (such as 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 6 one or more (such as 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 -R 6 each R 5 each R 6 are the same or different, and are as defined herein.

[0164] In some embodiments, LIN represents the following formula:

[0165] #-U-alkylene,

[0166] wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and

[0167] the alkylene is a substituted or unsubstituted straight-chained or branched C 1-60 alkylene (such as C 1-55alkylene chain, C 1-50 alkylene chain, C 1-45 alkylene chain, C 1-40 alkylene chain, C 1-35 alkylene chain, C 1-30 alkylene chain, C 1-25 alkylene chain, C 1-23 alkylene chain, C 1-22 alkylene chain, C 1-21 alkylene chain, C 1-20 alkylene chain, C 2-20 alkylene chain, C 1-19 alkylene chain, C 2-19 alkylene chain, C 1-18 alkylene chain, C 2-18 alkylene chain, C 1-17 alkylene chain, C 2-17 alkylene chain, C 1-16 alkylene chain, C 2-16 alkylene chain, C 1-15 alkylene chain, C 2-15 alkylene chain, C 1-14 alkylene chain, C 2-14 alkylene chain, C 1-13 alkylene chain, C 2-13 alkylene chain, C 1-12 alkylene chain, C 2-12 alkylene chain, C 1-11 alkylene chain, C 2-11 alkylene chain, C 1-10 alkylene chain, C 2-10 alkylene chain, C 3-10 alkylene chain, C 1-9 alkylene chain, C 2-9 alkylene chain, C 3-9 alkylene chain, C 1-8 alkylene chain, C 2-8 alkylene chain, C 3-8 alkylene chain, C 1-7 alkylene chain, C 2-7 alkylene chain, C 3-7 alkylene chain, C 1-6 alkylene chain, C 2-6 alkylene chain, C 3-6 alkylene chain, C 1-5 alkylene chain, C 2-5 alkylene chain, C 3-5 alkylene chain, C 1-4 alkylene chain, C 1-3 alkylene chain, C 1-2 alkylene chain, methylene). When the alkylene is a substituted straight or branched chain C 1-60When alkylene is present, examples of its substituents may be selected from C1-C3 alkyl (e.g., methyl, ethyl or propyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy), C1-C3 alkylamino (C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino C 1-3 Alkylene (NH2-C 1-3 Alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3 Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (eg, CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof.

[0168] In some embodiments, the alkylene group of LIN can be a substituted linear or branched C 1-60 Alkylene, for example, a straight-chain or branched C 1-60 Alkylene (e.g. C 1-55 Alkylene chain, C 1-50 Alkylene chain, C 1-45 Alkylene chain, C 1-40 Alkylene chain, C 1-35 Alkylene chain, C 1-30 Alkylene chain, C 1-25 Alkylene chain, C 1-23 Alkylene chain, C 1-22 Alkylene chain, C 1-21 Alkylene chain, C 1-20 Alkylene chain, C 2-20 Alkylene chain, C 1-19 Alkylene chain, C 2-19 Alkylene chain, C 1-18 Alkylene chain, C 2-18 Alkylene chain, C 1-17 Alkylene chain, C 2-17 Alkylene chain, C 1-16 Alkylene chain, C2-16 Alkylene chain, C 1-15 Alkylene chain, C 2-15 Alkylene chain, C 1-14 Alkylene chain, C 2-14 Alkylene chain, C 1-13 Alkylene chain, C 2-13 Alkylene chain, C 1-12 Alkylene chain, C 2-12 Alkylene chain, C 1-11 Alkylene chain, C 2-11 Alkylene chain, C 1-10 Alkylene chain, C 2-10 Alkylene chain, C 3-10 Alkylene chain, C 1-9 Alkylene chain, C 2-9 Alkylene chain, C 3-9 Alkylene chain, C 1-8 Alkylene chain, C 2-8 Alkylene chain, C 3-8 Alkylene chain, C 1-7 Alkylene chain, C 2-7 Alkylene chain, C 3-7 Alkylene chain, C 1-6 Alkylene chain, C 2-6 Alkylene chain, C 3-6 Alkylene chain, C 1-5 Alkylene chain, C 2-5 Alkylene chain, C 3-5 Alkylene chain, C 1-4 Alkylene chain, C 1-3 Alkylene chain, C 1-2 alkylene chain, methylene), the substituents are optionally selected from C1-C3 alkyl (such as methyl, ethyl or propyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy), C1-C3 alkylamino (C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino C 1-3 Alkylene (NH2-C 1-3 Alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. In a sub-embodiment of the present disclosure, the linear or branched C 1-60 The alkylene group optionally carries one or more, e.g., 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, identical or different substituents. The number of substituents is in principle not limited by any restriction or automatically by the size of the building block.

[0169] In some embodiments, LIN represents a group of the following: #-U-CH2-, #-U-(CH2)2-, #-U-(CH2)3-, #-U-(CH2)4-, #-U-(CH2)5-, #-U-(CH2)6-, #-U-(CH2)7-, #-U-(CH2)8-, #-U-(CH2)9-, #-U-(CH2) 10 -,-#-U-(CH2) 11 -,-#-U-(CH2) 12 -,-#-U-(CH2) 13 -,-#-U-(CH2) 14 -,-#-U-(CH2) 15 -,-#-U-(CH2) 16 -,-#-U-(CH2) 17 -,-#-U-(CH2) 18 -,-#-U-(CH2) 19 -,-#-U-(CH2) 20 -,-#-U-(CH2) 21 -,-#-U-(CH2) 22 -,-#-U-(CH2) 25 -,-#-U-(CH2) 30 -,-#-U-(CH2) 35 -,-#-U-(CH2) 40 -,-#-U-(CH2) 45 -,-#-U-(CH2) 50 -,-#-U-(CH2) 55 -,-#-U-(CH2)60 wherein the hydrogen of one or more CH2of said group is optionally further replaced by a substituent selected from the group consisting of C1-C3alkyl (e.g. methyl, ethyl or propyl), C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C3alkoxy (e.g. methoxy, ethoxy or propoxy), C1-C3alkylamino (C 1-3 alkylNH-, e.g. CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3alkyl (e.g. F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino-substituted C 1-3 alkylene(NH2-C 1-3 alkylene-, e.g. NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)-(e.g. CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH-(e.g. CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano or any combination thereof, and U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y.

[0170] In some embodiments, LINrepresents the following formula:

[0171] #-U-alkylene,

[0172] wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and

[0173] said alkylene is an unsubstituted or substituted straight-chain or branched C 2-60 alkylene, which is optionally interrupted in its main carbon chain by one or more groups R 2-60 and / or one or more groups R 5 or one or more groups R 6 or one or more groups R 5 in any combination with R 6 . In other words, when said straight-chain or branched C 2-60 alkylene is interrupted in its main carbon chain by one or more groups R 5 and / or one or more groups R 6 or one or more groups R5 with any combination of R 6 5 , R 6 or a group R 5 and R 6 interrupts a carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain. In some embodiments, each group R 5 is independently selected from O, N(R 7 ), C(O), C(O)O, OC(O), C(O)N(R 7 ), N(R 7 )C(O), or N(R 7 )C(O)N(R 7 ), wherein each R 7 independently represents H or C 1-3 alkyl (e.g., methyl, ethyl, or propyl), and when more than two groups R 2-60 are inserted in the main carbon chain of the straight or branched C 5 alkylene, each group R 5 is not directly attached to each other. In some embodiments, each group R 6 is independently selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are independently optionally further substituted with one or more (e.g., 1-4, 1-3, 1-2, or 1) groups selected from C 1-3 alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkylNH-, such as CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene-, such as NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 ​Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 In some embodiments, the group R 5 The number of R 6 The number or group R 5 With R 6 The number of any combination of can be, for example, 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1. The group R 5 、R 6 The number or group R 5 With R 6 The number of any combination of is not subject to any restrictions or automatically limited by the size of the building block. In some sub-embodiments, the linear or branched C 2-60 The main carbon chain of the alkylene group optionally contains one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) "-CH2-R 5 -CH2-" fragment and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH2-R 6 -CH2-" fragments and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH2-R 5 -R 6 -CH2-" fragment. Each R 5 Same or different, each R 6 the same or different, and as defined herein.

[0174] In this context, when the linear or branched C 2-60 One or more groups R are inserted into the main carbon chain of the alkylene group 5 and / or one or more groups R 6 or one or more groups R 5 With R 6formed backbone group complies with covalent bond theory and can contain one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 -CH2-” fragments and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 6 -CH2-” fragments and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 -R 6 -CH2-” fragments. Each R 5 is the same or different, each R 6 is the same or different, and is as defined herein.

[0175] In some embodiments, LIN can represent the following formula:

[0176] #-U-(C(R a1 )(R a2 )) n4 -(R 5 (C(R a3 )(R a4 )) n5 ) m6 -;

[0177] #-U-(C(R a1 )(R a2 )) n4 -(R 5 (C(R a3 )(R a4 )) n5 ) m6 -(R 5 (C(R a5 )(R a6 )) n6 ) m7 -;

[0178] #-U-(C(R a1 )(R a2 )) n4 -(R 5 (C(R a3 )(R a4 )) n5 ) m6 -(R 5 (C(R a5 )(Ra6 )) n6 ) m7 -(R 5 (C(R a7 )(R a8 )) n7 ) m8 -;

[0179] #-U-(C(R a1 )(R a2 )) n4 -(R 6 (C(R a3 )(R a4 )) n5 ) m6 -;

[0180] #-U-(C(R a1 )(R a2 )) n4 -(R 6 (C(R a3 )(R a4 )) n5 ) m6 -(R 6 (C(R a5 )(R a6 )) n6 ) m7 -;

[0181] #-U-(C(R a1 )(R a2 )) n4 -(R 6 (C(R a3 )(R a4 )) n5 ) m6 -(R 6 (C(R a5 )(R a6 )) n6 ) m7 -(R 6 (C(R a7 )(R a8 )) n7 ) m8 -;

[0182] #-U-(C(R a1 )(R a2 )) n4 -(R 5 -R 6 -(C(R a3 )(R a4 )) n5 ) m6-;

[0183] #-U-(C(R a1 )(R a2 )) n4 -(R 5 (C(R a3 )(R a4 )) n5 ) m6 -(R 6 (C(R a5 )(R a6 )) n6 ) m7 -;

[0184] #-U-(C(R a1 )(R a2 )) n4 -(R 6 -R 5 -(C(R a3 )(R a4 )) n5 ) m6 -; or

[0185] #-U-(C(R a1 )(R a2 )) n4 -(R 6 (C(R a3 )(R a4 )) n5 ) m6 -(R 5 (C(R a5 )(R a6 )) n6 ) m7 -;

[0186] wherein each group R 5 is independently selected from O, N(R 7 ), C(O), C(O)O, OC(O), C(O)N(R 7 ), N(R 7 )C(O), or N(R 7 )C(O)N(R 7 ), wherein each R 7 independently represents H or C 1-3 alkyl (e.g., methyl, ethyl, or propyl), and when more than two groups R 2-60 are inserted in the main carbon chain of said straight-chain or branched C 5 alkylene, each group R 5 is not directly attached to each other; each group R 6 is not directly attached to each other; each group Rindependently selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are independently of each other optionally substituted with one or more (e.g., 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of C1-C3alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-C3alkylamino (C 1-3 alkylNH- (e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC1-C3alkyl (e.g., F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, and CH2ClCH2-), amino-substituted C 1-3 alkylene(NH2-C 1-3 alkylene- (e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof;

[0187] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , and R a8 each independently represent H, C1-C3alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-C3alkylamino (C 1-3 alkylNH- (e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), amino-substituted C 1-3 alkylene(NH2-C 1-3alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), halo C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, CICH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2CICH2-) or cyano,

[0188] U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and

[0189] n4, n5, n6, n7, m6, m7, m8 are each independently selected from the group consisting of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0190] In some embodiments, LIN can represent the following formula:

[0191] #-U-(C(R a1 )(R a2 )) n4 -(O(C(R a3 )(R a4 )) n5 ) m6 -;

[0192] #-U-(C(R a1 )(R a2 )) n4 -(O(C(R a3 )(R a4 )) n5 ) m6 -(O(C(R a5 )(R a6 )) n6 ) m7 -;

[0193] #-U-(C(R a1 )(R a2 )) n4 -(O(C(R a3 )(R a4 )) n5 ) m6 -(O(C(R a5 )(R a6 )) n6 ) m7 -(O(C(R a7 )(R a8 )) n7 ) m8 -;

[0194] #-U-(C(R a1 )(R a2 )) n4 -(N(R 7 )(C(R a3 )(R a4 )) n5 ) m6 -;

[0195] #-U-(C(R a1 )(R a2 )) n4 -(N(R 7 )(C(R a3 )(R a4 )) n5 ) m6 -(N(R 7 )(C(R a5 )(R a6 )) n6 ) m7 -;

[0196] #-U-(C(R a1 )(R a2 )) n4 -(N(R 7 )(C(R a3 )(R a4 )) n5 ) m6 -(N(R 7 )(C(R a5 )(R a6 )) n6 ) m7 -(N(R 7 )(C(R a7 )(R a8 )) n7 ) m8 -;

[0197] #-U-(C(R a1 )(R a2 )) n4 -(C(O)N(R 7 )-(C(R a3 )(R a4 )) n5 ) m6 -;

[0198] #-U-(C(R a1 )(R a2 )) n4 -(C(O)N(R 7 )-(C(R a3 )(Ra4 )) n5 ) m6 -(C(O)N(R 7 )-(C(R a5 )(R a6 )) n6 ) m7 -;

[0199] #-U-(C(R a1 )(R a2 )) n4 -(C(O)N(R 7 )-(C(R a3 )(R a4 )) n5 ) m6 -(C(O)N(R 7 )-(C(R a5 )(R a6 )) n6 ) m7 -(C(O)N(R 7 )-(C(R a7 )(R a8 )) n7 ) m8 -;

[0200] #-U-(C(R a1 )(R a2 )) n4 -(C(O)N(R 7 )-(C(R a3 )(R a4 )) n5 ) m6 -(O-(C(R a5 )(R a6 )) n6 ) m7 -;

[0201] #-U-(C(R a1 )(R a2 )) n4 -C(O)N(R 7 )-(C(R a3 )(R a4 )) n5 -(O(C(R a5 )(R a6 )) n6 ) m6 -;

[0202] #-U-(C(R a1 )(R a2 )) n4 -(N(R7 )C(O)-(C(R a3 )(R a4 )) n5 ) m6 -;

[0203] #-U-(C(R a1 )(R a2 )) n4 -(N(R 7 )C(O)-(C(R a3 )(R a4 )) n5 ) m6 -(O-(C(R a5 )(R a6 )) n6 ) m7 -;

[0204] #-U-(C(R a1 )(R a2 )) n4 -(N(R 7 )C(O)-(C(R a3 )(R a4 )) n5 ) m6 -(O-(C(R a5 )(R a6 )) n6 ) m7 -(O-(C(R a7 )(R a8 )) n7 ) m8 -;

[0205] #-U-(C(R a1 )(R a2 )) n4 -N(R 7 )C(O)-(C(R a3 )(R a4 )) n5 -(O(C(R a5 )(R a6 )) n6 ) m6 -;

[0206] #-U-(C(R a1 )(R a2 )) n4 -N(R 7 )C(O)N(R 7 )-(C(R a3 )(R a4 )) n5 -;

[0207] #-U-(C(R a1 )(R a2 )) n4 -C(O)-(C(R a3 )(R a4 )) n5 -;

[0208] #-U-(C(R a1 )(R a2 )) n4 -CH=CH-(C(R a3 )(R a4 )) n5 -;

[0209] #-U-(C(R a1 )(R a2 )) n4 -C=C-(C(R a3 )(R a4 )) n5 -;

[0210] #-U-(C(R a1 )(R a2 )) n4 -C=C-C=C-(C(R a3 )(R a4 )) n5 -;

[0211] #-U-(C(R a1 )(R a2 )) n4 -(arylene-(C(R a3 )(R a4 )) n5 ) m6 -;

[0212] #-U-(C(R a1 )(R a2 )) n4 -(arylene-(C(R a3 )(R a4 )) n5 ) m6 -arylene-(C(R a5 )(R a6 )) n6 -;

[0213] #-U-(C(R a1 )(R a2 )) n4 -(heterocyclylene-(C(R a3 )(Ra4 )) n5 ) m6 -;

[0214] #-U-(C(R a1 )(R a2 )) n4 -(Heterocyclylene-(C(R a3 )(R a4 )) n5 ) m6 -(Heterocyclylene-(C(R a5 )(R a6 )) n6 ) m7 -;

[0215] #-U-(C(R a1 )(R a2 )) n4 -(heteroarylene-(C(R a3 )(R a4 )) n5 ) m6 -;

[0216] #-U-(C(R a1 )(R a2 )) n4 -(heteroarylene-(C(R a3 )(R a4 )) n5 ) m6 -(heteroarylene-(C(R a5 )(R a6 )) n6 ) m7 -;

[0217] #-U-(C(R a1 )(R a2 )) n4 -(cycloalkylene-(C(R a3 )(R a4 )) n5 ) m6 -;or

[0218] #-U-(C(R a1 )(R a2 )) n4 -(cycloalkylene-(C(R a3 )(R a4 )) n5 ) m6 -(cycloalkylene-(C(R a5 )(R a6 )) n6 ) m7 -;

[0219] wherein said cycloalkylene, said arylene, said heterocyclylene and said heteroarylene are each independently optionally substituted with one or more (e.g. 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of C1-C3alkyl (e.g. methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g. fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g. methoxy, ethoxy, or propoxy), C1-C3alkylamino (C 1-3 alkylNH- (e.g. CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC1-C3alkyl (e.g. F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, and CH2ClCH2-), amino-substituted C 1-3 alkylene(NH2-C 1-3 alkylene- (e.g. NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)- (e.g. CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g. CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof;

[0220] each R 7 independently represents H or C 1-3 alkyl (e.g. methyl, ethyl, or propyl);

[0221] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 each independently represents H, C1-C3alkyl (e.g. methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g. fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g. methoxy, ethoxy, or propoxy), C1-C3alkylamino (C 1-3 alkylNH- (e.g. CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC1-C3alkyl (e.g. F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, and CH2ClCH2-), amino-substituted C1-3 alkylene (NH2-C 1-3 alkylene (NH2-C

[0222] U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and

[0223] n4, n5, n6, n7, n8, m6, m7, m8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0224] In some embodiments, said cycloalkylene of LIN is optionally selected from the following groups:

[0225] cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydrocyclopenta-dienylene, octahydro-lH-indenylene, C 5-15 spirocyclylene, adamantlylene, noradamantylidene, menthylidene, bicyclo[2.2.1]heptylidene, or bicyclo[2.2.1]heptenylene,

[0226] wherein said cycloalkylene is optionally substituted by one or more (e.g. 1-4, 1-3, 1-2, or 1) groups selected from C1-C3alkyl (e.g. methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g. fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g. methoxy, ethoxy, or propoxy), C1-C3alkylamino (C 1-3 alkyl NH- (e.g. CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC1-C3alkyl (e.g. F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, and CH2ClCH2-), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene (NH2-C 1-3Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 The alkyl group is substituted with an alkyl-C(O)NH- (eg, CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), a cyano group, or any combination thereof.

[0227] In some embodiments, the arylene group of LIN is optionally selected from the following groups: phenyl or naphthyl, wherein the arylene group is optionally substituted by one or more (e.g., 1-4, 1-3, 1-2, or 1) selected from C1-C3 alkyl (e.g., methyl, ethyl, or propyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy), C1-C3 alkylamino (C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino-substituted C 1-3 Alkylene (NH2-C 1-3 Alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3 Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 The alkyl group is substituted with an alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), a cyano group, or any combination thereof.

[0228] In some embodiments, the heterocyclylene group of LIN is optionally selected from the following groups:

[0229] aziridinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxanylene or diazepanylene,

[0230] wherein the heterocyclyl group is optionally substituted by one or more (e.g. 1-4, 1-3, 1-2 or 1) selected from C1-C3 alkyl (e.g. methyl, ethyl or propyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy), C1-C3 alkylamino (C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino-substituted C 1-3 Alkylene (NH2-C 1-3 Alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3 Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 The alkyl group is substituted with an alkyl-C(O)NH- (eg, CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), a cyano group, or any combination thereof.

[0231] In some embodiments, the heteroarylene group of LIN is optionally selected from the following groups:

[0232] furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazylyene, benzo[1,2,3]thiadiazylyene, quinolinylene, isoquinolinylene, naphthidinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridinylene, 1H-pyrrolo[3,2-b]pyridinylene, 1H-pyrrolo[2,3-b]pyridinylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, or imidazo[2,1-b]thiazolylene,

[0233] wherein said heteroarylene is optionally substituted with one or more (e.g., 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of C1-C3alkyl (e.g., methyl, ethyl, or propyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-C3alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-C3alkylamino (e.g., methylamino, ethylamino, or propylamino), C 1-3 alkylNH- (e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC1-C3alkyl (e.g., F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, and CH2ClCH2-), amino-substituted C 1-3 alkylene(NH2-C 1-3 alkylene- (e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2- NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2- C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof.

[0234] In some embodiments, LIN represents a structure of the following formula:

[0235] #-U-CH2-O-CH2-, #-U-CH2-O-(CH2)2-, #-U-(CH2)1-O-(CH2)3-, #-U-(CH2)1-O-(CH2)4-, #-U-(CH2)1-O-(CH2)5-, #-U-(CH2)1-O-(CH2)6-, #-U-(CH2)1-O-(CH2)7-, #-U-(CH2)1-O-(CH2)8-, #-U-(CH2)1-O-(CH2) 10 -, #-U-(CH2)2-O-(CH2)1-, #-U-(CH2)2-O-(CH2)2-, #-U-(CH2)2-O-(CH2)3-, #-U-(CH2)2-O-(CH2)4-, #-U-(CH2)2-O-(CH2)5-, #-U-(CH2)2-O-(CH2)6-, #-U-(CH2)2-O-(CH2)7-, #-U-(CH2)2-O-(CH2)8-, #-U-(CH2)2-O-(CH2) 10 -, #-U-(CH2)2-O-(CH2) 11 -, #-U-(CH2)2-O-(CH2) 12-, -U-(CH2)3-O-(CH2)1-, -U-(CH2)3-O-(CH2)2-, -U-(CH2)3-O-(CH2)3-, -U-(CH2)3-O- (CH2)4-, -U-(CH2)3-O-(CH2)5-, -U-(CH2)3-O-(CH2)6-, -U-(CH2)3-O-(CH2)7-, -U- (CH2)4-O-(CH2)1-, -U-(CH2)4-O-(CH2)2-, -U-(CH2)4-O-(CH2)3-, -U-(CH2)4-O-(CH2)4-, -U- (CH2)4-O-(CH2)5-, -U-(CH2)4-O-(CH2)6-, -U-(CH2)5-O-(CH2)1-, -U-(CH2)5-O-(CH2)2-, -U- (CH2)5-O-(CH2)3-, -U-(CH2)5-O-(CH2)4-, -U-(CH2)5-O-(CH2)5-, -U-(CH2)6-O-(CH2)1-, -U- (CH2)6-O-(CH2)2-, -U-(CH2)6-O-(CH2)3-, -U-(CH2)6-O-(CH2)4-, -U-(CH2)7-O-(CH2)1-, -U- (CH2)7-O-(CH2)2-, -U-(CH2)7-O-(CH2)3-, -U-(CH2)8-O-(CH2)1-, -U-(CH2)8-O-(CH2)2-, -U- CH(CH3)-O-(CH2)1-, -U-CH(CH3)-O-(CH2)2-, -U-CH(CH3)-O-(CH2)3-, -U-CH(CH3)-O- (CH2)4-, -U-CH(CH3)-O-(CH2)5-, -U-CH(CH3)-O-(CH2)6-, -U-CH(CH3)-O-(CH2)7-, -U- CH(CH3)-O-(CH2)8-, -U-CH(CH3)-O-(CH2)9-, -U-CH(CH3)-O-(CH2) 10 -CH2-(O(CH2)2)2-, -U-CH2-(O(CH2)2)3-, -U-CH2-(O(CH2)2)4-, -U-CH2-(O(CH2)2)5-, -U- CH2-(O(CH2)2)6-, -U-CH2-(O(CH2)2)7-, -U-CH2-(O(CH2)2)8-, -U-CH2-(O(CH2)2)9-, -U- CH2-(O(CH2)2) 10#-U-CH2-(0(CH2)2)1-0CH2-, #-U-CH2-(0(CH2)2)2-0CH2-, #-U-CH2-(0(CH2)2)3-0CH2-, #-U-CH2-(0(CH2)2)4-0CH2-, #-U-CH2-(0(CH2)2)5-0CH2-, #-U-CH2-(0(CH2)2)6-0CH2-, #-U-CH2-(0(CH2)2)7-0CH2-, #-U-CH2-(0(CH2)2)8-0CH2-, #-U-CH2-(0(CH2)2)9-0CH2-, #-U-CH2-(0(CH2)2) 10 #-U-(CH2)2-(0(CH2)2)2-, #-U-(CH2)2-(0(CH2)2)3-, #-U-(CH2)2-(0(CH2)2)4-, #-U-(CH2)2-(0(CH2)2)5-, #-U-(CH2)2-(0(CH2)2)6-, #-U-(CH2)2-(0(CH2)2)7-, #-U-(CH2)2-(0(CH2)2)8-, #-U-(CH2)2-(0(CH2)2)9-, #-U-(CH2)2-(0(CH2)2) 10 #-U-(CH2)3-(0(CH2)2)2-, #-U-(CH2)3-(0(CH2)2)3-, #-U-(CH2)3-(0(CH2)2)4-, #-U-(CH2)3-(0(CH2)2)5-, #-U-(CH2)3-(0(CH2)2)6-, #-U-(CH2)3-(0(CH2)2)7-, #-U-(CH2)3-(0(CH2)2)8-, #-U-(CH2)3-(0(CH2)2)9-, #-U-(CH2)3-(0(CH2)2) 10 #-U-(CH2)4-(0(CH2)2)2-, #-U-(CH2)4-(0(CH2)2)3-, #-U-(CH2)4-(0(CH2)2)4-, #-U-(CH2)4-(0(CH2)2)5-, #-U-(CH2)4-(0(CH2)2)6-, #-U-(CH2)4-(0(CH2)2)7-, #-U-(CH2)4-(0(CH2)2)8-, #-U-(CH2)4-(0(CH2)2)9-, #-U-(CH2)4-(0(CH2)2) 10-#-U-CH2-(0(CH2)3)2-, -#-U-CH2-(0(CH2)3)3-, -#-U-CH2-(0(CH2)3)4-, -#-U-CH2- (0(CH2)3)5-, -#-U-CH2-(0(CH2)3)6-, -#-U-CH2-(0(CH2)3)7-, -#-U-CH2-(0(CH2)3)8-, -#-U- CH2-(0(CH2)3)9-, -#-U-CH2-(0(CH2)3)10- 10 -#-U-(CH2)2-(0(CH2)3)2-, -#-U-(CH2)2-(0(CH2)3)3-, -#-U-(CH2)2-(0(CH2)3)4-, -#-U- (CH2)2-(0(CH2)3)5-, -#-U-(CH2)2-(0(CH2)3)6-, -#-U-(CH2)2-(0(CH2)3)7-, -#-U-(CH2)2- (0(CH2)3)8-, -#-U-(CH2)2-(0(CH2)3)9-, -#-U-(CH2)2-(0(CH2)3) 10 -#-U-(CH2)3-(0(CH2)3)2-, -#-U-(CH2)3-(0(CH2)3)3-, -#-U-(CH2)3-(0(CH2)3)4-, -#-U- (CH2)3-(0(CH2)3)5-, -#-U-(CH2)3-(0(CH2)3)6-, -#-U-(CH2)3-(0(CH2)3)7-, -#-U-(CH2)3- (0(CH2)3)8-, -#-U-(CH2)3-(0(CH2)3)9-, -#-U-(CH2)3-(0(CH2)3) 10-CH2-O-(CH2)2-O-(CH2)3-, #-U-CH2-(O(CH2)2)2-(O(CH2)3)2-, #-U-CH2-(O(CH2)2)3-(O(CH2)3)3-, #-U-CH2-(O(CH2)2)4-(O(CH2)3)4-, #-U-CH2-(O(CH2)2)5-(O(CH2)3)5-, #-U-CH2-(O(CH2)2)6-(O(CH2)3)6-, #-U-(CH2)2-O-(CH2)2-O-(CH2)3-, #-U-(CH2)2-(O(CH2)2)2-(O(CH2)3)2-, #-U-(CH2)2-(O(CH2)2)3-(O(CH2)3)3-, #-U-(CH2)2-(O(CH2)2)4-(O(CH2)3)4-, #-U-(CH2)2-(O(CH2)2)5-(O(CH2)3)5-, #-U-(CH2)2-(O(CH2)2)6-(O(CH2)3)6-, #-U-(CH2)3-O-(CH2)2-O-(CH2)3-, #-U-(CH2)3-(O(CH2)2)2-(O(CH2)3)2-, #-U-(CH2)3-(O(CH2)2)3-(O(CH2)3)3-, #-U-(CH2)3-(O(CH2)2)4-(O(CH2)3)4-, #-U-(CH2)3-(O(CH2)2)5-(O(CH2)3)5-, #-U-(CH2)3-(O(CH2)2)6-(O(CH2)3)6-, #-U-CH2-O-(CH2)3-O-(CH2)2-, #-U-CH2-(O(CH2)3)2-(O(CH2)2)2-, #-U-CH2-(O(CH2)3)3-(O(CH2)2)3-, #-U-CH2-(O(CH2)3)4-(O(CH2)2)4-, #-U-CH2-(O(CH2)3)5-(O(CH2)2)5-, # -U-CH2-(O(CH2)3)6-(O(CH2)2)6-, # -U-(CH2)2-O-(CH2)3-O-(CH2)2-, # -U-(CH2)2-(O(CH2)3)2-(O(CH2)2)2-, # -U-(CH2)2-(O(CH2)3)3-(O(CH2)2)3-, # -U-(CH2)2-(O(CH2)3)4-(O(CH2)2)4-, # -U-(CH2)2-(O(CH2)3)5-(O(CH2)2)5-, # -U-(CH2)2-(O(CH2)3)6-(O(CH2)2)6-, # -U-(CH2)3-O-(CH2)3-O-(CH2)2-, # -U-(CH2)3-(O(CH2)3)2-(O(CH2)2)2-, # -U-(CH2)3-(O(CH2)3)3-(O(CH2)2)3-, # -U-(CH2)3-(O(CH2)3)4-(O(CH2)2)4-, # -U-(CH2)3-(O(CH2)3)5-(O(CH2)2)5-, # -U-(CH2)3-(O(CH2)3)6-(O(CH2)2)6-, # -U-CH2-O-(CH2)2-O-(CH2)2-, # -U-CH2-(O(CH2)2)2-(O(CH2)2)2-, # -U-CH2-(O(CH2)2)3-(O(CH2)2)3-, # -U-CH2-(O(CH2)2)4-(O(CH2)2)4-, # -U-CH2-(O(CH2)2)5-(O(CH2)2)5-, # -U-CH2-(O(CH2)2)6-(O(CH2)2)6-, # -U-(CH2)2-O-(CH2)2-O-(CH2)2-, # -U-(CH2)2-(O(CH2)2)2-(O(CH2)2)2-, # -U-(CH2)2-(O(CH2)2)3-(O(CH2)2)3-, # -U-(CH2)2-(O(CH2)2)4-(O(CH2)2)4-, # -U-(CH2)2-(O(CH2)2)5-(O(CH2)2)5-, # -U-(CH2)2-(O(CH2)2)6-(O(CH2)2)6-, # -U-(CH2)3-O-(CH2)2-O-(CH2)2-, # -U-(CH2)3-(O(CH2)2)2-(O(CH2)2)2-, # -U-(CH2)3-(O(CH2)2)3-(O(CH2)2)3-, # -U-(CH2)3-(O(CH2)2)4-(O(CH2)2)4-, # -U-(CH2)3-(O(CH2)2)5-(O(CH2)2)5-, # -U-(CH2)3-(O(CH2)2)6-(O(CH2)2)6-, # -U-CH2-O-(CH2)3-O-(CH2)2-, # -U-CH2-(O(CH2)3)2-(O(CH2)2)2-, # -U-CH2-(O(CH2)3)3-(O(CH2)2)3-, # -U-CH2-(O(CH2)3)4-(O(CH2)2)4-, # -U-CH2-(O(CH2)3)5-(O(CH2)2)5-, # -U-CH2-(O(CH2)3)6-(O(CH2)2)6-, # -U-(CH2)2-O-(CH2)3-O-(CH2)2-, # -U-(CH2)2-(O(CH2)3)2-(O(CH2)2)2-, # -U-(CH2)2-(O(CH2)3)3-(O(CH2)2)3-, # -U-(CH2)2-(O(CH2)3)4-(O(CH2)2)4-, # -U-(CH2)2-(O(CH2)3)5-(O(CH2)2)5-, # -U-(CH2)2-(O(CH2)3)6-(O(CH2)2)6-, # -U-(CH2)3-O-(CH2)3-O-(CH2)2-, # -U-(CH2)3-(O(CH2)3)2-(O(CH2)2)2-, # -U-(CH2)3-(O(CH2)3)3-(O(CH2)2)3-, # -U-(CH2)3-(O(CH2)3)4-(O(CH2)2)4-, # -U-(CH2)3-(O(CH2)3)5-(O(CH2)2)5-, # -U-(CH2)3-(O(CH2)3)6-(O(CH2)2)6-, # -U-CH2-O-(CH2)2-O-(CH2)2-, # -U-CH2-(O(CH2)2)2-(O(CH2)2)2-, # -U-CH2-(O(CH2)2)3-(O(CH2)2)3-, # -U-CH2-(O(CH2)2)4-(O(CH2)2)4-, # -U-CH2-(O(CH2)2)5-(O(CH2)2)5-, # -U-CH2-(O(CH2)2)6-(O(CH2)2)6-, # -U-(CH2)2-O-(CH2)2-O-(CH2)2-, # -U-(CH2)2-(O(CH2)2)2-(O(CH2)2)2-, # -U-(CH2)2-(O(CH2)2)3-(O(CH2)2)3-, # -U-(CH2)2-(O(CH2)2)4-(O(CH2)2)4-, # -U-(CH2)2-(O(CH2)2)5-(O(CH2)2)5-, # -U-(CH2)2-(O(CH2)2)6-(O(CH2)2)6-, # -U-(CH2)3-O-(CH2)2-O-(CH2)2-, # -U-(CH2)3-(O(CH2)2)2-(O(CH2)2)2-, # -U-(CH2)3-(O(CH2)2)3-(O(CH2)2)3-, # -U-(CH2)3-(O(CH2)2)4-(O(CH2)2-(0(CH2)3)6-(0(CH2)2)6-, -U-(CH2)3-0-(CH2)3-0-(CH2)2-, -U-(CH2)3-(0(CH2)3)2- (0(CH2)2)2-, -U-(CH2)3-(0(CH2)3)3-(0(CH2)2)3-, -U-(CH2)3-(0(CH2)3)4-(0(CH2)2)4-, -U- (CH2)3-(0(CH2)3)5-(0(CH2)2)5-, -U-(CH2)3-(0(CH2)3)6-(0(CH2)2)6-, -U-CH2-0-(CH2)2-0-CH2-, -U- (CH2)2-0-(CH2)2-0-CH2-, -U-(CH2)2-(0(CH2)2)2-0-(CH2)3-, -U-(CH2)2-(0(CH2)2)3-0-(CH2)3-, -U- (CH2)2-(0(CH2)2)4-0-(CH2)3-, -U-(CH2)5-(0(CH2)2)2-0-(CH2)5-, -U-(CH2)5-(0(CH2)2)2-0- (CH2)6-, -U-(CH2)1-N(R 7 )-(CH2)1-, -U-(CH2)1-N(R 7 )-(CH2)2-, -U-(CH2)1-N(R 7 )-(CH2)3-, -U-(CH2)1-N(R 7 )-(CH2)4-, -U-(CH2)1-N(R 7 )-(CH2)5-, -U-(CH2)1-N(R 7 )-(CH2)6-, -U-(CH2)1-N(R 7 )-(CH2)7-, -U-(CH2)1-N(R 7 )-(CH2)8-, -U-(CH2)1-N(R 7 )-(CH2)9-, -U-(CH2)1-N(R 7 )-(CH2) 10 -, -U-(CH2)2-N(R 7 )-(CH2)1-, -U-(CH2)2-N(R 7 )-(CH2)2-, -U-(CH2)2-N(R 7 )-(CH2)3-, -U-(CH2)2-N(R 7 )-(CH2)4-, -U-(CH2)2-N(R7 -(CH2)5-, -U-(CH2)2-N(R 7 -(CH2)6-, -U-(CH2)2-N(R 7 -(CH2)7-, -U-(CH2)2-N(R 7 -(CH2)8-, -U-(CH2)2-N(R 7 -(CH2)9-, -U-(CH2)2-N(R 7 -(CH2) 10 -, -U-(CH2)2-N(R 7 -(CH2) 11 -, -U-(CH2)2-N(R 7 -(CH2) 12 -, -U-(CH2)3-N(R 7 )-(CH2)1-, -U-(CH2)3-N(R 7 )-(CH2)2-, -U-(CH2)3-N(R 7 )-(CH2)3-, -U-(CH2)4-N(R 7 )-(CH2)1-, -U-(CH2)4-N(R 7 )-(CH2)2-, -U-(CH2)4-N(R 7 )-(CH2)3-, -U-(CH2)4-N(R 7 )-(CH2)4-, -U-(CH2)5-N(R 7 )-(CH2)1-, -U-(CH2)5-N(R 7 )-(CH2)2-, -U-(CH2)5-N(R 7 )-(CH2)3-, -U-(CH2)5-N(R 7 )-(CH2)4-, -U-(CH2)5-N(R 7 )-(CH2)5-, -U-(CH2)6-N(R 7 )-(CH2)1-, -U-(CH2)6-N(R 7 )-(CH2)2-, -U-(CH2)6-N(R 7 )-(CH2)3-, -U-(CH2)7-N(R 7 )-(CH2)1-, -U-(CH2)7-N(R 7 )-(CH2)2-, -U-(CH2)7-N(R 7-(CH2)3-, # -U- CH(CH3)-N(R 7 -(CH2)1-, # -U- CH(CH3)-N(R 7 -(CH2)2-, # -U- CH(CH3)-N(R 7 -(CH2)3-, # -U- CH(CH3)-N(R 7 -(CH2)1-, # -U- CH(CH3)-N(R 7 -(CH2)2-, # -U- CH(CH3)-N(R 7 -(CH2)3-, # -U- CH(CH3)-N(R 7 -(CH2)4-, # -U- CH(CH3)-N(R 7 -(CH2)5-, # -U- CH(CH3)-N(R 7 -(CH2)6-, # -U- CH(CH3)-N(R 7 -(CH2)7-, # -U- CH(CH3)-N(R 7 -(CH2)8-, # -U- CH(CH3)-N(R 7 -(CH2)9-, # -U- CH(CH3)-N(R 7 -(CH2) 10 -, # -U- CH2C(O)NHCH2-, # -U- (CH2)2C(O)NH(CH2)2-, # -U- (CH2)2C(O)NH(CH2)3-, # -U- (CH2)2C(O)NH(CH2)4-, # -U- (CH2)2C(O)NH(CH2)5-, # -U- (CH2)3C(O)NH(CH2)3-, # -U- (CH2)3C(O)NH(CH2)4-, # -U- (CH2)4C(O)NH(CH2)4-, # -U- (CH2)5C(O)NH(CH2)5-, # -U- (CH2)6C(O)NH(CH2)7-, # -U- (CH2)6C(O)NH(CH2)6-, # -U- (CH2)7C(O)NH(CH2)7-, # -U- (CH2)8C(O)NH(CH2)8, U- (CH2)9C(O)NH(CH2)9-, # -U- (CH2) 10 C(O)NH(CH2) 10- U-(CH2)2C(O)NH(CH2)2-O-(CH2)2-, - U-CH2NHC(O)CH2-, - U-(CH2)2NHC(O)(CH2)2-, - U-(CH2)2NHC(O)(CH2)3-, - U-(CH2)2NHC(O)(CH2)4-, - U-(CH2)2NHC(O)(CH2)5-, - U-(CH2)3NHC(O)(CH2)3-, - U-(CH2)3NHC(O)(CH2)4-, - U-(CH2)4NHC(O)(CH2)4-, - U-(CH2)5NHC(O)(CH2)5-, - U-(CH2)6NHC(O)(CH2)7-, - U-(CH2)6NHC(O)(CH2)6-, - U-(CH2)7NHC(O)(CH2)7-, - U-(CH2)8NHC(O)(CH2)8, - U-(CH2)9NHC(O)(CH2)9-, - U-(CH2) 10 NHC(O)(CH2) 10-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(O)-, -C(O)-CH2-, -C(O)-CH2-CH2-, -CH2-C(O)-CH2-, -CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-, -C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-CH2-, -CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-CH2-C(O)-(CH2)3-, -U-(CH2)5-phenylene-(CH2)4-, -U-(CH2)5-phenylene-(CH2)5-, -U- (CH2)5-phenylene-(CH2)6-, -U-(CH2)5-phenylene-(CH2)7-, -U-(CH2)5-phenylene- (CH2)8-, -U-(CH2)6-phenylene-(CH2)i-, -U-(CH2)6-phenylene-(CH2)2-, -U- (CH2)6-phenylene-(CH2)3-, -U-(CH2)6-phenylene-(CH2)4-, -U-(CH2)6-phenylene- (CH2)5-, -U-(CH2)6-phenylene-(CH2)6-, -U-(CH2)6-phenylene-(CH2)7-, -U- (CH2)6-phenylene-(CH2)8-, -U-(CH2)7-phenylene-(CH2)i-, -U-(CH2)7-phenylene- (CH2)2-, -U-(CH2)7-phenylene-(CH2)3-, -U-(CH2)7-phenylene-(CH2)4-, -U- (CH2)7-phenylene-(CH2)8-, -U-(CH2)8-phenylene-CH2-, -U-(CH2)8-phenylene- (CH2)2-, -U-(CH2)8-phenylene-(CH2)3-, -U-(CH2)8-phenylene-(CH2)4-, -U- (CH2)8-phenylene-(CH2)5-, -U-(CH2)8-phenylene-(CH2)6-, -U-(CH2)8-phenylene- (CH2)7-, -U-(CH2)8-phenylene-(CH2)8-, -U-CH2-N(R 7 )-CH2-phenylene-CH2-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)2-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)3-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)4-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)5-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)6-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)7-, -U-CH2-N(R 7 )-CH2-phenylene-(CH2)8-, -U-CH2-N(R 7 )-(CH2)2-phenylene-CH2-, -U-CH2-N(R7 )-(CH2)2-phenylene-(CH2)2-, #- U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)3-, #-U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)4-, #-U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)5-, #-U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)6-, #-U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)7-、#-U-CH2-N(R 7 )-(CH2)2-phenylene-(CH2)8-, #-U-(CH2)2-N(R 7 )-CH2-phenylene-CH2-, #-U- (CH2)2-N(R 7 )-CH2-phenylene-(CH2)2-, #-U-(CH2)2-N(R 7 )-CH2-phenylene-(CH2)3-, #-U-(CH2)2-N(R 7 )- CH2-phenylene-(CH2)4-, #-U-(CH2)2-N(R 7 )-CH2-phenylene-(CH2)5-, #-U-(CH2)2-N(R 7 )-CH2-phenylene-(CH2)6-、#-U-(CH2)2-N(R 7 )-CH2-phenylene-(CH2)7-, #-U-(CH2)2-N(R 7 )-CH2-phenylene-(CH2)8-, #-U- (CH2)3-N(R 7 )-CH2-phenylene-CH2-, #-U-(CH2)3-N(R 7 )-CH2-phenylene-(CH2)2-, #-U-(CH2)3-N(R 7 )- CH2-phenylene-(CH2)3-, #-U-(CH2)3-N(R 7 )-CH2-phenylene-(CH2)8-, #-U-(CH2)4-N(R 7 )-CH2-phenylene- CH2-, #-U-(CH2)4-N(R 7 )-CH2-phenylene-(CH2)2-, #-U-(CH2)4-N(R 7 )-CH2-phenylene-(CH2)3-, #-U- (CH2)4-N(R7 )-CH2-phenylene-(CH2)8-, -U-(CH2)5-N(R 7 )-CH2-phenylene-(CH2)3-, -U-(CH2)5-N(R 7 )-CH2-phenylene-(CH2)8-, -U-(CH2)6-N(R 7 )-CH2-phenylene-(CH2)3-, -U-(CH2)6-N(R 7 )-CH2-phenylene-(CH2)8-, -U-(CH2)7-N(R 7 )-CH2-phenylene-(CH2)3-, -U-(CH2)7-N(R 7 )-CH2-phenylene-(CH2)8-, -U-(CH2)8-N(R 7 )-CH2-phenylene-CH2-, -U-(CH2)8-N(R 7 )-CH2-phenylene-(CH2)2-, -U-(CH2)8-N(R 7 )- CH2-phenylene-(CH2)3-, -U-(CH2)8-N(R 7 )-CH2-phenylene-(CH2)4-, -U-(CH2)8-N(R 7 )-CH2-phenylene-(CH2)5-, -U-(CH2)8-N(R 7 )-CH2-phenylene-(CH2)6-, -U-(CH2)8-N(R 7 )-CH2-phenylene-(CH2)7-, -U-(CH2)8-N(R 7)-CH2-phenylene-(CH2)8-, #-U-CH2-piperazinylene-CH2-, #-U-CH2-piperazinylene-(CH2)2-, #-U-CH2-piperazinylene-(CH2)3-, #-U-CH2-piperazinylene-(CH2)4-, #-U-CH2-piperazinylene-(CH2)5-, #-U-CH2-piperazinylene-(CH2)6-, #-U-CH2-piperazinylene-(CH2)7-, #-U-CH2-piperazinylene-(CH2)8-, #-U-(CH2)2-piperazinylene-(CH2)1-, #-U-(CH2)2-piperazinylene-(CH2)2-, #-U-(CH2)2-piperazinylene-(CH2)3-, #-U-(CH2)2-piperazinylene-(CH2)4-, #-U-(CH2)2-piperazinylene-(CH2)5-, #-U-(CH2)2-piperazinylene-(CH2)6-, #-U-(CH2)2-piperazinylene-(CH2)7-, #-U-(CH2)2-piperazinylene-(CH2)8-, #-U-(CH2)3-piperazinylene-CH2-, #-U-(CH2)3-piperazinylene-(CH2)2-, #-U-(CH2)3-piperazinylene-(CH2)3-, #-U-(CH2)3-piperazinylene-(CH2)4-, #-U-(CH2)3-piperazinylene-(CH2)5-, #-U-(CH2)3-piperazinylene-(CH2)6-, #-U-(CH2)3-piperazinylene-(CH2)7-, #-U-(CH2)3-piperazinylene-(CH2)8-, #-U-(CH2)4-piperazinylene-CH2-, #-U-(CH2)4-piperazinylene-(CH2)2-, #-U-(CH2)4-piperazinylene-(CH2)3-, #-U-(CH2)4-piperazinylene-(CH2)4-, #-U-(CH2)4-piperazinylene-(CH2)5-, #-U-(CH2)4-piperazinylene-(CH2)6-, #-U-(CH2)4-piperazinylene-(CH2)7-, #-U-(CH2)4-piperazinylene-(CH2)8-, #-U-(CH2)5-piperazinylene-CH2-, #-U-(CH2)5-piperazinylene-(CH2)2-, #-U-(CH2)5-piperazinylene-(CH2)3-, #-U-(CH2)5-piperazinylene-(CH2)4-, #-U-(CH2)5-piperazinylene-(CH2)5-, #-U-(CH2)5-piperazinylene-(CH2)6-, #-U-(CH2)5-piperazinylene-(CH2)7-, #-U-(CH2)5-piperazinylene-(CH2)8-, #-U-(CH2)6-piperazinylene-CH2-, #-U-(CH2)6-piperazinylene-(CH2)2-, #-U-(CH2)6-piperazinylene-(CH2)3-, #-U-(CH2)6-piperazinylene-(CH2)4-, #-U-(CH2)6-piperazinylene-(CH2)5-, #-U-(CH2)6-piperazinylene-(CH2)6-, #-U-(CH2)6-piperazinylene-(CH2)7-, #-U-(CH2)6-piperazinylene-(CH2)8-,(CH2)2-, #-U-(CH2)6-piperazinylene-(CH2)3-, #-U-(CH2)6-piperazinylene-(CH2)4-, #-U-(CH2)6-piperazinylene-(CH2)5-, #-U-(CH2)6-piperazinylene-(CH2)6-, #-U-(CH2)6-piperazinylene-(CH2)7-, #-U-(CH2)6-piperazinylene-(CH2)8-, #-U-(CH2)7-piperazinylene-(CH2)1-, #-U-(CH2)7-piperazinylene-(CH2)2-, #-U-(CH2)7-piperazinylene-(CH2) (CH2)3-, #-U-(CH2)7-piperazinylene-(CH2)4-, #-U-(CH2)7-piperazinylene-(CH2)8-, #-U-(CH2)8-piperazinylene-CH2-, #-U-(CH2)8-piperazinylene-(CH2)2-, #-U-(CH2)8-piperazinylene-(CH2)3-, #-U-(CH2)8-piperazinylene-(CH2)4-, #-U-(CH2)8-piperazinylene-(CH2)5-, #-U-(CH2)8-piperazinylene-(CH2)6-, #-U-(CH2)8-piperazinylene-(CH2)7-, or #-U-(CH2)8-piperazinylene-(CH2)8-;

[0236] wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y;

[0237] Each R 7 independently represents H or C 1-3 Alkyl (eg, methyl, ethyl, or propyl); and

[0238] The phenylene group and the piperazinyl group are independently optionally substituted by one or more (e.g. 1-4, 1-3, 1-2 or 1) selected from C1-C3 alkyl (e.g. methyl, ethyl or propyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy), C1-C3 alkylamino (C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C1-C3 alkyl (such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- and CH2ClCH2-), amino-substituted C 1-3 Alkylene (NH2- C 1-3alkylene-, e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3- C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof.

[0239] In some embodiments, the compound of Formula (I) of the present disclosure is also a compound of Formula (II), or a salt (including a pharmaceutically acceptable salt), solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof:

[0240]

[0241] wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linking moiety, the remainder of the molecule of Formula (I) is a nicotinamide phosphoribosyltransferase (NAMPT) ligand, and ULM is covalently linked to the NAMPT ligand via LIN;

[0242] wherein ring B is a 5- to 11-membered heterocyclyl ring containing 1 nitrogen atom and optionally further containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, (R b ) m2 represents that ring B is optionally substituted with m2 R b groups, each R b is independently C 1-3 alkyl, hydroxy, amino, mercapto, halogen, C 1-3 alkoxy, C 1-3 alkylamino, haloC 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, or cyano, and m2 represents an integer of 0, 1, 2, 3, 4, or 5;

[0243] Ring A is the following group:

[0244]

[0245] (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R aindependently hydroxyl, amino, halogen or cyano, and m1 represents an integer 0, 1, 2, 3, 4 or 5;

[0246] R 1 and R 2 are the same or different and independently of each other H, cyano or methyl;

[0247] L1represents a substituted or unsubstituted straight-chain C 3-6 alkylene, or a substituted or unsubstituted straight-chain C 3-6 alkenylene, the optional substituents of the straight-chain C 3-6 alkylene and straight-chain C 3-6 alkenylene are selected from the group consisting of C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof;

[0248] Ring C is a 5- to 10-membered heteroarylene, or a 6-membered arylene, (R c ) m3 represents that ring C is optionally substituted by m3 R c groups, each R c is independently C 1-3 alkyl, C 3-5 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m3 represents an integer 0, 1, 2, 3, 4 or 5;

[0249] m represents an integer 0 or 1 ; and

[0250] Y represents -N(R 3 )-, wherein R 3 is hydrogen or C 1-3 alkyl; or

[0251] Y represents -O-; or

[0252] Y is n connected rings D represented by the following structural formula:

[0253]

[0254] each ring D is independently a 5- to 11-membered heterocyclene, (R d ) m4each ring D is optionally independently substituted with m4R d each R d independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, haloC 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano, and m4 represents an integer 0, 1, 2, 3, 4 or 5;

[0255] n is an integer 0, 1, 2 or 3, wherein when n represents an integer 2 or 3, each ring D can be the same or different, and

[0256] wherein m and n are not simultaneously 0;

[0257] provided that the following compounds are excluded:

[0258] The nicotinamide phosphoribosyltransferase (NAMPT) ligand represents the following structure:

[0259]

[0260] and ULM represents the structure of formula (IV):

[0261]

[0262] wherein Z1 represents C(O) or Z1 represents a bond, and Z2 represents H or CH3.

[0263] In some embodiments, L1 of the compound of formula (II) represents a substituted or unsubstituted straight chain C 3-6 alkylene. Exemplary examples of straight chain C 3-6 alkylene include, but are not limited to, propylene, butylene, pentylene, and hexylene. The straight chain C 3-6 alkylene is optionally further substituted with one or more groups selected from C 1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), haloC 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), C 1-3alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2- NHC(O)-, and CH3CH2CH2- NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2- C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. The number of substituents is in principle not limited by any or automatically by the size of the building block.

[0264] In some embodiments, L1of the compound of formula (II) represents a substituted or unsubstituted straight chain C 3-6 alkylene. Exemplary examples of straight chain C 3-6 alkylene. Exemplary examples of straight chain C the straight chain C 3-6 alkylene is optionally further substituted by one or more substituents selected from the group consisting of C 1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halogenated C 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), C 1-3 alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2- NHC(O)-, and CH3CH2CH2- NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2- C(O)NH-, and CH3CH2CH2-C(O)NH-), cyano, or any combination thereof. The number of substituents is in principle not limited by any or automatically by the size of the building block.

[0265] In some embodiments, ring B of the compound of formula (II) is a 5- to 11-membered heterocyclyl ene containing 1 to 3 nitrogen atoms.

[0266] In some embodiments, ring B of the compound of formula (II) is a piperidene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, sulfomorpholinylene, diazepinylene, or C 7-11 spiroheterocyclylene.

[0267] In some embodiments, when ring B of the compound of formula (II) represents a C 7-11 spiro heterocyclyl group, the C 7-11 spiro heterocyclyl group is the following group:

[0268]

[0269] wherein the symbol * represents the point of attachment to the group L1, X represents O, N(R e ), S or CH2or X represents a bond, R e represents hydrogen or methyl, and n1, n2and n3are each independently an integer of 1 or 2.

[0270] In some embodiments, when ring B of the compound of formula (II) represents a C 7-11 spiro heterocyclyl group, the C 7-11 spiro heterocyclyl group is the following group:

[0271]

[0272] wherein the symbol * represents the point of attachment to the group L1.

[0273] In some embodiments, ring B of the compound of formula (II) is optionally further substituted by m2R b groups, wherein m2represents an integer of 0, 1, 2, 3, 4 or 5, and each R b is independently C 1-3 alkyl (e.g., methyl, ethyl or propyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), C 1-3 alkoxy (e.g., methoxy, ethoxy or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkyl NH-, e.g., CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, - CHFCHF2, -CH2CF3and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene-, e.g., NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3alkyl-NHC(O)-(e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH-(e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano.

[0274] In some embodiments, the ring C of the compound of Formula (II) is a 5- to 10- membered heteroaryl group. Exemplary examples include, but are not limited to, the following groups:

[0275]

[0276] wherein the symbol * indicates the point of attachment to the group L1.

[0277] In some embodiments, the ring C of the compound of Formula (II) is a 5- to 10- membered heteroaryl group. Exemplary examples of the ring C include, but are not limited to, the following groups: phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, 1,2,4-triazinylene, 1,3,5-triazinylene, triazolylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazylyene, benzo[1,2,3]thiadiazylyene, quinolylene, isoquinolylene, naphthidylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, or imidazo[2,1-b]thiazolylene.

[0278] In some embodiments, the ring C of the compound of Formula (II) is optionally further substituted with m3R c groups, wherein m3 represents an integer of 0, 1, 2, 3, 4, or 5, and each R c is independently C 1-3 alkyl (e.g., methyl, ethyl, or propyl), C 3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-3Alkoxy (such as methoxy, ethoxy or propoxy), C 1-3 Alkylamino (e.g. C 1-3 Alkyl NH-, such as CH3NH-, CH3CH2NH- or CH3CH2CH2NH-), halogenated C 1-3 Alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 Alkylene (NH2-C 1-3 Alkylene-, such as NH2CH2-, NH2CH2CH2- and NH2CH2CH2CH2-), C 1-3 Alkyl-NHC(O)- (e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH- (e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-) or cyano.

[0279] In some embodiments, the compound of formula (II) Illustrative examples include, but are not limited to, the following groups: wherein the symbol *** represents the point of attachment to the group Y, or the symbol *** represents the point of attachment to the carbonyl group.

[0280] In some embodiments, the group Y of the compound of formula (II) represents -N(R 3 )-, where R 3 is hydrogen or C 1-3 alkyl.

[0281] In some embodiments, the group Y of the compound of formula (II) represents -O-.

[0282] In some embodiments, the group Y of the compound of formula (II) is n connected rings D represented by the following structural formula:

[0283]

[0284] wherein n is an integer of 0, 1, 2 or 3, wherein when n represents an integer of 2 or 3, each ring D may be the same or different, each ring D is independently a 5-membered to 11-membered heterocyclylene group, (R d ) m4 Indicates that each ring D can be optionally and independently replaced by m4 R d Group substitution, m4 represents an integer of 0, 1, 2, 3, 4 or 5, and each R d Independently C1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH- or cyano.

[0285] In some embodiments, exemplary examples of ring D of the compound of formula (II) include, but are not limited to, the following groups: piperidinylene, piperazinylene, morpholinylene, azetidinylene, oxetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, sulfomorpholinylene, dioxanylene, diazepanylene, or C 7-11 spiroheterosylidene.

[0286] In some embodiments, when ring D of the compound of formula (II) represents C 7-11 spiroheterosylidene, said C 7-11 spiroheterosylidene can be the following groups:

[0287]

[0288] wherein the symbol ** represents the point of attachment to ring C, X represents O, N(R e ), S or CH2or X represents a bond, wherein R e represents hydrogen or methyl, and n1, n2 and n3 are each independently an integer of 1 or 2.

[0289] In some embodiments, when ring D of the compound of formula (II) represents C 7-11 spiroheterosylidene, said C 7-11 spiroheterosylidene can be the following groups:

[0290]

[0291] wherein the symbol ** represents the point of attachment to ring C.

[0292] In some embodiments, ring D of the compound of formula (II) is optionally further substituted with m4 R d groups, wherein m4 represents an integer of 0, 1, 2, 3, 4 or 5, each R d is independently C 1-3 alkyl (e.g. methyl, ethyl or propyl), C 3-6cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, thiol, halogen (e.g., fluorine, chlorine, bromine, or iodine), oxo, C 1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C 1-3 alkylamino (e.g., C 1-3 alkyl NH-, e.g., CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-), haloC 1-3 alkyl (e.g., -CF3, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF2CF3, -CHFCF3, -CF2CHF2, -CHFCHF2, -CH2CF3, and -CH2CH2Cl), amino-substituted C 1-3 alkylene (NH2-C 1-3 alkylene-, e.g., NH2CH2-, NH2CH2CH2-, and NH2CH2CH2CH2-), C 1-3 alkyl-NHC(O)-(e.g., CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-), C 1-3 alkyl-C(O)NH-(e.g., CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-), or cyano.

[0293] In some embodiments, the compound of Formula (II) is Exemplary examples of the group of Formula (II) include, but are not limited to, the following groups: wherein the symbol ** indicates the point of attachment to ring C. Alternatively, in some embodiments, the symbol ** in the group can also indicate the point of attachment to the group LIN.

[0294] In some embodiments, the compound of Formula (II) is Exemplary examples of the group of Formula (II) include, but are not limited to, the following groups:

[0295]

[0296] wherein the symbol ## indicates the point of attachment to the group LIN.

[0297] The ULM and LIN of the compound of Formula (II) of the present disclosure are as defined in the embodiments of the compound of Formula (I) herein and sub-embodiments thereof.

[0298] In some embodiments, the compound of Formula (I) of the present disclosure is also a compound of Formula (V), or a salt (including a pharmaceutically acceptable salt), a solvate, an isotopically enriched analog, a polymorph, a prodrug, a stereoisomer (including an enantiomer), or a mixture of stereoisomers thereof:

[0299]

[0300] wherein any 1, 2, or 3 of X1, X2, X3, and X4represent N, and the remainder represent CH; and c m3 , m, ring B, (R b m2 , L1, R 1 , R 2 , (R a m1 as defined in any of the embodiments of the compound of Formula (I) herein, and subembodiments thereof.

[0301] In some embodiments, the compound of Formula (I) of the present disclosure is also a compound of Formula (VI), or a salt (including a pharmaceutically acceptable salt), solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof:

[0302]

[0303] wherein X5and X6are the same or different and independently represent CH or N; and

[0304] ULM, LIN, Y, ring C, (R c m3 , m, ring B, (R b m2 , L1, R 1 , R 2 , (R a m1 as defined in any of the embodiments of the compound of Formula (I) herein, and subembodiments thereof.

[0305] In some embodiments, the compound of Formula (I) of the present disclosure is also a compound of Formula (VII), or a salt (including a pharmaceutically acceptable salt), solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including an enantiomer), or mixture of stereoisomers thereof:

[0306]

[0307] wherein either X7and X8represent CH, and the other represents N, or X7and X8represent CH; and

[0308] ULM, LIN, Y, ring C, (R c m3 , m, ring B, (R b ​​​​​​​) m2 , L1, R 1 、R 2 、(R a ) m1 As defined herein in any one of the embodiments and subembodiments thereof of the compounds of formula (I).

[0309] In some embodiments, the compound of formula (I) of the present disclosure is also a compound of formula (VIII) or a salt (including a pharmaceutically acceptable salt), solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof:

[0310]

[0311] Among them, ULM, LIN, Y, ring C, (R c ) m3 ,m,ring B,(R b ) m2 , L1, R 1 、R 2 、(R a ) m1 As defined herein in any one of the embodiments and subembodiments thereof of the compounds of formula (I).

[0312] Those skilled in the art will appreciate that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features of another embodiment are also encompassed within the scope of the present invention.

[0313] In some embodiments, provided are compounds of Table 1 below and their salts (including pharmaceutically acceptable salts, such as their hydrochloride salts), prodrugs, solvates, isotopically enriched analogs, polymorphs, stereoisomers (including enantiomers and diastereomers), or mixtures of stereoisomers:

[0314] Table 1 Compounds of the present disclosure

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414] II. Other forms of the compounds (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs of the compounds)

[0415] The compounds of the present disclosure have the structure of any one of Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), or Formula (VIII). Unless otherwise specified, when referring to the compounds of the present disclosure, reference is made to include compounds of any one of Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), as well as specific compounds falling within the scope of these general formulas.

[0416] It is recognized that the compounds of the disclosure, including compounds of Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), and Formula (VIII), can have stereomeric configurations and thus exist in more than one stereoisomeric form. The disclosure also relates to compounds having stereomeric configurations that are optically enriched, such as about greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, as well as mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a substantially greater proportion of one enantiomer, and can be described by the enantiomeric excess (ee %). Purification of isomers and separation of mixtures of isomers can be achieved by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates), and / or chiral resolution, etc.).

[0417] In some embodiments, there are also provided polymorphic forms of the compounds of the disclosure or salts of the compounds of the disclosure. The salts of the compounds of the disclosure can be pharmaceutically acceptable salts, including but not limited to hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate, or p-toluenesulfonate, etc. The compounds of the disclosure can exist in a non-solvate or solvate form in a pharmaceutically acceptable solvent such as water, ethanol, etc. In some embodiments, the compounds of the disclosure can be prepared as prodrugs or proagents. Prodrugs are converted into the parent drugs in the body to exert their actions. In some embodiments, there are also provided isotopically-labeled compounds of the disclosure, examples of isotopes include deuterium (D or 2 H).

[0418] III. Pharmaceutical Compositions / Formulations

[0419] In some embodiments, the disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomeric forms), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.

[0420] In some embodiments, the pharmaceutically acceptable carrier includes, but is not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickening agents, coloring agents, solvents, or encapsulating materials. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and not deleterious to the patient, the carrier must be "acceptable". Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, dextrose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents, phosphate buffered saline solutions; polyoxyethylene, polyvinylpyrrolidone, polyacrylamide, poloxamer; and

[0421] The pharmaceutical composition described in the present disclosure further comprises at least one second therapeutic agent for treating or preventing a disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT). The second therapeutic agent can be combined with the compound of Formula (I) described in the present disclosure to treat a disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT), which includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a gene therapeutic agent, etc. In some embodiments, the disease or disorder associated with nicotinamide phosphoribosyltransferase (NAMPT) includes a tumor, an autoimmune disease, an inflammatory disease, a pregnancy-induced hypertension syndrome, a cardiovascular and cerebrovascular disease, obesity, and diabetic nephropathy.

[0422] In some embodiments, the disease or disorder associated with NAMPT includes:

[0423] colorectal cancer; breast cancer (including triple negative breast cancer, invasive breast cancer, infiltrating breast cancer); astrocytoma; pancreatic cancer; gastric cancer; prostate cancer; melanoma; leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia); ovarian cancer; liver cancer; lung cancer (e.g., non-small cell lung cancer and small cell lung cancer); glioblastoma; multiple myeloma; esophageal cancer; bladder cancer; thyroid cancer; endometrial cancer; lymphoma (e.g., diffuse large B-cell lymphoma, follicular B-cell lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma); neuroendocrine tumor; renal cancer (e.g., renal oncocytoma, renal clear cell carcinoma, renal urothelial carcinoma); pediatric glioma; rhabdomyosarcoma; leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; oral squamous cell carcinoma; autoimmune diseases (e.g., rheumatoid arthritis, autoimmune encephalitis); cardiovascular and cerebrovascular diseases (including coronary atherosclerosis, acute myocardial infarction, myocardial ischemia reperfusion injury, ischemic stroke); inflammatory diseases; pregnancy-induced hypertension syndrome; obesity and diabetic nephropathy.

[0424] The pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure can be prepared into a suitable formulation form according to a suitable administration route (including, but not limited to, intranasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration), such as a spray formulation, a patch, a tablet (e.g., a conventional tablet, a dispersible tablet, an oral disintegrating tablet), a capsule (e.g., a soft capsule, a hard capsule, an enteric capsule), a sugar-coated pill, a buccal tablet, a powder, a granule, a powder injection, a suppository, or a liquid formulation (e.g., a suspension (e.g., an aqueous or oily suspension), a solution, an emulsion, or a syrup), or a conventional injection form such as a sterile injection solution (e.g., a sterile injection solution prepared according to a method known in the art using water, Ringer's solution, or an isotonic sodium chloride solution, etc. as a carrier or solvent) or a lyophilized composition. The compound of formula (I) according to the present disclosure can also be prepared into a conventional, dispersible, chewable, oral rapidly disintegrating, or rapidly dissolving formulation, or a sustained release or controlled release capsule as needed by those skilled in the art.

[0425] IV. Kit / packaging article

[0426] The compound of formula (I) described in the present disclosure, or its pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers, is used as a medicament. The medicament of the present disclosure or the pharmaceutical composition of the present disclosure may be present in a medicine box / packaged product. The medicine box / packaged product may include packaging or container. The packaging or container includes but is not limited to ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, etc. The medicine box / packaged product may include product instructions for use.

[0427] V. Methods and Uses

[0428] The compounds of formula (I) described herein, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, can be used as medicaments. In particular, the compounds of formula (I) described herein, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, can be used to prepare medicaments for preventing and / or treating diseases or conditions associated with NAMPT.

[0429] A method for treating or preventing a NAMPT-associated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the NAMPT-associated disease or disorder comprises a tumor, an autoimmune disease, an inflammatory disease, a pregnancy-induced hypertension syndrome, a cardiovascular and cerebrovascular disease, obesity, and diabetic nephropathy. In some embodiments, the NAMPT-associated disease or disorder comprises, but is not limited to, colorectal cancer; breast cancer (including triple-negative breast cancer, invasive breast cancer, infiltrating breast cancer); astrocytoma; pancreatic cancer; gastric cancer; prostate cancer; melanoma; leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia); ovarian cancer; liver cancer; lung cancer (e.g., non-small cell lung cancer and small cell lung cancer); glioblastoma; multiple myeloma; esophageal cancer; bladder cancer; thyroid cancer; endometrial cancer; lymphoma (e.g., diffuse large B-cell lymphoma, follicular B-cell lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma); neuroendocrine tumor; renal cancer (e.g., renal oncocytoma, renal clear cell carcinoma, renal urothelial carcinoma); pediatric glioma; rhabdomyosarcoma; leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; oral squamous cell carcinoma; autoimmune disease (e.g., rheumatoid arthritis, autoimmune encephalitis); cardiovascular and cerebrovascular disease (including coronary atherosclerosis, acute myocardial infarction, myocardial ischemia reperfusion injury, ischemic stroke); inflammatory disease; pregnancy-induced hypertension syndrome; obesity, and diabetic nephropathy.

[0430] In a method for treating or preventing a NAMPT-associated disease or disorder in a subject, a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutical composition as described herein, is administered to the subject by at least one mode of administration selected from the group consisting of intranasal administration, inhalation administration, topical administration, oral administration, buccal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration.

[0431] The term "treatment" or "treatment" refers to administering to a subject a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, to slow the progression (lessen) of an undesired disease or disorder (e.g., a tumor). Beneficial or desired clinical results of the present disclosure include, but are not limited to, alleviation of symptoms, lessening of disease severity, stabilization of disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission of the disease.

[0432] A "therapeutically effective amount" of a compound of the present disclosure depends on a number of factors, including the activity of the particular compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, and diet of the patient, the mode and time of administration, the rate of excretion, the drug combination, and the severity of the disease or condition undergoing treatment. A person skilled in the art is capable of determining a suitable dose depending on these and other factors.

[0433] It should be understood that the selection of one or more active compounds and / or compositions and their dosages depends on the individual's basic situation (usually the individual's situation should be optimized for the best effect). The administration and administration regimen should be within the ability of a person skilled in the art, and the appropriate dose depends on many factors including the general technical level of knowledge of a physician, veterinarian or researcher (see, for example, Li Jun, ed., "Clinical Pharmacology", 4th edition, People's Medical Publishing House (2008)).

[0434] The patient or subject of the above treatment refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, and the like.

[0435] VI. Definitions

[0436] The following words, phrases and symbols used in the present specification are used in their ordinary sense, unless otherwise indicated.

[0437] Generally, the nomenclature used herein, including IUPAC nomenclature, and the laboratory procedures described below, include those generally used by those skilled in the art and are generally described in the literature. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Additionally, the use of the terms "a" or "an" or "the" or "one" or "said" or "this" or "that" or "these" or "those" in the claims and / or the specification are taken to cover "one", but also "one or more". Similarly, the use of the terms "another" or "other" is taken to cover "at least a second" or more.

[0438] It should be understood that whenever a particular aspect is described using the term "comprising" or "including", other aspects described by the terms "consisting of and / or "consisting essentially of are also provided.

[0439] The term "about" is used herein to mean approximately, roughly, around, or in the region of. When the term "about" is used in conjunction with a numerical value, it modifies that value by extending it by the margin of error equivalent to the precision of the measurement that is used. Generally, the term "about" can modify a value by a variation of, e.g., 10%, 5%, 2%, or 1% above and below the stated value.

[0440] In the present text, the expression "represents a bond" means that it is a bond linker (i.e. it means that it is not present). For example, the expression "R represents a bond" means that R is a bond linker. In other words, when R is a bond, the group W of the structure of formula (III) is directly connected to the phenyl ring of the structure of formula (III).

[0441] As used herein, the expression "straight-chain or branched-chain C 2-60 inserted into the main carbon chain of the alkylene group is one or more groups R 5 and / or one or more groups R 6 or one or more groups R 5 in any combination with R 6 "inserted" has the definition known in the art, i.e. it can mean that one or more carbon-carbon bonds between one or more pairs of adjacent carbon atoms of the main carbon chain are interrupted by a group R 5 , R 6 or a group R 5 in any combination with R 6 In the present text, examples of the above expression "inserted into the main carbon chain of the alkylene group is one or more" can include, but are not limited to, one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R 5 and / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R 6 and / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R 5 in any combination with R 6 , whereby the main chain group formed complies with the theory of covalent bonds. For example, the expression "straight-chain or branched-chain C 2-60 inserted into the main carbon chain of the alkylene group is one or more groups R 5 and / or one or more groups R 6 or one or more groups R 5 in any combination with R 6 , whereby the main chain group formed complies with the theory of covalent bonds. For example, the expression "straight-chain or branched-chain C 2-60one or more (e.g. 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) R 5 and / or one or more groups R 6 and / or one or more groups R 5 and / or one or more groups R 6 in any combination to form one or more (e.g. 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 -CH2-” segments and / or one or more (e.g. 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 6 -CH2-” segments and / or one or more (e.g. 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “-CH2-R 5 -R 6 -CH2-” segments, wherein each R 5 is the same or different, each R 6 is the same or different, and is as defined herein.

[0442] In the context of the present disclosure, it is understood that the expression “the main carbon chain of said linear or branched C 2-60 may optionally be interrupted by one or more groups R 5 and / or one or more groups R 6 or one or more groups R 5 in any combination” includes the embodiment of “the main carbon chain of said linear or branched C 6 interrupted by one or more groups R 2-60 and / or one or more groups R 5 or one or more groups R 6 in any combination” and the embodiment of “the main carbon chain of said linear or branched C 5 not interrupted by one or more groups R 6 and / or one or more groups R 2-60 or one or more groups R 5 in any combination”. 6 5 6 In the context of the present disclosure, it is understood that the expression “the main carbon chain of said linear or branched C

[0443] In the present text, a bond broken by a wavy line shows the point of attachment of the drawn group to the rest of the molecule. For example, the group represented by the ULM drawn below​​

[0444]

[0445] Z1 of the group represents a bond to the alkylene group in the group LIN of the compound of formula (I).

[0446] In this document, the term "the linear or branched C x-y "One or more CH2 hydrogen atoms of an alkylene group are replaced by..." means a straight or branched C x-y Any one or more hydrogen atoms in the CH2 atoms in the alkylene group are replaced by a substituent as defined herein. As used herein, the group #-U-CH2-, #-U-(CH2)2-, #-U-(CH2)3-, #-U-(CH2)4-, #-U-(CH2)5-, #-U-(CH2)6-, #-U-(CH2)7-, #-U-(CH2)8-, #-U-(CH2)9-, #-U-(CH2) 10 -、#-U-(CH2) 11 -、#-U-(CH2) 12 -, #-U-(CH2) 13 -、#-U-(CH2) 14 -、#-U-(CH2) 15 -、#-U-(CH2) 16 -、#-U-(CH2) 17 -、#-U-(CH2) 18 -、#-U- (CH2) 19 -、#-U-(CH2) 20 -、#-U-(CH2) 21 -、#-U-(CH2) 22 -、#-U-(CH2) 25 -、#-U-(CH2) 30 -、#-U-(CH2) 35 -, #-U-(CH2) 40 -、#-U-(CH2) 45 -、#-U-(CH2) 50 -、#-U-(CH2) 55 -, or #-U-(CH2) 60-one or more hydrogens of CH2 may refer to part or all of the hydrogens of the mentioned alkylene groups, including but not limited to 1-80 hydrogens. In some embodiments, the term "one or more hydrogens of CH2" may refer to part or all of the hydrogens of the mentioned alkylene groups, including but not limited to 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1 hydrogen. In some embodiments, the term "one or more hydrogens of CH2" may refer to 1-3 of the multiple hydrogens of the mentioned alkylene groups. This number is in principle not subject to any restrictions or automatically limited by the size of the building block.

[0447] As used herein, the phrases "optionally substituted with" and "unsubstituted or substituted" are used interchangeably. The term "substituted" generally means that one or more hydrogen atoms in the referenced structure are replaced with the same or different substituents of the specified substituent.

[0448] As used herein, the term "oxo" or "oxo" refers to =0.

[0449]

[0046] As used herein, the term "C(O)" or "C(=O)" or "C=O," alone or in combination, refers to a carbonyl group.

[0450] As used herein, the term "nicotinoyl" refers to

[0451] As used herein, the term "halogen atom" or "halogen" alone or in combination refers to fluorine, chlorine, bromine or iodine.

[0452] As used herein, the term "alkyl" used alone or in combination refers to a straight chain or branched chain alkyl group. x -C y Alkyl" or "C x-y "alkyl" (x and y are each an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms. The term "C 1-10 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms. 1-10 Examples of alkyl groups include C 1-9 Alkyl, C 1-8 Alkyl, C 2-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, and C 1-4 Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term "C 1-3"C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl and isopropyl. In the present disclosure, the "alkyl" is optionally substituted, and the substituents are optionally one or more selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 The substituent may be an alkoxy group, a trifluoromethyl group, a heterocyclic group or a combination thereof.

[0453] As used herein, the term "haloalkyl" alone or in combination refers to a linear or branched alkyl group substituted with one or more halogens, wherein one or more hydrogen atoms in the alkyl group are replaced with halogens. x -C y Alkyl" or "halogenated C x-y "alkyl" (x and y are each an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms substituted by one or more halogens. The term "halogenated C 1-10 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms substituted by one or more halogens. 1-10 Examples of alkyl groups include halo-C 1-9 Alkyl groups, such as halogenated C 1-8 Alkyl, halogenated C 2-8 Alkyl, halogenated C 1-7 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-5 Alkyl, or halogenated C 1-4 Representative examples include halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halogenated isobutyl, halogenated sec-butyl, halogenated tert-butyl, halogenated pentyl, halogenated isopentyl, halogenated neopentyl, halogenated tert-pentyl, halogenated hexyl, halogenated heptyl, halogenated octyl, halogenated nonyl and halogenated decyl. The term "halogenated C 1-3 "Alkyl" or "halogenated C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms substituted by one or more halogens, representative examples of which include halomethyl, haloethyl, halo-n-propyl and halo-isopropyl.

[0454] As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. x -C y "Alkylene" or "C x-y "alkylene" (x and y are each an integer) refers to a straight or branched chain alkylene containing x to y carbon atoms. 60 Examples of alkylene groups include C1-C 55 Alkylene, C1-C 50alkylene, C1-C 45 alkylene, C1-C 40 alkylene, C1-C 35 alkylene, C1-C 30 alkylene, C1-C 29 alkylene, C1-C 28 alkylene, C1-C 27 alkylene, C1-C 26 alkylene, C1-C 25 alkylene, C1-C 24 alkylene, C1-C 23 alkylene, C1-C 22 alkylene, C1-C 21 alkylene, C1-C 20 alkylene, C1-C 19 alkylene, C1-C 18 alkylene, C1-C 17 alkylene, C1-C 16 alkylene, C1-C 15 alkylene, C1-C 14 alkylene, C1-C 13 alkylene, C1-C 12 alkylene, C1-C 11 alkylene, C1-C 10 alkylene, C1-C9alkylene, C1-C8alkylene, C1-C7alkylene, C1-C6alkylene, C1- C5alkylene, C1-C4alkylene, C1-C3alkylene, or C1-C2alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, isopentylene, neopentylene, t-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene. In the present disclosure, the “alkylene” is optionally substituted, and the substituents can optionally be one or more selected from the group consisting of C1-C3alkyl, C 3-6 cycloalkyl, hydroxyl, amino, thiol, halogen, C1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkyl, aminoC 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0455] The term "alkoxy," employed alone or in combination, refers to a straight or branched chain alkoxy group having the formula alkyl-O-. Optionally, the alkyl portion of the alkoxy group can contain from 1 to 10 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, n-butyloxy, isobutyloxy, t-butyloxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. The term "C1-C3alkoxy" or "C 1-3 The term "alkoxy" refers to a straight or branched chain alkoxy group having from 1 to 3 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. 1-3 The term "alkoxy" refers to a straight or branched chain alkoxy group having from 1 to 3 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0456] The term "alkylamino," employed alone or in combination, refers to a straight or branched chain alkylamino group having the formula alkyl-NH-. Optionally, the alkyl portion of the alkylamino group can contain from 1 to 10 carbon atoms. Representative examples of "alkylamino" include, but are not limited to, methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, t-butyl-NH-, pentyl-NH-, hexyl-NH-, and the like. The term "C1-C3alkyl-NH-" or "C 1-3 The term "alkylamino" refers to a straight or branched chain alkylamino group having from 1 to 3 carbon atoms. Representative examples of "alkylamino" include, but are not limited to, methyl-NH-, ethyl-NH-, n-propyl-NH-, and isopropyl-NH-. 1-3 The term "alkylamino" refers to a straight or branched chain alkylamino group having from 1 to 3 carbon atoms. Representative examples of "alkylamino" include, but are not limited to, methyl-NH-, ethyl-NH-, n-propyl-NH-, and isopropyl-NH-.

[0457] The term "amino-substituted alkylene," employed alone or in combination, refers to an amino-substituted straight or branched chain alkylene group having the formula NH2-alkylene-. Optionally, the alkylene portion of the amino-substituted alkylene group can contain from 1 to 10 carbon atoms. The term "amino-substituted C 1-3 The term "amino-substituted alkylene" refers to an amino-substituted straight or branched chain alkylene group having from 1 to 3 carbon atoms. Representative examples of "amino-substituted alkylene" include, but are not limited to, NH2-CH2-, NH2-CH2CH2-, and NH2-CH2CH2CH2-. 1-3 The term "amino-substituted alkylene" refers to an amino-substituted straight or branched chain alkylene group having from 1 to 3 carbon atoms. Representative examples of "amino-substituted alkylene" include, but are not limited to, NH2-CH2-, NH2-CH2CH2-, and NH2-CH2CH2CH2-. 1-3 The term "amino-substituted alkylene" refers to an amino-substituted straight or branched chain alkylene group having from 1 to 3 carbon atoms. Representative examples of "amino-substituted alkylene" include, but are not limited to, NH2-CH2-, NH2-CH2CH2-, and NH2-CH2CH2CH2-.

[0458] The term "alkyl-NHC(O)-," employed alone or in combination, refers to a straight or branched chain alkyl-NHC(O)- group having the formula alkyl-NHC(O)-. Optionally, the alkyl portion of the alkyl-NHC(O)- group can contain from 1 to 10 carbon atoms. The term "C1-C3alkyl-NHC(O)-" or "C 1-3"Alkyl-NHC(O)-" means straight-chained or branched alkyl-NHC(O)- containing from 1 to 3 carbon atoms. C 1-3 Representative examples of alkyl-NHC(O)- include, but are not limited to, CH3-NHC(O)-, CH3CH2-NHC(O)-, and CH3CH2CH2-NHC(O)-.

[0459] The term "alkyl-C(O)NH-" as used herein, alone or in combination, means straight-chained or branched alkyl-C(O)NH- having the formula alkyl-C(O)NH-. Optionally, the alkyl portion of alkyl-C(O)NH- can contain from 1 to 10 carbon atoms. The term "C1-C3 alkyl-C(O)NH-" or "C 1-3 "Alkyl-C(O)NH-" means straight-chained or branched alkyl-C(O)NH- containing from 1 to 3 carbon atoms. C 1-3 Representative examples of alkyl-C(O)NH- include, but are not limited to, CH3-C(O)NH-, CH3CH2-C(O)NH-, and CH3CH2CH2-C(O)NH-.

[0460] In the present application, the term "heteroaryl" used alone or in combination refers to a 5- to 20-membered (optionally 5 to 15 membered, 5 to 12 membered, 5 to 11 membered, 5 to 10 membered, 5 to 9 membered, 5 to 8 membered, 5 to 7 membered, 5 to 6 membered, 6 to 15 membered, or 6 membered to 9 membered) monocyclic or bicyclic or polycyclic aromatic ring radical containing at least one aromatic ring having one or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic, or tetracyclic heteroaryl groups in which one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other ring(s) can be saturated, partially unsaturated, or aromatic and can be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, and imidazo[2,1-b]thiazolyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, and xanthenyl. The heteroaryl group can be unsubstituted or substituted. Substituted heteroaryl refers to a heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent group, which is optionally selected from C1-C3alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkyl, aminoC 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0461] In the present invention, the term "heteroarylene" used alone or in combination refers to a 5- to 20-membered (optionally 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15-membered, or 6- to 9-membered) monocyclic or bicyclic or polycyclic divalent aromatic ring group containing at least one aromatic ring having 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene groups include bicyclic, tricyclic, or tetracyclic heteroarylene groups, in which one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated, or aromatic rings and may be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylene groups include, but are not limited to, indolylene, isoindolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, 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, oxazolopyridinylene, furopyridinylene, pteridinylene, purinylene, pyridopyridinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyridinylene, pyrimidine, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolylene and imidazo[2,1-b]thiazolylene. Examples of tricyclic heteroarylene groups include, but are not limited to, acridinyl, benzindolyl, carbazolylene, dibenzofuranyl, and xanthenyl. Substituted heteroarylene refers to a heteroarylene group substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent, wherein the substituent is optionally selected from C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.

[0462] In the present disclosure, the term "aryl" used alone or in combination refers to a monovalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the "aryl" is optionally substituted aryl. Substituted aryl refers to aryl that is substituted one or more times (e.g., 1-4, 1-3 times, or 1-2 times) with a substituent group, such as aryl that is mono-, di-, or tri-substituted, wherein the substituent group is optionally, for example, selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl- substituted amino, halo, cyano, or any combination thereof. 3-6 cycloalkyl, hydroxyl, amino, thiol, halogen, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino, halo, cyano, or any combination thereof. 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0463] In the present disclosure, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene or naphthylene or fluorenylene. In the present disclosure, the "arylene" is optionally substituted arylene. Substituted arylene refers to arylene that is substituted one or more times (e.g., 1-4, 1-3 times, or 1-2 times) with a substituent group, such as arylene that is mono-, di-, or tri-substituted, wherein the substituent group is optionally, for example, selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino, halo, cyano, or any combination thereof. 3-6 cycloalkyl, hydroxyl, amino, thiol, halogen, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino, halo, cyano, or any combination thereof. 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0464] In the present disclosure, the term "cycloalkyl" used alone or in combination refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic ring hydrocarbon group having, in some embodiments, 3 to 20 carbon atoms (i.e., C 3-20 cycloalkyl), or 3 to 15 carbon atoms (i.e., C 3-15 cycloalkyl), 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), or 3 to 11 carbon atoms (i.e., C 3-11 cycloalkyl), or 3 to 10 carbon atoms (i.e., C 3-10 cycloalkyl), or 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 carbon atoms (i.e., C 3-6cycloalkyl groups. The term "cycloalkyl" includes monocyclic, bicyclic, or tricyclic cycloalkyl groups having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic cycloalkyl groups include bridged cycloalkyl, fused ring, and spirocyclic cycloalkyl groups, such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-lH-indenyl, spirocycloalkyl, adamantyl, noradamantyl, borneolyl, norbornyl (IUPAC systematic name bicyclo[2.2.1]heptanyl). In this context, the "cycloalkyl" groups are optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups. The substituents of the substituted "cycloalkyl" groups are optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl- substituted amino, C1-C3 alkyl-NHC(O)-, C1-C3 alkyl-O-C(O)-, C1-C3 alkyl-C(O)NH-, cyano, or any combination thereof. Representative examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. 3-6 cycloalkyl, hydroxyl, amino, thiol, halo, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino, C1-C3 alkyl-NHC(O)-, C1-C3 alkyl-O-C(O)-, C1-C3 alkyl-C(O)NH-, cyano, or any combination thereof. Representative examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof. Representative examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. 3-6 cycloalkyl, hydroxyl, amino, thiol, halo, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino, C1-C3 alkyl-NHC(O)-, C1-C3 alkyl-O-C(O)-, C1-C3 alkyl-C(O)NH-, cyano, or any combination thereof. Representative examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0465] In this context, the "cycloalkyl" groups are optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups. The substituents of the substituted "cycloalkyl" groups are optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkyl- substituted amino, C1-C3 alkyl-NHC(O)-, C1-C3 alkyl-O-C(O)-, C1-C3 alkyl-C(O)NH-, cyano, or any combination thereof. Representative examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. 3-6cycloalkyl, hydroxy, amino, thiol, halogen, C1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0466] The term "C x-y spirocycloalkylene" or "C x-y spirocyclylene" (each of x and y is an integer) means a spirocycloalkylene group containing from x to y carbon atoms. The term "C 7-11 spirocycloalkylene" means a spirocycloalkylene group containing from 7 to 11 (e.g., 7-10, 7-9) carbon atoms. The term "C 7-11 spirocycloalkylene" includes, but is not limited to, spiro[3.3]heptanediyl, spiro[2.5]octanediyl, spiro[3.5]nonanediyl, spiro[4.4]nonanediyl, spiro[4.5]decanediyl, or spiro[5.5]undecanediyl. The "C 7-11 spirocycloalkylene" is optionally further substituted with one or more substituents selected from C1-C3alkyl, C 3-6 cycloalkyl, hydroxy, amino, thiol, halogen, C1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkyl, amino-substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano, or any combination thereof.

[0467] The term "C x-y spiroheterocyclylene" or "C x-y spiroheteroclylene" (each of x and y is an integer) means a spiroheterocyclyl group containing one or more (e.g., containing 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen and containing from x to y carbon atoms. The term "C 7-11 spiroheterocyclylene" means a spiroheterocyclyl group containing from 7 to 11 (e.g., 7-10, or 7-9) carbon atoms and containing one or more (e.g., containing 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. The term "C 7-11 spiroheterocyclylene" includes, but is not limited to, spiro[3.3]heptanediyl, spiro[2.5]octanediyl, spiro[3.5]nonanediyl, spiro[4.4]nonanediyl, spiro[4.5]decanediyl, or spiro[5.5]undecanediyl.

[0468] The "C 7-11 spiroheterocyclylene" is optionally further substituted with one or more substituents selected from C1-C3alkyl, C 3-6Cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 The group is substituted with alkyl-C(O)NH-, cyano or any combination thereof.

[0469] As used herein, the term "heterocyclyl" or "heterocycloalkyl" used alone or in combination refers to a 3-20 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl containing one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. In some embodiments, "heterocyclyl" may refer to a 3-15 membered (optionally 3-14, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6 or 3-5 membered) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl containing one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepan-1-yl), and diazacyclooctanyl. Bicyclic and tricyclic heterocyclic groups include bridged heterocyclic groups, fused heterocyclic groups, and spiro heterocyclic groups, such as, but not limited to, representative examples including, but not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, and azaspirocyclic groups (e.g., 3-azaspiro[5.5]undec-3-yl). The heterocyclyl group may be unsubstituted or substituted as explicitly defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C1-3 alkyl-C(O)NH-, cyano or any combination thereof.

[0470] As used herein, the term "heterocyclylene" or "heterocycloalkylene" used alone or in combination refers to a 3-20 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclylene" may, for example, refer to a 3-15 membered (optionally 3-14, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, or 3-5 membered) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of monocyclic heterocyclylene groups include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxanylene, and diazepanylene (e.g., 1,4-diazepanylene, 4,5-diazepanylene, 1,3-diazepanylene). Bicyclic and tricyclic heterocyclylene groups include bridged heterocyclylenes, fused heterocyclylenes, and spiro heterocyclylenes, such as, but not limited to, representative examples including, but not limited to, 6-azabicyclo[3.1.1]heptanylidene, 2,5-diazabicyclo[2.2.1]heptanylidene, 3,6-diazabicyclo[3.1.1]heptanylidene, 3-azabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 2,5-diazabicyclo[2.2.2]octanylidene, and azaspirocyclylene (e.g., 3-azaspiro[5.5]undecylidene). The heterocyclylene group may be unsubstituted or substituted as clearly defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents may be selected from C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.

[0471] The term "alkynylene," used alone or in combination, refers herein to a straight or branched divalent hydrocarbon group comprising 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynylene groups include, but are not limited to, ethynylene, 1 -propynylene, 1 -butynylene, and 1,3- diynylene.

[0472] The term "alkenylene," used alone or in combination, refers herein to a straight or branched divalent hydrocarbon group comprising 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene groups include, but are not limited to, ethenylene (e.g., -CH=CH-), 1 -propenylene, alenylene, 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.

[0473] The term "bornyl" or "bornyl group" refers herein to a monovalent group derived from borneol, i.e., the group remaining after removal of a hydrogen from borneol. Representative examples of "bornyl" groups include, but are not limited to, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-5-yl, or 1,7,7-trimethylbicyclo[2.2.1]heptan-6-yl,

[0474] In the present text, the term "bicyclo[2.2.1]heptane" (also known as norbornane) has the definition known to the person skilled in the art. In the present text, "bicyclo[2.2.1]heptanyl" means a monovalent radical of bicyclo[2.2.1]heptane, i.e. the radical which remains if one hydrogen in bicyclo[2.2.1]heptane is removed. Representative examples of "bicyclo[2.2.1]heptanyl" 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.

[0475] In the present text, the term "bicyclo[2.2.1]heptene" (also known as norbornene) has the definition known to the person skilled in the art. In the present text, "bicyclo[2.2.1]heptenyl" means a monovalent radical of bicyclo[2.2.1]heptene, i.e. the radical which remains if one 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-ene-2-yl, bicyclo[2.2.1]hept-5-ene-3-yl, or bicyclo[2.2.1]hept-5-ene-7-yl.

[0476] In the present text, the term "adamantane" (also known as Tricyclo[3.3.1.1 3,7 ]decane) has the definition known to the person skilled in the art, the structural formula of which is, for example, as follows: In the present text, "adamantyl" means a monovalent radical of adamantane, i.e. the radical which remains if one hydrogen in adamantane is removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl or 10-adamantyl.

[0477] In the present text, the term "noradamantane" (also known as octahydro-2,5-methanopentalene) has the definition known to the person skilled in the art, the structural formula of which is, for example, as follows: In the present text, "noradamantyl" refers to a monovalent radical of noradamantane, i.e. the radical remaining after removal of any one hydrogen from noradamantane. Representative examples of "noradamantyl" include, but are not limited to, 1-noradamantyl, 2-noradamantyl, 3-noradamantyl, 4-noradamantyl, 5-noradamantyl, 6-noradamantyl, 7-noradamantyl, 8-noradamantyl, or 9-noradamantyl.

[0478] In the present text, the term "adamantylamine" has the definition known to the person skilled in the art, i.e. refers to adamantane having an amino substituent, wherein the amino group can replace a hydrogen on a carbon at any position of adamantane. One example of "adamantylamine" can be adamantane-1 -amine (which corresponds to the English chemical nomenclature name adamantan-1 -amine or Tricyclo[3.3.1.13]decan-1 -amine; CAS: 768-94-5), having the following structural formula 3,7 ]decan-1 -amine; CAS: 768-94-5), having the following structural formula

[0479]

[0480] The salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula (I) according to the present disclosure are also encompassed within the scope of the present disclosure.

[0481] In all embodiments of the present disclosure, the salts or pharmaceutically acceptable salts of the compounds of formula (I) refer to nontoxic inorganic or organic acid and / or base addition salts. Examples include: sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate or p-toluenesulfonate, and the like.

[0482] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, with which a compound useful in the present disclosure is carried or transported in or to the patient or administered to the patient, such that it can perform its intended function. Typically, such a construct is carried or transported from one organ or part of the body to another organ or part of the body. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful in the present disclosure, and not injurious to the patient. Some examples of materials which can serve 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 waxes; 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents, phosphate buffered saline; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0483] The term "room temperature" of the present disclosure refers to ambient temperature, such as a temperature of 20-30 °C.

[0484] In the present text, "stereoisomers" refer to compounds which have the same chemical constitution, but which differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0485] In the present text, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present application. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

[0486] In the present text, the term "chiral" refers to a molecule which does not have the property of superimposability with its mirror image; while "achiral" refers to a molecule which is superimposable with its mirror image.

[0487] In the present text, the term "enantiomers" refers to two isomers of a compound which cannot be superimposed and are mirror images of each other.

[0488] As used herein, the term "diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not a mirror image of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC. Examples

[0489] In the following description, numerous specific details are set forth to provide a thorough understanding of the present application. The present application, however, can be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present application. While the present application will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the present application to these embodiments.

[0490] The following abbreviations are used throughout the specification and examples:

[0491] Bipy bipyridine

[0492] Boc tert-butyloxycarbonyl

[0493] BnCl benzyl chloride

[0494] (COCl)2 oxalyl chloride

[0495] Con. concentration

[0496] DCM dichloromethane

[0497] DMF N,N-dimethylformamide

[0498] DMSO dimethyl sulfoxide

[0499] DIPEA N,N-diisopropylethylamine

[0500] (COCl)2 oxalyl chloride

[0501] EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0502] ESI electrospray ionization

[0503] equiv equivalent

[0504] EtOH ethanol

[0505] HATU 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0506] HOAT N-hydroxy-7-azabenzotriazole

[0507] HPLC high performance liquid chromatography

[0508] HRMS high resolution mass spectrum

[0509] LC-MS liquid chromatography-mass spectrometry

[0510] LRMS low resolution mass spectrum

[0511] LC liquid chromatography

[0512] Me methyl

[0513] MeCN acetonitrile

[0514] MeOH methanol

[0515] MS mass spectrum

[0516] MsCl methanesulfonyl chloride

[0517] MsO- methanesulfonate

[0518] NMM N-methylmorpholine

[0519] NMP N-methylpyrrolidinone

[0520] 1 H NMR nuclear magnetic resonance hydrogen spectrum

[0521] -OTs p-toluenesulfonate

[0522] PEG polyethylene glycol chain

[0523] rt room temperature

[0524] tBu tert-butyl

[0525] t-BuONO tert-butyl nitrite

[0526] TEA triethylamine

[0527] TFA trifluoroacetic acid

[0528] TLC thin layer chromatography

[0529] TMS trimethylsilyl

[0530] In the present invention, 1HNMR spectra were measured on a Bruker-500MHz NMR spectrometer, using CD3OD (δ = 3.31 ppm) containing 0.1% TMS (as an internal standard) as the solvent; or CDCl3 (δ = 7.26 ppm) containing 0.1% TMS (as an internal standard) as the solvent; or DMSO-d6 (δ = 2.50 ppm) containing 0.03% TMS (as an internal standard) as the solvent; LRMS spectra were measured on an AB Triple 4600 mass spectrometer, HPLC preparation was measured on a SHIMADZU LC-20AP instrument, and HPLC purity was measured on a SHIMADZU LC-30AP or Waters 1525 instrument. All reactions were carried out under an air atmosphere unless otherwise specified; reactions were monitored by TLC or LC-MS.

[0531] The solvents and reagents were treated as follows:

[0532] The solvents used in the reactions, such as DCM, DMF, anhydrous EtOH, anhydrous MeOH, etc., were purchased from National Pharmaceutical Group;

[0533] The solvents used in the reactions, such as DCM, DMF, anhydrous EtOH, anhydrous MeOH, etc., were purchased from National Pharmaceutical Group;

[0534] Unless otherwise specified, daprodexine and various different lengths of carbon chain linking units linker (i.e., compounds used to form the groups represented by LIN), as well as other reaction substrates, reagents, and chemicals, can be directly purchased through commercial channels.

[0535] The materials and reagents used in the following examples, unless otherwise specified, can be directly used as purchased from commercial channels, or can be synthesized or prepared according to methods known in the art.

[0536] General synthetic methods

[0537] The compounds and / or pharmaceutically acceptable salts thereof described in the present disclosure can be synthesized using commercially available starting materials by synthetic techniques known in the art. The synthetic schemes described below illustrate the preparation of most of the compounds. The starting materials or reagents used in each scheme can be purchased from commercial channels or prepared by methods known to those skilled in the art. The skilled person can prepare the salts, racemates, enantiomers, phosphates, sulfates, hydrochlorides, and prodrug forms of the compounds of formula (I) of the present disclosure according to conventional techniques in the art.

[0538] General preparation method of daprodexine derivatives (Nampt inhibitors):

[0539]

[0540] General synthesis method of intermediate LM

[0541] General preparation method of intermediate LM (Pomalidomide-N-Linker-COOH):

[0542]

[0543] In step 1, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (1 equiv; CAS Reg. No. 835616-60-9), the corresponding starting amine (1.2 equiv) and N,N-diisopropylethylamine (5 equiv) were added together into a 30 mL microwave reaction tube, followed by NMP (8 mL). The reaction mixture was stirred at room temperature for 10 minutes. The microwave reaction tube was then purged with argon slowly, placed on a microwave reactor, warmed to 110 °C, and the reaction mixture was stirred for 2 h. The reaction was allowed to cool to room temperature, poured into 90% brine, and extracted with ethyl acetate (4 x 50 mL). The organic phases were combined, washed with water (2 x 30 mL), saturated brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (eluent (v / v): petroleum ether / ethyl acetate = 1:1) to give the Boc-protected intermediate.

[0544] In step 2, the Boc-protected intermediate was added to a 50 mL single neck flask, 20 mL of 88% formic acid. The reaction mixture was stirred at room temperature for 12 h, and the reaction solvent was evaporated under reduced pressure. The resulting residue was lyophilized with water to give the corresponding final target compound.

[0545] General preparation method of intermediate LM (Lenalidomide-N-Linker-COOH):

[0546]

[0547] Lenalidomide (1 equiv), NMP (8 mL), the corresponding starting bromo-t-butyl ester (1.2 equiv), and N,N-diisopropylethylamine (3 equiv) were added together into a single neck flask, and the reaction was carried out at 110 °C for 12 h. The reaction was allowed to cool to room temperature, and the resulting reaction mixture was prepared and purified by C18 reverse phase column (eluent (v / v): acetonitrile / (water + 0.1% TFA) = 10% - 100%) to give the corresponding t-butyl ester intermediate compound.

[0548] The t-butyl ester intermediate compound from the first step was added to a single neck flask, followed by the addition of DCM (6 mL) and TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h, and the reaction solvent was evaporated under reduced pressure. The resulting residue was lyophilized with water to give the corresponding final target compound.

[0549] General preparation method of intermediate LM (Pomalidomide-N-alkylene chain-I):

[0550]

[0551] Step 1:

[0552] Dissolve 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1 equiv) in 25 mL NMP, add the corresponding primary amine (1.0 equiv) and N,N-diisopropylethylamine (1.5 equiv) sequentially, and heat the reaction at 100 °C for 4 h. After the reaction is complete, cool the reaction to room temperature, pour into saturated brine, and extract with ethyl acetate (4 x 50 mL). Combine the organic phases, wash with water (2 x 30 mL), wash with saturated brine (50 mL), dry over anhydrous Na2SO4, and remove the solvent under reduced pressure. Purify the resulting crude product by column chromatography (eluent (v / v): petroleum ether / ethyl acetate = 1:1) to obtain the intermediate. Dissolve the intermediate in 50 mL tetrahydrofuran, add tetrabutylammonium fluoride (1 equiv), and stir at room temperature for 2 h until the reaction is complete. Add saturated brine (200 mL), extract with ethyl acetate (4 x 50 mL), combine the organic phases, wash with water (2 x 30 mL), wash with saturated brine (50 mL), dry over anhydrous Na2SO4, remove the solvent under reduced pressure, and obtain the crude product for use in the next step.

[0553] Step 2:

[0554] Dissolve the crude product obtained in Step 1 in 40 mL of a mixed solvent (DCM / pyridine = 3 / 1), and add triethylamine (3.0 equiv) and methanesulfonyl chloride (1.5 equiv) sequentially under ice bath conditions, and react at room temperature for 12 h. After the reaction is complete, wash the reaction with saturated brine, and remove the solvent under reduced pressure. Purify the resulting residue by column chromatography to obtain the corresponding sulfonate intermediate.

[0555] Step 3: Add NaI to a solution of the corresponding sulfonate intermediate of Step 2 in acetone, heat to 60 °C, and react overnight to obtain the target compound.

[0556] General method for preparing intermediate LM (lenalidomide / pomalidomide-alkynyl-linker-OMs):

[0557]

[0558] Step 1:

[0559] Dissolve 3-(4-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione or 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (1 equiv) in 5 mL DMF, bubble Ar gas for 5 min, add the corresponding ynoic alcohol (2 equiv), Pd(PPh3)2Cl2(0.1 equiv) and Cul (0.2 equiv) successively. Stir the reaction mixture for 5 min, add 2.5 mL triethylamine, heat to 80 °C and react overnight. Cool the mixture to room temperature, quench the reaction with 50 mL water and extract with ethyl acetate (3 x 50 mL). Combine the organic phases, wash with water (2 x 30 mL), saturated brine (50 mL), dry over anhydrous Na2SO4and evaporate the solvent under reduced pressure. Purify the resulting crude product by column chromatography (eluent (v / v): DCM / MeOH = 5 / 1) to obtain the corresponding alcohol intermediate.

[0560] Step 2:

[0561] Dissolve the alcohol intermediate obtained in Step 1 in 15 mL DCM, add triethylamine (3 equiv) and methylsulfonyl chloride (1.5 equiv) successively, the system becomes clear, and react overnight. Wash the reaction mixture with saturated brine, evaporate the solvent under reduced pressure. Purify the resulting residue by column chromatography (eluent (v / v): DCM / MeOH = 5 / 1) to obtain the corresponding target compound.

[0562] General preparation method of intermediate LM (lenalidomide / pomalidomide-alkylene chain-OMs):

[0563]

[0564] In Step 1, dissolve the corresponding ynoic alcohol compound substituted at position 4 of lenalidomide / pomalidomide (1 equiv) in 10 mL ethanol, add 10% Pd / C (5 mg) and PtO2(5 mg) as catalyst, react under hydrogen atmosphere at normal pressure at 50 °C for 12 h. Filter the reaction mixture, evaporate the solvent under reduced pressure from the filtrate, and directly use the resulting crude product in the next step.

[0565] Dissolve the reduced product obtained in Step 1 in 15 mL DCM, add triethylamine (3 equiv) and methylsulfonyl chloride (1.5 equiv) successively, the system becomes clear, and react overnight. Wash the reaction mixture with saturated brine, evaporate the solvent under reduced pressure. Purify the resulting residue by column chromatography (eluent (v / v): DCM / MeOH = 5 / 1) to obtain the corresponding target compound.

[0566] General preparation method of intermediate LM (pomalidomide-S-alkylene chain-COOH):

[0567] General preparation method of intermediate LM (pomalidomide-S-alkylene chain-COOH):

[0568] Step 1:

[0569] Compound 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (20 g, 72.4 mmol) was added to a 250 mL eggplant flask, followed by the addition of anhydrous N,N-dimethylformamide (150 mL), and sodium sulfide nonahydrate (28 g, 108.6 mmol) was added portionwise with stirring at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 6 h. Then the reaction solution was slowly poured into a 400 mL ice water mixture, and the pH of the reaction solution was slowly adjusted to 2-3 with 6N aqueous hydrochloric acid with stirring, the solution color gradually changed from blood red to light yellow, and a large amount of off-white solid precipitated. The reaction mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water 3 times; then the filter cake was slurried with 100 mL of anhydrous acetone, filtered, and the filter cake was washed with acetone 3 times, and dried under reduced pressure to give the intermediate compound 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014).

[0570] Step 2:

[0571] The intermediate compound 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014) obtained in Step 1 (1 equiv) was added to a 100 mL eggplant flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv), and the corresponding bromine-substituted tert-butyl-protected alkyl chain acid (1.2 equiv) was slowly added dropwise with stirring at room temperature, and stirring was continued at room temperature for 0.5 h after the dropwise addition was completed. After the raw material was completely reacted, 50 mL of water was poured into the reaction mixture, and extraction was performed with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with water (3 x 20 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (eluent (v / v): dichloromethane / ethyl acetate = 20:1) to give the corresponding tert-butyl ester intermediate product. The corresponding tert-butyl ester intermediate product was added to a 25 mL eggplant flask, followed by the addition of 88% formic acid (10 mL), and the reaction mixture was stirred at room temperature for 12 h, the solvent was evaporated under reduced pressure, and the resulting residue was lyophilized with water to give the corresponding target compound.

[0572] General preparation method of intermediate LM (pomalidomide-S-PEG n -COOH):

[0573]

[0574] Compound 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014) (1 equiv) was added to a 100 mL egg flask, followed by anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv), and the bromo-substituted OTs-protected PEG chain acid of different length (1.2 equiv) was added dropwise slowly with stirring at room temperature. After the dropwise addition was completed, the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed, 50 mL of water was poured into the reaction mixture, and extraction was performed with ethyl acetate (2 x 50 mL). The combined organic phase was washed with water (3 x 20 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (eluent (v / v): dichloromethane / ethyl acetate = 20:1 ) to obtain the corresponding tert-butyl ester intermediate. The obtained tert-butyl ester intermediate compound was added to a 25 mL egg flask, followed by the addition of DCM and TFA, and the obtained mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, and the obtained residue was freeze-dried with water to obtain the target compound.

[0575] General preparation method of intermediate LM (lenalidomide-S-alkylene chain-COOH):

[0576]

[0577] Step 1 : Sodium thiosulfate pentahydrate (53.7 g, 216.3 mmol), benzyl chloride (27.4 g, 216.3 mmol), copper sulfate pentahydrate (77.4 mg, 0.31 mmol) and bipyridine (0.72 g, 4.6 mmol) were added to a 500 mL egg flask containing methanol (120 mL) and water (120 mL), followed by slowly warming to 80 °C and stirring for 2 h. Then the reaction solution was lowered to room temperature, 3-(4-amino-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (i.e. lenalidomide) (8.0 g, 30.9 mmol) was added, and finally tert-butyl nitrite (4.78 g, 46.4 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was again warmed to 80 °C and stirred for 8 h. After the reaction was completed, the reaction solution was lowered to room temperature, water (200 mL) was added, and extraction was performed with ethyl acetate (2 x 200 mL). The combined organic phase was washed with water (2 x 50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (eluent (v / v): petroleum ether / ethyl acetate = 1 :2) to obtain compound SIAIS171088.

[0578] Step 2: Anhydrous aluminum chloride (2.61 g, 19.6 mmol) and anhydrous toluene (70 mL) were added to a 250 mL eggplant flask, and compound (SIAIS171088) (1.8 g, 4.9 mmol) was added slowly with stirring. After the addition was completed, the mixture was stirred at 35 °C overnight. After the reaction was completed, 20% aqueous citric acid solution was slowly added to the reaction mixture with stirring, and a large amount of solid was precipitated. The mixture was then filtered, and the filter cake was washed with water and ethyl acetate, respectively. The filter cake was dried to give compound (SIAIS171095).

[0579] Step 3: Intermediate compound SIAIS171095 (1 equiv) was added to a 100 mL eggplant flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv). The corresponding bromine-substituted tert-butyl-protected alkyl chain acid (1.2 equiv) was slowly added dropwise with stirring at room temperature, and stirring was continued at room temperature for 0.5 h after the addition was completed. After the starting material was consumed, 50 mL of water was added to the reaction mixture, and ethyl acetate (2 x 50 mL) was added. The combined organic phase was washed with water (3 x 20 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography (eluent (v / v): dichloromethane / ethyl acetate = 20:1) to give the corresponding tert-butyl ester intermediate. The corresponding tert-butyl ester intermediate was added to a 25 mL eggplant flask, followed by the addition of 88% formic acid (10 mL), and stirring was continued at room temperature for 12 h. The solvent was removed under reduced pressure. The resulting residue was freeze-dried with water to give the target compound.

[0580] General preparation method of intermediate LM (lenalidomide-S-PEG n -COOH):

[0581]

[0582] Into a 100 mL egg flask, intermediate compound SIAIS171095 (1 equiv) was added, followed by anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv), and the corresponding bromo-substituted OTs-protected PEG chain acid (1.2 equiv) was added dropwise slowly with stirring at room temperature for 0.5 h. After the completion of the reaction, 50 mL of water was poured into the reaction mixture, and extracted with ethyl acetate (2 x 50 mL). The organic phase was combined, washed with water (3 x 20 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (eluent (v / v): dichloromethane / ethyl acetate = 20:1) to obtain the corresponding tert-butyl ester intermediate. The corresponding tert-butyl ester intermediate was added to a 25 mL egg flask, followed by TFA (5 mL) and DCM (10 mL). The reaction mixture was stirred at room temperature for 12 h, and the solvent was evaporated under reduced pressure. The resulting residue was freeze-dried with water to obtain the target compound.

[0583] General preparation method of intermediate LM (lenalidomide / pomalidomide-S-alkylene chain-Br):

[0584]

[0585] Into a 100 mL egg flask, intermediate compound SIAIS171095 (1 equiv) was added, followed by anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv), and the corresponding bromo-substituted OTs-protected PEG chain acid (1.2 equiv) was added dropwise slowly with stirring at room temperature for 0.5 h. After the completion of the reaction, 50 mL of water was poured into the reaction mixture, and extracted with ethyl acetate (2 x 50 mL). The organic phase was combined, washed with water (3 x 20 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (eluent (v / v): dichloromethane / ethyl acetate = 20:1) to obtain the corresponding tert-butyl ester intermediate. The corresponding tert-butyl ester intermediate was added to a 25 mL egg flask, followed by TFA (5 mL) and DCM (10 mL). The reaction mixture was stirred at room temperature for 12 h, and the solvent was evaporated under reduced pressure. The resulting residue was freeze-dried with water to obtain the target compound.

[0586] General preparation method of intermediate LM (lenalidomide-O-alkylene chain-Br):

[0587]

[0588] Step 1 : 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1 equiv) was dissolved in 20 mL of DMF, K2CO3 (3 equiv) was added, the corresponding bromo-substituted tert-butyl protected alkyl chain acid (1.2 equiv) was added and the reaction was stirred at room temperature for 2 h. The reaction was poured into 50 mL of water and extracted twice with dichloromethane. The organic phases were combined and the organic phase was washed with saturated brine and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (v / v): DCM to DCM / MeOH (10 / 1 )) to give the tert-butyl ester intermediate compound.

[0589] General method for the preparation of intermediate LM (Pomalidomide-O-alkylene chain-COOH):

[0590]

[0591] Step 1 : 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1 equiv) was dissolved in 20 mL of DMF, K2CO3 (3 equiv) was added, the corresponding bromo-substituted tert-butyl protected alkyl chain acid (1.2 equiv) was added and the reaction was stirred at room temperature for 2 h. The reaction was poured into 50 mL of water and extracted twice with dichloromethane. The organic phases were combined and the organic phase was washed with saturated brine and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (v / v): DCM to DCM / MeOH (10 / 1 )) to give the tert-butyl ester intermediate compound.

[0592] Step 2: The corresponding tert-butyl ester intermediate compound was added to a 25 mL vial followed by the addition of TFA (5 mL), DCM (10 mL). The reaction mixture was stirred at room temperature for 12 h and the solvent was evaporated under reduced pressure. The resulting residue was lyophilized from water to give the target compound.

[0593] General method for the preparation of intermediate LM (Pomalidomide-O-alkylene chain-COOH):

[0594]

[0595] The corresponding starting diacid (2.5 equiv) was added into a 250 mL three-necked flask, followed by the addition of anhydrous DMF (10 mL) and anhydrous dichloromethane (150 mL), DIPEA (10.0 mmol, 5 equiv), VHL-1 (2 mmol, 1 equiv), HOAT (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) were added successively under ice-water bath stirring. After the addition, the reaction mixture was stirred in ice-water bath for 5 h, then was raised to room temperature and stirred overnight. After the reaction was completed, 1 mL of deionized water was added to quench the reaction, and the dichloromethane was evaporated under reduced pressure. The obtained residue was then prepared and purified by C18 reverse phase column (eluent (v / v): acetonitrile / (water + 0.1% TFA) = 10% - 100%). The collected fractions were evaporated under reduced pressure, and the residue was lyophilized to obtain the corresponding target compound.

[0596] General synthetic method of the compounds of the present application:

[0597]

[0598]

[0599]

[0600] General synthetic method of the intermediates:

[0601]

[0602] According to the target compound, the above-mentioned each scheme and its reaction substrate, reaction condition (including reaction amount, temperature, time, etc.), post-treatment, etc. can be appropriately modified and adjusted by the technology and method well-known to those skilled in the art to obtain the desired target compound, and the obtained target compound can be further modified by substituent group, etc. to obtain other target compounds according to the method well-known to those skilled in the art.

[0603] Preparation example of the intermediates

[0604] Preparation example 1 of the intermediates: Preparation of daprodexil derivative 1 (SIAIS630006)

[0605]

[0606] Daprodexil derivative 1 (SIAIS630006) was prepared according to Scheme 1.

[0607] Step 1: Preparation of (E)-N-(4-(piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS524135)

[0608] To a 50 mL round bottom flask, was added (E)-3-(pyridin-3-yl)acrylic acid (1 g, 1.5 equiv), 10 mL DCM, and 0.7 mL oxalyl chloride (1.8 equiv) was added dropwise under ice bath. After the addition was complete, 2 drops of DMF was added to initiate the reaction. The reaction mixture was stirred at 60 °C for 3 h. A small amount of the reaction mixture was taken and dissolved in methanol. The reaction was monitored by LC-MS. When the corresponding methyl ester was formed, the reaction mixture was dried under vacuum. To another 50 mL round bottom flask, was added tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate (860 mg, 0.75 equiv), 10 mL DCM, and 1 mL TEA (1.5 equiv). The acyl chloride solution in DCM was added slowly to the mixture under ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS. When the reaction was complete, the reaction mixture was quenched with water. Silica gel was added to the mixture and the mixture was purified by column chromatography using 5% CH3OH / DCM as eluent to give a yellow oil. The yellow oil was dissolved in 10 mL DCM and 2 mL TFA was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. When the reaction was complete, the reaction mixture was dried under vacuum. The pH of the residue was adjusted to basic with saturated aqueous NaHCO3solution. The mixture was extracted with dichloromethane / methanol (10:1) three times. The organic phase was combined, washed with saturated NaCl aqueous solution twice, dried over anhydrous Na2SO4, and filtered. The filtrate was dried under vacuum. The residue was separated by C18 reverse phase column using CH3CN and water as eluent. The collected fractions were dried under vacuum and the residue was lyophilized to give a white solid (SIAIS524135, 823 mg, 64% overall yield for two steps). 1 H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.85-8.80 (m, 2H), 8.12-7.98 (m, 1H), 7.63 (d, J = 15.8 Hz, 1H), 7.02 (d, J = 15.9 Hz, 1H), 3.44-3.27 (m, 5H), 3.05-2.95 (m, 2H), 1.95 (dd, J = 13.6, 3.4 Hz, 2H), 1.60 (p, J = 7.1 Hz, 3H), 1.45-1.27 (m, 7H). HRMS (ESI) C 17 H 26 N3O + [M+H] + , calc. 288.2070; found, 288.2074.

[0609] Step 2: Preparation of (E)-N-(4-(1-(4-(piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630006)

[0610] To a 50 mL round bottom flask was added SIAIS524135 (860 mg, 1 equiv), 4-(4-(tert- butoxycarbonyl)piperazin-1-yl)benzoic acid (881 mg, 1 equiv), HATU (1.36. g, 1.2 equiv), 5 mL DMF, 1.6 mL DIPEA (3 equiv) at room temperature and reacted overnight at 60 °C. After the reaction was completed by LC-MS, the reaction mixture was filtered and the filtrate was separated by C18 reverse phase column with CH3CN and water as eluent. The collected fractions were spun dry to remove CH3CN and the residue was lyophilized to get a yellow solid which was directly used for the next reaction. To the solution of the yellow solid in 10 mL DCM was added 2 mL TFA and reacted at room temperature for 2 h. After the reaction was completed by LC-MS, the reaction solution was spun to remove the solvent. To the resulting residue was added saturated aqueous sodium bicarbonate solution to adjust the pH to basic. The organic phase was combined and extracted with dichloromethane / methanol (10:1) three times, washed with saturated NaCl aqueous solution twice, dried over anhydrous sodium sulfate and filtered. The filtrate was spun dry and the resulting residue was separated by C18 reverse phase column with CH3CN and water as eluent. The collected fractions were spun dry to remove CH3CN and the residue was lyophilized to get a yellow solid (SIAIS630006, 1.1 g, 64% overall yield for two steps). 1 HNMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.87 (dd, J = 18.8, 6.9 Hz, 2H), 8.15 (dd, J = 8.2, 5.7 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.50-7.42 (m, 2H), 7.26-7.16 (m, 2H), 7.05 (d, J = 15.8 Hz, 1H), 4.98 (br, 4H), 3.63 (s, 4H), 3.43 (s, 4H), 3.34 (t, J = 7.0 Hz, 2H), 1.94-1.75 (m, 2H), 1.70-1.56 (m, 3H), 1.49-1.40 (m, 2H), 1.40-1.32 (m, 2H), 1.31-1.19 (m, 2H). HRMS (ESI) C 28 H 38 N5O2 + [M+H] + , calculated 476.3020; found, 476.3024.

[0611] Intermediate Preparation Example 2: Preparation of daplnavir derivative 2 (SIAIS630020)

[0612] Daplnetide derivative 2 was prepared according to Scheme 1 using similar methods as for Daplnetide derivative 1, intermediate synthesis data and structure characterization data are as follows:

[0613]

[0614] (E)-N-(4-(4-(4-(piperazin-1-yl)benzoyl)piperazin-1-yl)butyl)-3-(pyridin-3- yl)acrylamide (SIAIS630020). (White solid, 258 mg, 63% overall yield for two steps). 1 H NMR (500 MHz, CD3OD) δ 9.07 (s, 1H), 8.82-8.77 (m, 2H), 8.08 (dd, J = 8.3, 5.6 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 15.9 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 15.9 Hz, 1H), 3.65 (br, 3H), 3.61-3.56 (m, 4H), 3.56-3.51 (m, 1H), 3.44-3.36 (m, 7H), 3.42-3.36 (m, 5H), 1.91-1.86 (m, 2H), 1.73-1.68 (m, 2H). HRMS (ESI) C 27 H 37 N6O2 + [M+H] + : calculated 477.2973, found 477.2975.

[0615] Intermediate Preparation Example 3: Preparation of Daplnetide derivative 3 (SIAIS631127)

[0616] Daplnetide derivative 3 was prepared according to Scheme 1 using similar methods as for Daplnetide derivative 1, intermediate synthesis data and structure characterization data are as follows:

[0617]

[0618] (E)-N-(4-(1-(4-(piperidin-4-yl)benzoyl)piperidin-4-yl)butyl)-3-(pyridin-3- yl)acrylamide (SIAIS631127). (Yellow oily liquid, 359 mg, 73% yield). 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.92-8.83 (m, 2H), 8.15 (dd, J = 8.2, 5.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.44 - 7.30 (m, 4H), 7.03 (d, J = 15.9 Hz, 1H), 4.60 (d, J = 12.9 Hz, 1H), 3.71 (d, J = 13.3 Hz, 1H), 3.52 (d, J = 13.1 Hz, 2H), 3.34 (t, J = 7.1 Hz, 2H), 3.20 - 3.10 (m, 3H), 3.02 - 2.94 (m, 1H), 2.85 (t, J = 12.8 Hz, 1H), 2.11 - 2.04 (m, 2H), 2.03 - 1.91 (m, 2H), 1.88 - 1.82 (m, 1H), 1.73 - 1.67 (m, 1H), 1.64-1.56 (m, 3H), 1.48-1.40 (m, 2H), 1.38-1.32 (m, 2H), 1.25 - 1.06 (m, 2H). HRMS (ESI) C 29 H 39 N4O2 + [M+H] + : calculated 475.3068, found 475.3072.

[0619] Intermediate Preparation Example 4: Preparation of daplimomab derivative 4 (SIAIS632004)

[0620] Daplimomab derivative 4 was prepared according to Scheme 1 using a similar method to that used for daplimomab derivative 1 in Intermediate Preparation Example 1. The intermediate synthesis data and structural characterization data are as follows:

[0621]

[0622] (E)-N-(4-(1-(6-(piperazin-1-yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632004). (Yellow oily liquid, 359 mg, yield 73%). 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.43 (d, J = 9.5 Hz, 1H), 6.76 (d, J = 15.8 Hz, 1H), 4.63 (d, J = 12.9 Hz, 1H), 3.99 (t, J = 5.3 Hz, 3H), 3.94 (d, J = 14.3 Hz, 1H), 3.44 (p, J = 1.6 Hz, 1H), 3.39 - 3.36 (m, 4H), 3.33 (br, 3H), 3.16 (p, J = 1.7 Hz, 2H), 1.88 (d, J = 13.8 Hz, 1H), 1.72 (d, J = 13.5 Hz, 1H), 1.60 - 1.56 (m, 3H), 1.48 - 1.43 (m, 2H), 1.37 - 1.33 (m, 2H), 1.25 - 1.22 (m, 2H). HRMS (ESI) C 26 H 36 N7O2 + [M+H] + : calculated 478.2925, found 478.2928.

[0623] Intermediate Preparation Example 5: Preparation of daplnavir derivative 5 (SIAIS631135)

[0624] Step 1: Preparation of 6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid (SIAIS631145)

[0625]

[0626] 6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid (SIAIS631145) was prepared according to Scheme 17.

[0627] 6-chloropyridazine-3-carboxylic acid (1 equiv) was dissolved in 20 mL DMF, DIPEA (5 equiv) was added, tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2 equiv) was added, and the reaction was stirred at 130 °C for 3 h. The reaction was poured into 50 mL water, and extracted with dichloromethane twice. The organic phase was combined and washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent (v / v): DCM to DCM / MeOH (10 / 1)) to give intermediate compound SIAIS631145, ESI [M+H] + 392.

[0628] Step 2: Preparation of (E)-N-(4-(l-(6-(4-(piperazin-l-yl)piperidin-l- yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS631135)

[0629]

[0630] Daplimomab derivative 5 ((E)-N-(4-(l-(6-(4-(piperazin-l-yl)piperidin-l- yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; SIAIS631135) (yellow oily liquid, 359 mg, 73% yield) was prepared using a similar procedure to that used for the preparation of daplimomab derivative 1, Intermediate Preparation Example 1, according to Scheme 1, using the intermediate SIAIS631145 prepared in Step 1. 1 H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.95-8.80 (m, 2H), 8.17-7.97 (m, 3H), 7.64 (d, J = 15.8 Hz, 1H), 7.01 (dd, J = 15.8, 5.5 Hz, 1H), 4.60-4.53 (m, 2H), 4.02 (d, J = 13.3 Hz, 1H), 3.87 (s, 1H), 3.72 (s, 7H), 3.46 (t, J = 12.5 Hz, 2H), 3.34 (t, J = 7.1 Hz, 3H), 3.20 (t, J = 12.2 Hz, 1H), 3.02-2.85 (m, 1H), 2.48 (d, J = 12.1 Hz, 2H), 2.19-2.01 (m, 2H), 1.98-1.85 (m, 1H), 1.79 (d, J = 13.0 Hz, 1H), 1.69-1.55 (m, 3H), 1.50-1.32 (m, 4H), 1.30-1.17 (m, 2H). HRMS (ESI) C 31 H 45 N8O2 + [M+H] + Calcd. 561.3660, Found 561.3665.

[0631] Intermediate Preparation Example 6: Preparation of daplimomab derivative 6 (SIAIS632025)

[0632] Daplimomab derivative 6 was prepared according to Scheme 1 using a similar procedure to that used for the preparation of daplimomab derivative 1, Intermediate Preparation Example 1, using the intermediate synthesis data and structure characterization data as follows:

[0633]

[0634] (E)-N-(4-(1-(6-(piperazin-1-yl)nicotinoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632025). (Yellow oily liquid, 241 mg, yield 74%). 1 H NMR (500MHz, CD3OD) δ9.14(s,1H),8.92(s,1H),8.73(d,J=8.2Hz,1H),8.25(d,J=2.1Hz,1H),8.09(s,1H),7. 73–7.59(m,2H),7.00(d,J=9.0Hz,1H),6.92(d,J=15.8Hz,1H),3.97–3.90(m,4H),3.84(s,2H),3.35–3.32(m, 8H),1.80(br,2H),1.63-1.56(m,3H),1.46-1.40(m,2H),1.39–1.28(m,2H),1.19(br,2H).HRMS(ESI)C 27 H 37 N6O2 + [M+H] + :Calculated value 477.2973, measured value 477.2976.

[0635] Intermediate Preparation Example 7: Preparation of Dapoline Derivative 7 (SIAIS632044)

[0636] Step 1: Preparation of 6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)nicotinic acid (SIAIS631147)

[0637]

[0638] 6-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)nicotinic acid (SIAIS 631147) was prepared according to Scheme 17.

[0639] 6-Chloronicotinic acid (1 equiv) was dissolved in 20 mL of DMF, and DIPEA (5 equiv) was added, followed by tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2 equiv). The reaction mixture was allowed to react at 130°C for 3 h. The reaction solution was poured into 50 mL of water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (v / v): DCM to DCM / MeOH (10 / 1)) to obtain the intermediate compound SIAIS631147, ESI [M+H]+ 391.

[0640] Step 2: Preparation of (E)-N-(4-(l-(6-(4-(piperazin-l-yl)piperidin-l- yl)nicotinoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632044)

[0641]

[0642] Daplimomab derivative 7 ((E)-N-(4-(l-(6-(4-(piperazin-l-yl)piperidin-l- yl)nicotinoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (SIAIS632044) was prepared using a similar procedure to that used for the preparation of daplimomab derivative 1, intermediate preparation example 1, according to scheme 1, using the intermediate SIAIS631147 prepared in step 1. (White solid, 132 mg, 30% yield). 1 H NMR (500 MHz, CD3OD) δ 9.04 (s, 1H), 8.80 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.04 - 7.94 (m, 1H), 7.86 (dd, J = 9.2, 2.4 Hz, 1H), 7.63 (d, J = 15.8 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 6.91 (d, J = 15.9 Hz, 1H), 4.48 (d, J = 14.1 Hz, 4H), 3.54 - 3.49 (m, 6H), 3.34 (d, J = 7.2 Hz, 2H), 3.26 - 3.16 (m, 3H), 2.25 (d, J = 11.6 Hz, 4H), 1.87 - 1.76 (m, 5H), 1.62 - 1.58 (m, 4H), 1.46 - 1.41 (m, 2H), 1.38 - 1.28 (m, 2H), 1.23 - 1.13 (m, 2H). HRMS (ESI) C 32 H 46 N7O2 + [M+H] + : calculated 560.3708, found 560.3711.

[0643] Intermediate Preparation Example 8: Preparation of (3-(((S)-l-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l- oxobutan-2-yl)amino)-3-oxopropanoic acid (SIAIS352066)

[0644]

[0645] Compound (SIAIS352066) was prepared according to the procedure of Scheme 14, under appropriate conditions as can be appreciated in the art, except that the starting diacid used was malonic acid. Compound (SIAIS352066) was obtained as a white solid, 0.82 g, 68% yield. ESI [M+H] + 517.

[0646] Intermediate Preparation Example 9: Preparation of 16-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthioazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)- 16-oxohexadecanoic acid (SIAIS164189)

[0647]

[0648] Compound (SIAIS164189) was prepared according to the procedure of Scheme 14, under appropriate conditions as can be appreciated in the art, except that the starting diacid used was hexadecandioic acid. Compound (SIAIS164189) was obtained as a white solid, 0.88 g, 67% yield, ESI [M+H] + 699.

[0649] Intermediate Preparation Example 10: Preparation of 3-(4-((8-bromooctyl)oxy)-1- carbonylisochromane-2-yl)piperidine-2,6-dione (SIAIS1222063)

[0650]

[0651] Referring to Scheme 12, 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.8 mmol) was dissolved in 20 mL DMF, K2CO3(0.27 g, 1.9 mmol) was added, stirred for 15 min, 1,8-dibromo octane (2.0 g, 7.6 mmol) was added, heated to 80 °C, and the reaction was allowed to proceed for 12 h. The reaction was poured into 50 mL water, extracted with dichloromethane twice, the organic phase was washed with saturated brine, the solvent was removed under reduced pressure, and column chromatography on silica gel (eluent (v / v): DCM to DCM / MeOH (10 / 1)) gave SIAIS1222063 (white powder, yield 32%). ESI [M+H] + 451.

[0652] Example 11: Preparation of intermediate 4-((8-bromooctyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS1224003)

[0653]

[0654] The compound (SIAIS1224003) was obtained according to the procedure of Scheme 11 under appropriate conditions as understood in the art, except that the starting compounds used were 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione and 1,8-dibromo octane. The compound (SIAIS1224003) was obtained as a white solid, 0.92 g, 71% yield. ESI [M+H] + 481.

[0655] Example of preparation of a compound of the application

[0656] Example 1: Preparation of (E)-N-(4-(1-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propionyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS630009)

[0657] According to Scheme 15, the Nampt inhibitor, namely the daprodexil derivative 1 (SIAIS630006) (0.02 mmol, 1 equiv), the intermediate LM (SIAIS151026; 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid; CAS Registry Number 2225940-46-3) (0.02 mmol, 1 equiv), HATU (0.024 mmol, 1.2 equiv), 2 mL of DMF, DIPEA (0.06 mmol, 3 equiv) were successively added in a reaction flask at room temperature and the reaction was left overnight at room temperature. After the end of the reaction, which was monitored by LC-MS, the reaction mixture was filtered and the filtrate was separated by HPLC-prep, the collected fractions were evaporated to remove acetonitrile and the residue was lyophilized to obtain the final target compound (SIAIS630009) as a yellow solid, 6.3 mg, 46% yield. 1HNMR (500MHz, DMSO-d6) δ 11.09 (s, 1H), 9.00 (s, 1H), 8.80-8.75 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.33 (t, J = 5.7 Hz, 1H), 7.88 (dd, J = 8.2, 5.4 Hz, 1H), 7.62-7.49 (m, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 15.9 Hz, 1H), 6.79 (s, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.67-3.50 (m, 9H), 3.30-3.13 (m, 6H), 2.92-2.83 (m, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.63-2.55 (m, 1H), 2.49-2.44 (m, 1H), 2.01-1.96 (m, 1H), 1.67 (d, J = 12.5 Hz, 2H), 1.49-1.42 (m, 2H), 1.36-1.18 (m, 4H), 1.09-1.00 (m, 2H). HRMS (ESI) C 44 H 51 N8O7 + [M+H] + , calculated 803.3875; found, 803.3879.

[0658] Example 2: Preparation of (E)-N-(4-(1-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630010)

[0659] The target compound (SIAIS630010) (yellow solid, 6.8 mg, yield 49%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151019; 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoic acid; CAS Registry Number 2225940-47-4). 1H NMR (500MHz, DMSO-d6) δ 11.09 (s, 1H), 8.99 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.37 - 8.27 (m, 1H), 7.86 (dd, J=8.2, 5.3 Hz, 1H), 7.58 (dd, J=8.6, 7.0 Hz, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.88 (d, J=15.9 Hz, 1H), 6.67 (s, 1H), 5.05 (dd, J=12.7, 5.4 Hz, 1H), 3.63 - 3.57 (m, 6H), 3.34 (t, J=7.2 Hz, 3H), 3.27 - 3.14 (m, 6H), 2.93-2.85 (m, 2H), 2.63 - 2.53 (m, 1H), 2.54-2.50 (m, 1H), 2.46 (t, J=7.1 Hz, 2H), 2.07 - 1.97 (m, 1H), 1.82 (p, J=7.1 Hz, 2H), 1.66 (d, J=12.5 Hz, 2H), 1.53 - 1.41 (m, 3H), 1.31-1.20 (m, 4H), 1.11-1.00 (m, 2H). HRMS (ESI) C 45 H 53 N8O7 + [M+H] + , calculated 817.4032; found, 817.4038.

[0660] Example 3: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630011)

[0661] The target compound (SIAIS630011) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151020; 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid; CAS Registry Number 2225940-48-5) following the procedure of Example 1 (yellow solid, 6.0 mg, yield 43%). 1H NMR (500MHz, CD3OD) δ8.85(s,1H),8.63(d,J=5.1Hz,1H),8.36(d,J=8.1Hz,1H),7.77–7.70(m, 1H),7.63–7.48(m,2H),7.31(d,J=8.8Hz,2H),7.07(d,J=8.5Hz,1H),6.99(dd,J=17.8,7.9Hz, 3H),6.81(d,J=15.8Hz,1H),5.03(dd,J=12.6,5.5Hz,1H),3.70(dt,J=16.9,5.3Hz,4H),3.41– 3.35(m,2H),3.35-3.33(m,2H),3.24-3.21(m,6H),2.88-2.81(m,1H),2.77–2.71(m,1H),2.5 2-2.51(m,2H),2.13–2.02(m,1H),1.75(t,J=3.3Hz,5H),1.59(p,J=6.9Hz,4H),1.43(br,2H), 1.37-1.32(m,2H),1.29(br,2H),.18(br,2H).HRMS(ESI)C 46 H 55 N8O7 + [M+H] + ,Calculated value 831.4188; Measured value ,831.4190.

[0662] Example 4: Preparation of (E)-N-(4-(1-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632014)

[0663] Referring to the method in Example 1, according to Scheme 15, dapoline derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204057; (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid; CAS registration number 2103656-92-2) were used to prepare the target compound (SIAIS632014) (white solid, 5.2 mg, yield 17%). 1HNMR (500MHz, CD3OD) δ 8.96 (d, J = 9.8 Hz, 1H), 8.73 (dd, J = 7.5, 5.6 Hz, 1H), 8.60 (dd, J = 23.2, 8.3 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.61 (dd, J = 15.8, 2.7 Hz, 1H), 7.38 - 7.26 (m, 3H), 7.12 - 6.98 (m, 3H), 6.88 (dd, J = 15.8, 4.2 Hz, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 16.9 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H), 3.78 (br, 2H), 3.54 - 3.47 (m, 2H), 3.40 - 3.32 (m, 12H), 2.97 - 2.86 (m, 1H), 2.83 - 2.77 (m, 1H), 2.54 - 2.44 (m, 1H), 2.25 - 2.17 (m, 1H), 1.75 (br, 1H), 1.58 (q, J = 7.3 Hz, 3H), 1.43 (br, 2H), 1.37 - 1.25 (m, 3H), 1.16 (br, 2H). HRMS (ESI) C 43 H 51 N8O6 + [M+H] + , calculated 775.3926; found, 775.3928.

[0664] Example 5: Preparation of (E)-N-(4-(1-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632015)

[0665] The target compound (SIAIS632015) (white solid, 4.7 mg, yield 15%) was prepared according to Scheme 15, using daprodustat derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204085; 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butanoic acid; CAS Registry Number 1781226-49-0) following the procedure of Example 1. 1HNMR (500MHz, CD3OD) δ 9.00 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.69 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 8.2, 5.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.37 - 7.29 (m, 3H), 7.10 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.95 - 6.89 (m, 2H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 16.8 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 3.71 (dt, J = 32.4, 5.3 Hz, 4H), 3.39 - 3.35 (m, 7H), 3.24-3.17 (m, 5H), 3.03 - 2.89 (m, 1H), 2.84-2.79 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 2.56 - 2.40 (m, 1H), 2.24 - 2.17 (m, 1H), 2.02 (t, J = 6.9 Hz, 2H), 1.79 (br, 1H), 1.61 (t, J = 7.4 Hz, 4H), 1.48-1.45 (m, 2H), 1.39-1.34 (m, 2H), 1.18 (br, 2H). HRMS (ESI) C 45 H 55 N8O6 + [M+H] + , calculated 803.4239; found, 803.4240.

[0666] Example 6: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632016)

[0667] The target compound (SIAIS632016) (white solid, 4.1 mg, yield 14%) was prepared according to Scheme 15, using daprodustat derivative 1 (SIAIS630006) and intermediate LM (SIAIS1210133; 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)pentanoic acid; CAS Registry Number 2338824-29-4) following the procedure of Example 1. 1HNMR (500MHz, CD3OD) δ 9.07 (d, J = 2.0 Hz, 1H), 8.87 - 8.75 (m, 2H), 8.12 (dd, J = 8.2, 5.8 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 15.3, 8.1 Hz, 3H), 7.19 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 15.8 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.0 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 3.81 - 3.68 (m, 4H), 3.42 - 3.35 (m, 10H), 3.27 (t, J = 5.2 Hz, 3H), 3.00 - 2.89 (m, 1H), 2.83 - 2.75 (m, 1H), 2.58 - 2.42 (m, 3H), 2.23 - 2.13 (m, 1H), 1.82 - 1.70 (m, 5H), 1.59 (q, J = 7.3 Hz, 3H), 1.47 - 1.40 (m, 2H), 1.38 - 1.30 (m, 2H), 1.17 (br, 2H). HRMS (ESI) C 46 H 57 N8O6 + [M+H] + , calculated 817.4396; found 817.4398.

[0668] Example 7: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632017)

[0669] The target compound (SIAIS632017) (white solid, 5.3 mg, yield 16%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204061; 6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)hexanoic acid: CAS Registry Number 2338824-30-7). 1HNMR (500MHz, DMSO-d6) δ 11.01 (s, 1H), 9.00 (d, J = 26.7 Hz, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.54 (d, J = 15.8 Hz, 1H), 7.32 - 7.23 (m, 3H), 7.00 - 6.75 (m, 5H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.26 (d, J = 17.4 Hz, 1H), 4.16 (d, J = 17.4 Hz, 1H), 3.58 (br, 6H), 3.28 - 3.07 (m, 9H), 2.95-2.86 (m, 3H), 2.65 - 2.58 (m, 1H), 2.36 (dd, J = 8.3, 6.5 Hz, 2H), 2.31 - 2.22 (m, 1H), 2.07 - 1.95 (m, 1H), 1.71 - 1.52 (m, 5H), 1.49-1.35 (m, 5H), 1.32 (br, 2H), 1.25 (t, J = 7.6 Hz, 2H), 1.11 - 0.99 (m, 2H). HRMS (ESI) C 47 H 59 N8O6 + [M+H] + , calculated 831.4552; found, 831.4554.

[0670] Example 8: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632018)

[0671] The target compound (SIAIS632018) (white solid, 5.7 mg, yield 17%) was prepared according to Scheme 15, using daprodustat derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204063; 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoic acid; CAS Registry Number 22338824-32-9) following the procedure of Example 1. 1HNMR (500MHz, CD3OD) δ 9.00 (s, 1H), 8.76 (d, J = 5.6 Hz, 1H), 8.70 (dt, J = 8.2, 1.8 Hz, 1H), 8.01 (dd, J = 8.3, 5.6 Hz, 1H), 7.62 (d, J = 15.8 Hz, 1H), 7.41 - 7.29 (m, 3H), 7.13 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.94 - 6.85 (m, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.34 (d, J = 16.9 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 3.70 (dt, J = 22.2, 5.3 Hz, 4H), 3.34 (d, J = 7.0 Hz, 5H), 3.29 - 3.21 (m, 7H), 2.95-2.88 (m, 1H), 2.81-2.76 (m, 1H), 2.52 - 2.38 (m, 3H), 2.20-2.16 (m, 1H), 1.72-1.64 (m, 4H), 1.59 (p, J = 7.4 Hz, 4H), 1.52 - 1.38 (m, 6H), 1.36-1.32 (m, 3H), 1.16 (br, 2H). HRMS (ESI) C 48 H 61 N8O6 + [M+H] + , calculated 845.4709; found, 845.4711.

[0672] Example 9: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630012)

[0673] The target compound (SIAIS630012) (yellow solid, 6.1 mg, yield 44%) was prepared according to Scheme 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS151086; 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid: CAS Registry Number 2225940-50-9) following the procedure of Example 1. 1H NMR (500MHz, DMSO-d6) δ 11.09 (s, 1H), 8.96 (d, J = 26.7 Hz, 1H), 8.74 (d, J = 20.1 Hz, 1H), 8.39 (d, J = 69.3 Hz, 2H), 7.82 (d, J = 44.1 Hz, 1H), 7.58 (dd, J = 8.6, 7.1 Hz, 1H), 7.52 (dd, J = 15.9, 9.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.96 (dd, J = 9.2, 4.5 Hz, 2H), 6.92 - 6.80 (m, 1H), 6.54 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.62 - 3.53 (m, 6H), 3.30 (t, J = 7.1 Hz, 3H), 3.25-3.15 (m, 6H), 2.93-2.85 (m, 2H), 2.62 - 2.54 (m, 1H), 2.53 - 2.52 (m, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.07 - 1.98 (m, 1H), 1.72-1.63 (m, 2H), 1.61 - 1.43 (m, 7H), 1.39-1.30 (m, 6H), 1.25 (t, J = 7.5 Hz, 2H), 1.10-0.99 (m, 2H). HRMS (ESI) C 48 H 59 N8O7 + [M+H] + , calculated 859.4501 ; found, 859.4505.

[0674] Example 10: Preparation of (E)-N-(4-(1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630013)

[0675] The target compound (SIAIS630013) (white solid, 3.1 mg, yield 24%) was prepared according to Scheme 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS171090; 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)thio)acetic acid; CAS Registry Number 2378582-40-0) following the procedure of Example 1. 1HNMR (500MHz, CD3OD) δ 8.94 (d, J = 17.6 Hz, 1H), 8.73 (d, J = 6.4 Hz, 1H), 8.61 (s, 1H), 7.93 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.66 - 7.52 (m, 2H), 7.32 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.87 (t, J = 14.0 Hz, 1H), 5.16 (dd, J = 13.4, 5.2 Hz, 1H), 4.56 (d, J = 17.4 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.00 (s, 2H), 3.69 (t, J = 9.4 Hz, 5H), 3.35 - 3.33 (m, 3H), 3.22 (t, J = 5.3 Hz, 6H), 2.95-2.85 (m, 1H), 2.83 - 2.72 (m, 1H), 2.54 - 2.42 (m, 1H), 2.21-2.15 (m, 1H), 1.77 (br, 2H), 1.67 - 1.50 (m, 5H), 1.47-1.40 (m, 2H), 1.39 - 1.27 (m, 2H), 1.18 (br, 2H). HRMS (ESI) C 43 H 50 N7O6S + [M+H] + , calculated 792.3538; found, 792.3540.

[0676] Example 11: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)pentanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630014)

[0677] The target compound (SIAIS630014) (white solid, 4.0 mg, yield 29%) was prepared according to Scheme 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS171079; 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)thio)pentanoic acid; CAS Registry Number 2378582-43-3) following the procedure of Example 1. 1HNMR (500MHz, DMSO-d6) δ 10.98 (s, 1H), 8.92 (d, J = 45.5 Hz, 1H), 8.70 (d, J = 38.9 Hz, 1H), 8.50 - 8.18 (m, 2H), 7.82 (s, 1H), 7.64 (dd, J = 7.5, 1.2 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.26 (d, J = 8.3 Hz, 2H), 6.99 - 6.92 (m, 2H), 6.89 - 6.76 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 17.4 Hz, 1H), 4.22 (d, J = 17.4 Hz, 1H), 3.60-3.55 (m, 10H), 3.24-3.16 (m, 5H), 3.11 (t, J = 6.5 Hz, 2H), 2.95-2.85 (m, 2H), 2.65-2.54 (m, 1H), 2.49-2.44 (m, 1H), 2.41-2.36 (m, 2H), 2.05-1.95 (m, 1H), 1.68-1.62 (m, 5H), 1.52-1.40 (m, 2H), 1.35-1.20 (m, 4H), 1.13-0.96 (m, 2H). HRMS (ESI) C 46 H 56 N7O6S + [M+H] + , calculated 834.4007; found, 834.4011.

[0678] Example 12: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630037)

[0679] The target compound (SIAIS6320037) (white solid, 4.6 mg, yield 33%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS171091; 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)thio)hexanoic acid; CAS Registry Number 2378582-44-4) following the procedure of Example 1. 1H NMR (500MHz, CD3OD) δ 8.77 (s, 1H), 8.56 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.59-7.57 (m, 1H), 7.52 (dd, J = 14.7, 7.1 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 15.8 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.40 (d, J = 17.3 Hz, 1H), 3.69 (dt, J = 25.7, 5.2 Hz, 5H), 3.35 (br, 3H), 3.29 - 3.22 (m, 5H), 3.08 (td, J = 7.1, 2.4 Hz, 3H), 2.95 - 2.85 (m, 1H), 2.82 - 2.74 (m, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.21 - 2.10 (m, 1H), 1.72 - 1.55 (m, 10H), 1.45 - 1.40 (m, 2H), 1.36 - 1.30 (m, 4H), 1.16 (br, 2H). HRMS (ESI) C 47 H 58 N7O6S + [M+H] + , calculated 848.4164; found, 848.4168.

[0680] Example 13: Preparation of (E)-N-(4-(1-(4-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)ethoxy)acetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630038)

[0681] The target compound (SIAIS630038) (white solid, 4.3 mg, yield 31%) was prepared according to Scheme 15, using daprodustat derivative 1 (SIAIS630006) and intermediate LM (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)acetic acid; CAS Registry Number 2378582-21-7) following the procedure of Example 1. 1HNMR (500MHz, CD3OD) δ 8.84 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.64 (d, J = 6.7 Hz, 1H), 7.58 (d, J = 15.9 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 15.9 Hz, 1H), 5.14 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.23 (s, 2H), 3.74 (td, J = 6.2, 2.1 Hz, 2H), 3.68 (br, 2H), 3.59 (t, J = 5.3 Hz, 2H), 3.33 (d, J = 7.2 Hz, 2H), 3.29 (d, J = 6.2 Hz, 2H), 3.21 (br, 4H), 3.08 (br, 1H), 2.95 - 2.85 (m, 1H), 2.83 - 2.73 (m, 1H), 2.55 - 2.45 (m, 1H), 2.20 - 2.10 (m, 1H), 1.77 (br, 2H), 1.59 (p, J = 7.1 Hz, 3H), 1.47 - 1.40 (m, 2H), 1.39 - 1.27 (m, 4H), 1.21 - 1.13 (m, 2H). HRMS (ESI) C 45 H 54 N7O7S + [M+H] + , calculated 836.3800; found, 836.3805.

[0682] Example 14: Preparation of (E)-N-(4-(1-(4-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630039)

[0683] The target compound (SIAIS630039) was prepared according to Scheme 15 using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1213131; 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetic acid; CAS Registry Number 2378582-22-8) following the procedure of Example 1 (white solid, 4.2 mg, 31% yield). 1 H NMR (500 MHz, CD3OD) δ 8.89 (s, 1H), 8.67 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.70-7.64 (m, 2H), 7.59 (d, J = 15.9 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 15.8 Hz, 1H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.41 (d, J = 17.3 Hz, 1H), 4.25 (s, 2H), 3.72-3.60 (m, 11H), 3.35-3.33 (m, 2H), 3.29-3.21 (m, 5H), 3.05 (br, 1H), 2.93-2.84 (m, 1H), 2.81-2.74 (m, 1H), 2.54-2.45 (m, 1H), 2.18-2.10 (m, 1H), 1.75 (br, 2H), 1.59 (p, J = 7.1 Hz, 3H), 1.47-1.39 (m, 2H), 1.37-1.26 (m, 4H), 1.21-1.11 (m, 2H). HRMS (ESI) C 47 H 58 N7O8S + [M+H] + , calculated 880.4062; found, 880.4065.

[0684] Example 15: Preparation of (E)-N-(4-(1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)ethyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630130)

[0685] According to Scheme 16, the Nampt inhibitor, i.e. daprodustat derivative 1 (SIAIS630006) (0.04 mmol, 1 equiv), intermediate LM (SIAIS213137; 3-(4-(2-bromoethylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-57-9) (0.048 mmol, 1.2 equiv), 2 mL DMF, DIPEA (0.12 mmol, 3 equiv) were sequentially added into a reaction vial at room temperature, and reacted at 60 °C for 8 h. After the reaction was detected by LC-MS, the reaction mixture was filtered, and the filtrate was separated by HPLC preparation. The collected fractions were evaporated to remove acetonitrile, and the residue was lyophilized to obtain the final target compound (SIAIS630130) (white solid, 6.2 mg, yield 20%). 1 H NMR (500 MHz, CD3OD) δ 8.92 (s, 1H), 8.70 (d, J = 5.3 Hz, 1H), 8.50 (dt, J = 8.2, 1.8 Hz, 1H), 7.92 - 7.74 (m, 3H), 7.67 - 7.56 (m, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 15.8 Hz, 1H), 5.19 (dd, J = 13.5, 5.3 Hz, 1H), 4.56 (d, J = 17.5 Hz, 1H), 4.49 (d, J = 17.7 Hz, 1H), 3.81 (br, 1H), 3.72 (t, J = 6.6 Hz, 1H), 3.54 - 3.40 (m, 6H), 3.33 (d, J = 7.2 Hz, 4H), 3.17 (t, J = 6.6 Hz, 1H), 2.98 - 2.85 (m, 1H), 2.84 - 2.75 (m, 1H), 2.60-2.56 (m, 1H), 2.25-2.15 (m, 1H), 1.76 (d, J = 54.3 Hz, 2H), 1.65-1.54 (m, 4H), 1.45-1.27 (m, 1H), 1.38 - 1.27 (m, 2H), 1.15 (br, 2H). HRMS (ESI) C 43 H 52 N7O5S + [M+H] + , calculated 778.3745; found 778.3748.

[0686] Example 16: Preparation of (E)-N-(4-(1-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)propyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630131)

[0687] The target compound (SIAIS630131) (white solid, 6.4 mg, yield 21%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS213132; 3-(4-(3-bromopropylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-58-0) following the procedure of Example 15. 1 HNMR (500MHz, CD3OD) δ 8.78 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.72 - 7.57 (m, 3H), 7.52 - 7.43 (m, 2H), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 15.9 Hz, 1H), 5.09 (dd, J = 13.4, 5.2 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.4 Hz, 1H), 3.77 (d, J = 65.1 Hz, 3H), 3.54 (br, 2H), 3.25 (dd, J = 16.0, 7.7 Hz, 4H), 3.15 - 3.00 (m, 7H), 2.86-2.79 (m, 1H), 2.72-2.68 (m, 1H), 2.48-2.40 (m, 1H), 2.13-2.09 (m, 1H), 2.06 - 1.94 (m, 2H), 1.81 - 1.58 (m, 2H), 1.49 (p, J = 7.1 Hz, 4H), 1.37 - 1.27 (m, 2H), 1.27 - 1.16 (m, 3H), 1.06 (br, 2H). HRMS (ESI) C 44 H 54 N7O5S + [M+H] + , calculated 792.3902; found, 792.3905.

[0688] Example 17: Preparation of (E)-N-(4-(1-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)butyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630123)

[0689] The target compound (SIAIS630123) (white solid, 5.6 mg, yield 23%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-59-1) by reference to the method of Example 15. 1 HNMR (500MHz, CD3OD) δ 8.88 (d, J = 2.2 Hz, 1H), 8.66 (dd, J = 5.3, 1.5 Hz, 1H), 8.39 (dt, J = 8.1, 1.8 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.63 - 7.55 (m, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 15.8 Hz, 1H), 5.20 (dd, J = 13.4, 5.2 Hz, 1H), 4.52 (d, J = 17.3 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 3.90 (d, J = 68.5 Hz, 3H), 3.65 (br, 2H), 3.35 (d, J = 7.1 Hz, 4H), 3.26 - 3.11 (m, 9H), 2.98-2.91 (m, 1H), 2.84-2.79 (m, 1H), 2.60-2.51 (m, 1H), 2.24-2.19 (m, 1H), 2.01-1.94 (m, 2H), 1.84-1.73 (m, 3H), 1.61 (p, J = 7.3 Hz, 3H), 1.48-1.42 (m, 2H), 1.40 - 1.28 (m, 3H), 1.18 (br, 2H). HRMS (ESI) C 45 H 56 N7O5S + [M+H] + , calculated 806.4058; found, 806.4061.

[0690] Example 18: Preparation of (E)-N-(4-(l-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)thio)pentyl)piperazin-l-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630132)

[0691] The target compound (SIAIS630132) (white solid, 6.1 mg, yield 19%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216049; 3-(4-((5-bromopentyl)thio)-l-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-60-4) following the procedure of Example 15. 1 H NMR (500MHz, CD3OD) δ 8.89 (d, J = 2.1 Hz, 1H), 8.67 (dd, J = 5.4, 1.5 Hz, 1H), 8.45 (dt, J = 8.2, 1.8 Hz, 1H), 7.80 (dd, J = 8.2, 5.3 Hz, 1H), 7.66 (ddd, J = 7.5, 6.5, 1.0 Hz, 2H), 7.55 (dd, J = 15.7, 8.1 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 15.9 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.3 Hz, 1H), 4.41 (d, J = 17.4 Hz, 1H), 3.94 - 3.74 (m, 3H), 3.64 (br, 2H), 3.33 (d, J = 7.1 Hz, 4H), 3.24 - 3.05 (m, 9H), 2.95 - 2.88 (m, 1H), 2.84 - 2.75 (m, 1H), 2.58 - 2.49 (m, 1H), 2.22 - 2.16 (m, 1H), 1.86 - 1.67 (m, 6H), 1.64 - 1.52 (m, 5H), 1.45 - 1.39 (m, 2H), 1.36 - 1.26 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 46 H 58 N7O5S + [M+H] + , calculated 820.4215; found, 820.4217.

[0692] Example 19: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)hexyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630133)

[0693] The target compound (SIAIS630133) (white solid, 6.4 mg, yield 19%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216133; 3-(4-(6-bromohexylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: CAS Registry Number 2378582-61-5) by reference to the method of Example 15. 1 HNMR (500MHz, CD3OD) δ 8.88 (d, J = 2.1 Hz, 1H), 8.65 (dd, J = 5.3, 1.5 Hz, 1H), 8.41 (dt, J = 8.1, 1.8 Hz, 1H), 7.77 (dd, J = 8.1, 5.3 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.61 - 7.52 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 15.9 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.47 (d, J = 17.3 Hz, 1H), 4.41 (d, J = 17.3 Hz, 1H), 3.98 - 3.77 (m, 3H), 3.64 (br, 2H), 3.33 (d, J = 7.0 Hz, 3H), 3.19 - 3.03 (m, 10H), 2.95-2.86 (m, 1H), 2.82-2.77 (m, 1H), 2.58-2.49 (m, 1H), 2.21-2.16 (m, 1H), 1.81 - 1.67 (m, 6H), 1.62-1.51 (m, 5H), 1.46-1.38 (m, 4H), 1.36-1.30 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 47 H 60 N7O5S + [M+H] + , calculated 834.4371; found, 834.4375.

[0694] Example 20: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)heptyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630134)

[0695] The target compound (SIAIS630134) (white solid, 6.7 mg, yield 20%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216135: 3-(4-(7-bromoheptylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-62-6) by reference to the method of Example 15. 1 HNMR (500MHz, CD3OD) δ 8.86 (d, J = 2.2 Hz, 1H), 8.64 (dd, J = 5.3, 1.5 Hz, 1H), 8.39 (dt, J = 8.2, 1.8 Hz, 1H), 7.75 (dd, J = 8.1, 5.3 Hz, 1H), 7.65 (dt, J = 7.0, 1.3 Hz, 2H), 7.62 - 7.47 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 15.8 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.40 (d, J = 17.3 Hz, 1H), 3.98 - 3.79 (m, 3H), 3.64 (br, 2H), 3.33 (d, J = 7.1 Hz, 3H), 3.26 - 3.00 (m, 10H), 2.93-2.87 (m, 1H), 2.82-2.76 (m, 1H), 2.58-2.49 (m, 1H), 2.21-2.16 (m, 1H), 1.82-1.74 (m, 3H), 1.72-1.65 (m, 2H), 1.61-1.56 (m, 3H), 1.51-1.47 (m, 2H), 1.46-1.28 (m, 9H), 1.16 (br, 2H). HRMS (ESI) C 48 H 62 N7O5S + [M+H] + , calculated 848.4528; found, 848.4531.

[0696] Example 21: Preparation of (E)-N-(4-(1-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)hexyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630135)

[0697] The target compound (SIAIS630135) (white solid, 6.9 mg, yield 20%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216137; 3-(4-((8-bromooctyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-63-7) following the procedure of Example 15. 1 H NMR (500MHz, CD3OD) δ 8.84 (d, J = 14.4 Hz, 1H), 8.63 (dd, J = 11.6, 5.1 Hz, 1H), 8.40 - 8.29 (m, 1H), 7.77 - 7.68 (m, 1H), 7.69 - 7.62 (m, 2H), 7.62 - 7.50 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.82 (t, J = 14.1 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.40 (d, J = 17.3 Hz, 1H), 3.96 (d, J = 13.4 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.33 (d, J = 5.1 Hz, 6H), 3.24 - 3.02 (m, 8H), 2.95 - 2.85 (m, 1H), 2.83 - 2.75 (m, 1H), 2.58 - 2.49 (m, 1H), 2.21 - 2.16 (m, 1H), 1.75 (br, 3H), 1.68 (q, J = 7.4 Hz, 2H), 1.59 (p, J = 7.3 Hz, 3H), 1.53 - 1.28 (m, 12H), 1.18 (br, 2H). HRMS (ESI) C 49 H 64 N7O5S + [M+H] + , calculated 862.4684; found, 862.4689.

[0698] Example 22: Preparation of (E)-N-(4-(1-(4-(4-(11-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)undecyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630136)

[0699] The target compound (SIAIS630136) (white solid, 7.0 mg, yield 20%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1220015; 3-(4-((11-bromoundecyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-66-0) by reference to the method of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.83 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 5.2, 1.6 Hz, 1H), 8.33 (dt, J = 8.2, 1.8 Hz, 1H), 7.70 (dd, J = 8.1, 5.2 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.59 - 7.50 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.95 - 3.78 (m, 3H), 3.67 (br, 2H), 3.33 (d, J = 7.1 Hz, 3H), 3.24 - 3.02 (m, 10H), 2.94 - 2.86 (m, 1H), 2.81 - 2.76 (m, 1H), 2.57 - 2.48 (m, 1H), 2.21 - 2.15 (m, 1H), 1.84 - 1.72 (m, 3H), 1.69 - 1.63 (m, 2H), 1.60 - 1.55 (m, 2H), 1.50 - 1.24 (m, 20H), 1.15 (br, 3H). HRMS (ESI) C 52 H 70 N7O5S + [M+H] + , calculated 904.5154; found, 904.5155.

[0700] Example 23: Preparation of (E)-N-(4-(1-(4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)pent-4-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630129)

[0701] The target compound (SIAIS630129) (white solid, 5.3 mg, yield 17%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS255121; 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1- yl methanesulfonate; CAS Registry Number 2138441-31-1) in reference to the method of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.75 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 5.2, 1.5 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.63 (dd, J = 8.1, 5.2 Hz, 1H), 7.57 (dd, J = 7.8, 1.0 Hz, 1H), 7.48 (d, J = 15.9 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 15.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.2 Hz, 1H), 4.48 (d, J = 17.5 Hz, 1H), 4.41 (d, J = 17.5 Hz, 1H), 3.88 (br, 2H), 3.61 (br, 3H), 3.33 - 3.25 (m, 2H), 3.24-3.22 (m, 5H), 3.14-2.99 (m, 2H), 2.86-2.79 (m, 1H), 2.72-2.67 (m, 1H), 2.60 (t, J = 6.9 Hz, 2H), 2.48-2.40 (m, 1H), 2.14-1.99 (m, 3H), 1.67 (d, J = 53.2 Hz, 2H), 1.52-1.46 (m, 3H), 1.38-1.27 (m, 2H), 1.28-1.18 (m, 3H), 1.07 (br, 3H). HRMS (ESI) C 46 H 54 N7O5 + [M+H] + , calculated 784.4181; found, 784.4183.

[0702] Example 24: Preparation of (E)-N-(4-(l-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)hex-5-yn-l-yl)piperazin-l-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630119)

[0703] The target compound (SIAIS630119) (white solid, 5.6 mg, yield 24%) was prepared according to Scheme 16, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS255119; 6-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)hex-5-yn-l- yl methanesulfonate; CAS Registry Number 2570254-40-7) by the method described in Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.88 (s, 1H), 8.70 - 8.61 (m, 1H), 8.41 (d, J = 8.2 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.68 - 7.55 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 15.9 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.56 (d, J = 17.5 Hz, 1H), 4.50 (d, J = 17.5 Hz, 1H), 3.95 (br, 1H), 3.70 (br, 3H), 3.33 (d, J = 7.1 Hz, 5H), 3.29 - 3.26 (m, 7H), 2.95-2.88 (m, 1H), 2.81-2.76 (m, 1H), 2.63 (t, J = 6.9 Hz, 2H), 2.57-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.03-1.97 (m, 2H), 1.85-1.70 (m, 4H), 1.59 (p, J = 7.1 Hz, 3H), 1.45-1.39 (m, 2H), 1.36-1.31 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 47 H 56 N7O5 + [M+H] + , calculated 798.4337; found, 798.4339.

[0704] Example 25: Preparation of (E)-N-(4-(1-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hepta-6-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630120)

[0705] The target compound (SIAIS630120) (white solid, 5.8 mg, yield 25%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hepta-6-yn-1- yl methanesulfonate; CAS Registry Number 2570254-41-8) following the procedure of Example 15. 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.89 (s, 1H), 8.72 - 8.61 (m, 1H), 8.26 (t, J = 5.3 Hz, 2H), 7.71 (t, J = 8.2 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 15.9 Hz, 2H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.33 (d, J = 17.7 Hz, 1H), 3.89 (d, J = 13.0 Hz, 2H), 3.55 (br, 4H), 3.25 - 3.15 (m, 3H), 3.15 - 3.05 (m, 5H), 2.95 - 2.87 (m, 1H), 2.68 - 2.57 (m, 1H), 2.56 - 2.53 (m, 1H), 2.47 - 2.39 (m, 1H), 2.06 - 1.97 (m, 1H), 1.84 - 1.75 (m, 2H), 1.72 - 1.60 (m, 4H), 1.52 - 1.43 (m, 5H), 1.36 - 1.26 (m, 2H), 1.25 - 1.20 (m, 2H), 1.09 - 0.98 (m, 2H). HRMS (ESI) C 48 H 58 N7O5 + [M+H] + , calculated 812.4494; found 812.4496.

[0706] Example 26: Preparation of (E)-N-(4-(1-(4-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630121)

[0707] The target compound (SIAIS630121) (white solid, 5.7 mg, yield 24%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl methanesulfonate; CAS Registry Number 2570254-42-9) in reference to the method of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.84 (d, J = 2.2 Hz, 1H), 8.63 (dd, J = 5.2, 1.5 Hz, 1H), 8.37 - 8.32 (m, 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.71 (dd, J = 8.1, 5.2 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 15.9 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.53 (d, J = 17.4 Hz, 1H), 4.47 (d, J = 17.4 Hz, 1H), 3.95 (br, 1H), 3.67 (br, 2H), 3.39 - 3.32 (m, 6H), 3.25 - 3.19 (m, 4H), 3.18 - 3.11 (m, 2H), 2.95 - 2.86 (m, 1H), 2.84 - 2.75 (m, 1H), 2.57 - 2.49 (m, 3H), 2.24 - 2.15 (m, 1H), 1.86 - 1.80 (m, 2H), 1.70 (p, J = 6.9 Hz, 3H), 1.65 - 1.55 (m, 5H), 1.53 - 1.39 (m, 4H), 1.37 - 1.27 (m, 3H), 1.24 - 1.07 (m, 2H). HRMS (ESI) C 49 H 60 N7O5 + [M+H] + , calculated 826.4650; found, 826.4655.

[0708] Example 27: Preparation of (E)-N-(4-(1-(4-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)non-8-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS630122)

[0709] The target compound (SIAIS630122) (white solid, 6.3 mg, yield 25%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS255127; 9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)non-8-yn-1- yl methanesulfonate; CAS Registry Number 2600734-35-6) in reference to the method of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.75 (s, 1H), 8.55 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 7.6, 1.0 Hz, 1H), 7.61 (dd, J = 7.7, 1.0 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.36 (dd, J = 8.8, 1.8 Hz, 2H), 7.06 (dd, J = 9.0, 2.5 Hz, 2H), 6.75 (d, J = 15.9 Hz, 1H), 5.19 (dd, J = 13.4, 5.2 Hz, 1H), 4.53 (d, J = 17.4 Hz, 1H), 4.46 (d, J = 17.5 Hz, 1H), 3.94 (d, J = 13.6 Hz, 2H), 3.83 (br, 1H), 3.64 (d, J = 11.9 Hz, 2H), 3.35 - 3.32 (m, 2H), 3.25 - 3.16 (m, 4H), 3.11 (br, 2H), 2.98 (s, 2H), 2.96 - 2.86 (m, 2H), 2.84-2.76 (m, 1H), 2.61 - 2.48 (m, 2H), 2.25-2.16 (m, 1H), 1.83-1.75 (m, 3H), 1.67 (p, J = 6.9 Hz, 3H), 1.62-1.53 (m, 4H), 1.50 - 1.38 (m, 6H), 1.37 - 1.27 (m, 4H), 1.21 - 1.13 (m, 2H). HRMS (ESI) C 50 H 62 N7O5 + [M+H] + , calculated 840.4807; found, 840.4809.

[0710] Example 28: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(3-oxo-3-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)propanamido)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631001)

[0711] The target compound (SIAIS631001) (white solid, 11.9 mg, yield 31%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM: SIAIS352066, referring to the method of Example 1. 1 HNMR (500 MHz, DMSO-d6) δ 9.05 (d, J = 6.4 Hz, 2H), 8.82 (d, J = 4.2 Hz, 1H), 8.61 (d, J = 6.2 Hz, 2H), 8.39 (t, J = 5.5 Hz, 1H), 8.25 (d, J = 9.4 Hz, 1H), 8.03 - 7.94 (m, 1H), 7.55 (d, J = 15.9 Hz, 1H), 7.41 (q, J = 8.4 Hz, 4H), 7.27 (dd, J = 8.6, 5.2 Hz, 2H), 7.02 - 6.91 (m, 3H), 4.54 (d, J = 9.4 Hz, 1H), 4.47 - 4.39 (m, 3H), 4.37-4.34 (m, 1H), 4.25 - 4.19 (m, 1H), 3.68 (dd, J = 10.6, 4.1 Hz, 2H), 3.64 - 3.57 (m, 5H), 3.54 (d, J = 15.5 Hz, 1H), 3.49 - 3.42 (m, 2H), 3.30 - 3.14 (m, 6H), 3.13 - 3.07 (m, 1H), 2.94 - 2.67 (m, 2H), 2.45 (s, 3H), 2.07 - 2.00 (m, 1H), 1.95 - 1.85 (m 1H), 1.70 - 1.64 (m, 1H), 1.46 (p, J = 7.1 Hz, 3H), 1.35 - 1.28 (m, 2H), 1.29 - 1.22 (m, 2H), 1.09 - 0.99 (m, 2H), 0.95 (s, 9H). HRMS (ESI) C 53 H 68 N9O7S + [M+H] + , calculated 974.4957; found, 974.4959.

[0712] Example 29: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-oxo-4-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)butyryl)phenyl)piperazin-1-yl)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631002)

[0713] The target compound (SIAIS631002) (white solid, 11.5 mg, yield 30%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074011; 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4- oxobutanoic acid; CAS Registry Number 2172819-72-4) referring to the method of Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 9.08 (d, J = 5.9 Hz, 2H), 8.84 (d, J = 4.3 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.41 (t, J = 5.5 Hz, 1H), 8.02 (dd, J = 8.1, 5.5 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 15.9 Hz, 1H), 7.41 (q, J = 8.3 Hz, 4H), 7.30 - 7.23 (m, 2H), 7.06 - 6.92 (m, 3H), 4.52 (d, J = 9.3 Hz, 1H), 4.46 - 4.38 (m, 3H), 4.36 - 4.33 (m, 1H), 4.26 - 4.18 (m, 1H), 3.71 - 3.57 (m, 6H), 3.45 (t, J = 5.3 Hz, 1H), 3.28 (t, J = 5.3 Hz, 1H), 3.19 (p, J = 6.6, 6.0 Hz, 5H), 2.65 - 2.53 (m, 3H), 2.45 (s, 3H), 2.44 - 2.35 (m, 2H), 2.06 - 2.00 (m, 1H), 1.95-1.85 (m, 1H), 1.66 (d, J = 12.4 Hz, 2H), 1.51 - 1.42 (m, 3H), 1.36 - 1.28 (m, 2H), 1.26-1.21 (m, 2H), 1.09 - 1.00 (m, 2H), 0.93 (s, 9H). HRMS (ESI) C 54 H 70 N9O7S+ [M+H] + Calcd 988.5113; Found 988.5116.

[0714] Example 30: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(5-oxo-5-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidin-1-yl)phenyl)piperazin-1-yl)pentanoylamino)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631003)

[0715] The target compound (SIAIS631003) (white solid, 12.8 mg, yield 33%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074012; 5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5- oxopentanoic acid; CAS Registry Number 2172819-73-5) following the procedure of Example 1. 1H NMR (500 MHz, CD3OD) δ 9.66 (d, J = 19.2 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.86 - 8.77 (m, 2H), 8.13 (dd, J = 8.2, 5.8 Hz, 1H), 7.64 (d, J = 15.9 Hz, 1H), 7.57 - 7.46 (m, 4H), 7.36 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 15.9, 1.0 Hz, 1H), 4.62 (d, J = 1.8 Hz, 1H), 4.59 - 4.52 (m, 2H), 4.52 - 4.47 (m, 1H), 4.38 (dd, J = 15.7, 3.6 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.84 - 3.72 (m, 3H), 3.54 - 3.48 (m, 3H), 3.41 - 3.32 (m, 12H), 2.57 (s, 3H), 2.48 (t, J = 7.5 Hz, 1H), 2.40 - 2.34 (m, 2H), 2.34 - 2.28 (m, 1H), 2.26 - 2.20 (m, 1H), 2.11-2.04 (m, 1H), 1.91 (dt, J = 17.0, 7.5 Hz, 2H), 1.60 (p, J = 6.8 Hz, 3H), 1.47 - 1.29 (m, 5H), 1.21 - 1.11 (m, 2H), 1.04 (s, 9H). HRMS (ESI) C 55 H 72 N9O7S + [M+H] + , calculated 1002.5270; found, 1002.5273.

[0716] Example 31: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(6-oxo-6-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)phenyl)piperazin-1-yl)hexanoylamino)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS630007)

[0717] The target compound (SIAIS630007) (white solid, 13.4 mg, yield 34%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074013; 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-6-oxohexanoic acid; CAS Registry Number 2172819-74-6) according to the method of Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 9.04 - 8.98 (m, 2H), 8.79 - 8.74 (m, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.53 - 8.42 (m, 1H), 8.31 (d, J = 6.1 Hz, 1H), 7.86 (d, J = 9.4 Hz, 2H), 7.53 (dd, J = 15.9, 2.6 Hz, 1H), 7.44 - 7.35 (m, 4H), 7.27 (dd, J = 11.5, 8.6 Hz, 2H), 7.02 - 6.94 (m, 2H), 6.88 (dd, J = 15.9, 7.5 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.38 - 4.32 (m, 1H), 4.21 (dd, J = 15.9, 5.5 Hz, 1H), 3.65 - 3.57 (m, 10H), 3.43 (d, J = 5.6 Hz, 2H), 3.25 - 3.14 (m, 6H), 2.44 (s, 3H), 2.37 - 2.33 (m, 1H), 2.31 - 2.25 (m, 1H), 2.20 - 2.11 (m, 1H), 2.06 - 2.00 (m, 1H), 1.93 - 1.88 (m, 1H), 1.69 - 1.61 (m, 2H), 1.53 - 1.42 m, 7H), 1.35 - 1.20 (m, 4H), 1.09 - 1.02 (m, 2H), 0.93 (s, 9H). HRMS (ESI) C 56 H 74 N9O7S + [M+H] + , calculated 1016.5426; found, 1016.5428.

[0718] Example 32: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(7-oxo-7-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)heptanoylamino)butanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631004)

[0719] The target compound (SIAIS631004) (white solid, 12.1 mg, yield 30%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074014; 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid; CAS Registry Number 2162120-87-6) following the procedure of Example 1. 1H NMR (500MHz, DMSO-d6) δ9.08(d, J=2.0Hz,1H),9.06(d,J=3.2Hz,1H),8.83(d,J=4.3Hz,1H),8.64(d,J=8.3Hz,1H),8.58(t,J= 6.1Hz,1H),8.40(q,J=5.4Hz,1H),8.01(dd,J=8.2,5.5Hz,1H),7.85(dd,J=9.4,2.7Hz,1H),7.5 6(d,J=15.9Hz,1H),7.44–7.34(m,4H),7.27(dd,J=8.8,2.5Hz,2H),7.05–6.91(m,3H),4.53(d, J=9.3Hz,1H),4.45–4.40(m,3H),4.36–4.32(m,1H),4.21(dd,J=15.9,5.5Hz,1H),3.71-3.56 (m,6H),3.45(dd,J=6.5,4.0Hz,1H),3.25(t,J=5.2Hz,1H),3.23-3.15(m,5H),2.95-2.65(m, 2H),2.44(s,3H),2.33(t,J=7.5Hz,1H),2.26-2.21(m,1H),2.19–2.08(m,1H),2.06–1.99(m,1 H),1.94-1.90(m,1H),1.72–1.62(m,2H),1.54–1.40(m,7H),1.35–1.20(m,7H),1.08-1.00(m, 2H),0.93(s,9H)..HRMS(ESI)C 57 H 76 N9O7S + [M+H] + ,Calculated value 1030.5583; Measured value, 1030.5585.

[0720] Example 33: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(8-oxo-8-(4-(4-(4-((E)-3-(pyridin-3-yl)acrylamido)butyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)octanamido)butyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631005)

[0721] The target compound (SIAIS631005) was prepared according to Scheme 15, using daploridine derivative 1 (SIAIS630006) and intermediate LM (SIAIS074015; 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8- oxooctanoic acid; CAS Registry Number 2172819-75-7) according to the procedure of Example 1 (white solid, 14.8 mg, 36% yield). 1 H NMR (500 MHz, CD3OD) δ 9.17 (d, J = 23.5 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.84 - 8.70 (m, 2H), 8.14 - 7.96 (m, 1H), 7.63 (d, J = 15.8 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.43 (m, 2H), 7.38 - 7.30 (m, 2H), 7.05 (dd, J = 26.6, 8.8 Hz, 2H), 6.92 (d, J = 15.8 Hz, 1H), 4.64 (s, 1H), 4.61 - 4.53 (m, 2H), 4.50 (s, 1H), 4.42 - 4.33 (m, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 10.9, 3.9 Hz, 1H), 3.75-3.69 (m, 3H), 3.53 - 3.47 (m, 1H), 3.40 - 3.33 (m, 12H), 3.25 (t, J = 5.4 Hz, 1H), 2.50 (s, 3H), 2.45 (t, J = 7.6 Hz, 1H), 2.34 - 2.26 (m, 2H), 2.25 - 2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.67 - 1.55 (m, 8H), 1.47 - 1.29 (m, 9H), 1.20 - 1.12 (m, 2H), 1.03 (s, 9H). HRMS (ESI) C 58 H 78 N9O7S + [M+H] + , calculated 1044.5739; found 1044.5741.

[0722] Example 34: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(9-oxo-9-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)phenyl)piperazin-1-yl)nonanoylamino)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631006)

[0723] The target compound (SIAIS631006) (white solid, 18 mg, yield 43%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074016; 9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9-oxononanoic acid; CAS Registry Number 2172819-76-8) referring to the method of Example 1. 1 H NMR (500 MHz, CD3OD) δ 8.93 (d, J = 7.1 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.68 (dd, J = 5.3, 1.4 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.1, 5.4 Hz, 1H), 7.60 (d, J = 15.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 15.9 Hz, 1H), 4.63 (s, 1H), 4.58 (d, J = 8.7 Hz, 1H), 4.54 (d, J = 15.8 Hz, 1H), 4.50 (d, J = 4.1 Hz, 1H), 4.36 (d, J = 15.4 Hz, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 11.0, 3.9 Hz, 1H), 3.74 - 3.68 (m, 4H), 3.40 - 3.33 (m, 12H), 3.23 (t, J = 5.4 Hz, 1H), 2.48 (s, 3H), 2.44 (t, J = 7.6 Hz, 1H), 2.32 - 2.26 (m, 2H), 2.26 - 2.19 (m, 1H), 2.11 - 2.05 (m, 1H), 1.65 - 1.56 (m, 8H), 1.41 - 1.31 (m, 11H), 1.22 - 1.11 (m, 2H), 1.03 (s, 9H). HRMS (ESI) C 59 H80 N9O7S + [M+H] + Calcd 1058.5896; Found 1058.5898.

[0724] Example 35: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(10-oxo-10-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidin-1-yl)phenyl)piperazin-1-yl)decanoylamino)butanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631007)

[0725] The target compound (SIAIS631007) was prepared according to Scheme 15 using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074019; 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-10-oxodecanoic acid; CAS Registry Number 2172819-77-9) following the procedure of Example 1 (white solid, 18.3 mg, yield 43%). 1H NMR (500 MHz, DMSO-de) δ 9.11 - 9.00 (m, 2H), 8.84 - 8.73 (m, 1H), 8.64 - 8.51 (m, 2H), 8.36 (t, J = 5.6 Hz, 1H), 7.96 (dd, J = 8.2, 5.4 Hz, 1H), 7.83 (d, J = 9.3 Hz, 1H), 7.55 (d, J = 15.9 Hz, 1H), 7.45 - 7.36 (m, 4H), 7.26 (d, J = 8.5 Hz, 2H), 6.99 (dd, J = 8.9, 3.7 Hz, 2H), 6.92 (d, J = 15.9 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.46 - 4.38 (m, 3H), 4.35 (dd, J = 4.8, 2.5 Hz, 1H), 4.21 (dd, J = 15.9, 5.5 Hz, 1H), 3.68 - 3.62 (m, 2H), 3.59 (d, J = 5.4 Hz, 4H), 3.44 (dd, J = 6.6, 3.9 Hz, 1H), 3.26 - 3.14 (m, 6H), 2.95-2.70 (m, 2H), 2.44 (s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 2.28 - 2.20 (m, 1H), 2.13 - 2.05 (m, 1H), 2.07 - 2.00 (m, 1H), 1.95 - 1.86 (m, 1H), 1.69 - 1.62 (m, 2H), 1.52 - 1.42 (m, 7H), 1.36 - 1.20 (m, 13H), 1.10 - 0.98 (m, 2H), 0.93 (s, 9H). HRMS (ESI) C 60 H 82 N9O7S + [M+H] + , calculated 1072.6052; found, 1072.6055.

[0726] Example 36: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(11-oxo-11-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)phenyl)undecanoylamino)butanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631008)

[0727] The target compound (SIAIS631008) was prepared according to Scheme 15 using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS074020; 11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-11-oxoundecanoic acid; CAS Registry Number 2172819-78-0) according to the method of Example 1 (white solid, 21 mg, 49% yield). 1 H NMR (500 MHz, DMSO-d6) δ 9.10 - 9.01 (m, 2H), 8.83 (dd, J = 5.5, 1.3 Hz, 1H), 8.65 - 8.51 (m, 2H), 8.38 (t, J = 5.6 Hz, 1H), 8.00 (dd, J = 8.2, 5.5 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 15.9 Hz, 1H), 7.45 - 7.37 (m, 4H), 7.28 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 15.9 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.48 - 4.40 (m, 3H), 4.38 - 4.33 (m, 1H), 4.22 (dd, J = 15.9, 5.6 Hz, 1H), 3.68-3.59 (m, 6H), 3.34 - 3.12 (m, 7H), 2.95-2.70 (m, 2H), 2.45 (s, 3H), 2.34 (t, J = 7.5 Hz, 2H), 2.28 - 2.23 (m, 1H), 2.13 - 2.08 (m, 1H), 2.07 - 2.00 (m, 1H), 1.93 - 1.88 (m, 1H), 1.67 (d, J = 12.8 Hz, 2H), 1.55 - 1.43 (m, 8H), 1.36 - 1.30 (m, 2H), 1.28 - 1.20 (m, 12H), 1.08 - 0.99 (m, 2H), 0.93 (s, 9H). HRMS (ESI) C 61 H 84 N9O7S + [M+H] + , calculated 1086.6209; found, 1086.6211.

[0728] Example 37: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(2-oxo-2-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidin-1-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetylamino)butanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631010)

[0729] The target compound (SIAIS631010) was prepared according to Scheme 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS151010; 2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetic acid; CAS Registry Number 2172820-08-3) according to the procedure of Example 1 (white solid, 14.1 mg, yield 34%). 1H NMR (500 MHz, CD3OD) δ 9.18 (d, J = 38.0 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 5.5 Hz, 1H), 8.81-8.74 (m, 1H), 8.09-8.04 (m, 1H), 7.63 (d, J = 15.9 Hz, 1H), 7.53-7.39 (m, 4H), 7.36 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.93 (dd, J = 15.9, 1.6 Hz, 1H), 4.70 (d, J = 8.3 Hz, 1H), 4.61-4.54 (m, 2H), 4.50 (t, J = 7.7 Hz, 1H), 4.37 (s, 1H), 4.06 (dd, J = 6.8, 2.2 Hz, 2H), 3.88 (d, J = 10.8 Hz, 1H), 3.81 (dd, J = 11.1, 3.7 Hz, 1H), 3.77-3.73 (m, 4H), 3.73-3.69 (m, 1H), 3.53-3.49 (m, 2H), 3.38 (dd, J = 6.6, 3.9 Hz, 2H), 3.35-3.32 (m, 11H), 3.28-3.22 (m, 1H), 2.52 (s, 3H), 2.24 (dd, J = 13.2, 7.7 Hz, 1H), 2.13-2.07 (m, 1H), 1.78-1.70 (m, 1H), 1.62-1.55 (m, 3H), 1.47-1.40 (m, 2H), 1.38-1.30 (m, 2H), 1.22-1.10 (m, 2H), 1.04 (s, 9H). HRMS (ESI) C 56 H 74 N9O9S + [M+H] + , calculated 1048.5325; found, 1048.5327.

[0730] Example 38: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(3-(2-(3-oxo-3-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)propoxy)ethoxy)propionylamino)butyryl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS631011)

[0731] The target compound (SIAIS631011) was prepared according to Scheme 15, using daploridine derivative 1 (SIAIS630006) and intermediate LM (SIAIS151002; 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid; CAS Registry Number 2172820-09-4) according to the procedure of Example 1 (white solid, 14.2 mg, 33% yield). 1 H NMR (500 MHz, CD3OD) δ 9.45 (d, J = 34.6 Hz, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.86-8.80 (m, 2H), 8.11 (dd, J = 8.2, 5.8 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.55-7.44 (m, 4H), 7.35 (t, J = 9.2 Hz, 2H), 7.07 (dd, J = 11.4, 8.8 Hz, 2H), 6.95 (dd, J = 15.8, 1.8 Hz, 1H), 4.65 (s, 1H), 4.60-4.53 (m, 2H), 4.52-4.47 (m, 1H), 4.37 (d, J = 15.7 Hz, 1H), 3.89 (d, J = 10.9 Hz, 1H), 3.84-3.67 (m, 9H), 3.63-3.57 (m, 4H), 3.51 (dd, J = 6.6, 3.9 Hz, 1H), 3.42-3.33 (m, 11H), 3.27 (d, J = 5.3 Hz, 1H), 2.71 (t, J = 6.3 Hz, 1H), 2.53 (s, 3H), 2.48-2.42 (m, 1H), 2.26-2.20 (m, 1H), 2.12-2.04 (m, 1H), 1.85-1.70 (m, 1H), 1.59 (p, J = 7.2 Hz, 3H), 1.47-1.40 (m, 2H), 1.38-1.30 (m, 2H), 1.22-1.11 (m, 2H), 1.03 (s, 9H). HRMS (ESI) C 58 H 78 N9O9S + [M+H] + , calculated 1076.5638; found, 1076.5641.

[0732] Example 39: Preparation of (2S,4R)-1-((S)-2-(tert-butyl)-4,16-dioxo-16-(4-(4-(4- (4-((E)-3-(pyridin-3-yl)propenoyl)amino)butyl)piperazin-1-yl)-7,10,13-trioxa-3- azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (SIAIS631012)

[0733] The target compound (SIAIS631012) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151003; (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1- carboxylate; CAS Registry Number 2140807-42-5) according to the procedure of Example 1 (white solid, 14.8 mg, 34% yield). 1 H NMR (500 MHz, CD3OD) δ 9.52 (d, J = 11.8 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.74 (dd, J = 12.9, 7.0 Hz, 2H), 8.03 (dd, J = 8.2, 5.7 Hz, 1H), 7.54 (d, J = 15.8 Hz, 1H), 7.46 - 7.34 (m, 4H), 7.31 - 7.23 (m, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.00 - 6.95 (m, 1H), 6.92 (d, J = 15.9 Hz, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.50 - 4.46 (m, 1H), 4.45 - 4.39 (m, 2H), 4.28 (d, J = 15.8 Hz, 1H), 3.81 (d, J = 11.1 Hz, 1H), 3.75 - 3.59 (m, 8H), 3.57 - 3.48 (m, 10H), 3.44 - 3.39 (m, 2H), 3.34 - 3.23 (m, 7H), 2.67 (t, J = 6.1 Hz, 1H), 2.53 - 2.36 (m, 6H), 2.17 - 2.12 (m, 1H), 2.01-1.95 (m, 1H), 1.67 (d, J = 43.4 Hz, 2H), 1.52-1.46 (m, 3H), 1.34-1.30 (m, 2H), 1.27 - 1.20 (m, 2H), 1.04 (br, 2H), 0.94 (s, 9H). HRMS (ESI) C 60 H 82 N9O10 S + [M+H] + , calculated 1120.5900; found, 1120.5905.

[0734] Example 40: Preparation of (2S,4R)-1-((S)-2-(tert-butyl)-4,19-dioxo-19-(4-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)-7,10,13,16- tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (SIAIS631013)

[0735] The target compound (SIAIS631013) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151008; (S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azadocosanoic acid; CAS Registry Number 2172820-12-9) according to the procedure of Example 1 (white solid, 15.2 mg, yield 33%). 1HNMR (500 MHz, CD3OD) δ 9.59 (d, J = 1.6 Hz, 1H), 9.09 (d, J = 2.1 Hz, 1H), 8.86-8.82 (m, 2H), 8.17-8.09 (m, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.56-7.47 (m, 4H), 7.39-7.29 (m, 2H), 7.08 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 15.8 Hz, 1H), 4.65 (s, 1H), 4.61-4.54 (m, 2H), 4.52-4.50 (m, 1H), 4.38 (d, J = 15.7 Hz, 1H), 3.90 (d, J = 12.1 Hz, 1H), 3.84-3.78 (m, 2H), 3.77-3.70 (m, 4H), 3.67-3.59 (m, 12H), 3.55-3.49 (m, 3H), 3.40 -3.36 (m, 4H), 3.36-3.28 (m, 6H), 2.64-2.46 (m, 7H), 2.28-2.20 (m, 1H), 2.11-2.05 (m, 1H), 1.81 (br, 2H), 1.60 (p, J = 6.9 Hz, 3H), 1.46-1.40 (m, 2H), 1.36-1.32 (m, 2H), 1.20-1.10 (m, 2H), 1.04 (s, 9H). HRMS (ESI) C 62 H 86 N9O 11 S + [M+H] + , calculated 1164.6162; found, 1164.6165.

[0736] Example 41: Preparation of (2S,4R)-1-((S)-2-(tert-butyl)-4,22-dioxo-22-(4-(4-(4- (4-((E)-3-(pyridin-3-yl)propenoylamino)butyl)piperazin-1-yl)-7,10,13,16,19- pentaaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide (SIAIS631014)

[0737] The target compound (SIAIS631014) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151009; (S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoic acid; CAS Registry Number 2172820-14-1) according to the method of Example 1 (white solid, 17.6 mg, 36% yield). 1 H NMR (500 MHz, CD3OD) δ 9.10 (d, J = 12.4 Hz, 1H), 8.96 (s, 1H), 8.75 - 8.61 (m, 2H), 7.98 (dd, J = 8.2, 5.7 Hz, 1H), 7.53 (d, J = 15.8 Hz, 1H), 7.42 - 7.30 (m, 4H), 7.25 (dd, J = 10.0, 8.7 Hz, 2H), 6.96 (dd, J = 15.0, 8.8 Hz, 2H), 6.87 (dd, J = 15.9, 2.0 Hz, 1H), 4.55 (s, 1H), 4.50 - 4.46 (m, 1H), 4.45 - 4.39 (m, 2H), 4.27 (d, J = 15.6 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.73 - 3.60 (m, 10H), 3.55-3.50 (m, 18H), 3.42-3.41 (m, 1H), 3.31 - 3.22 (m, 5H), 3.18 (t, J = 5.3 Hz, 1H), 2.63 (t, J = 6.1 Hz, 1H), 2.53 - 2.43 (m, 2H), 2.41-2.37 (m, 4H), 2.16-2.11 (m, 1H), 2.05 - 1.95 (m, 1H), 1.66 (br, 2H), 1.52-1.46 (m, 3H), 1.36-1.28 (m, 2H), 1.24-1.22 (m, 2H), 1.10 - 1.02 (m, 2H), 0.94 (s, 9H). HRMS (ESI) C 64 H 90 N9O 12 S + [M+H] + , calculated 1208.6424; found, 1208.6427.

[0738] Example 42: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(16-oxo-16-(4-(4-(4-((E)-3-(pyridin-3- yl)propenoylamino)butyl)piperazin-1-yl)phenyl)piperazin-1-yl)hexadecanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS630008)

[0739] The target compound (SIAIS630008) (white solid, 7.0 mg, yield 37%) was prepared according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS164189) by referring to the method of Example 1. 1 HNMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 15.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 3H), 7.42–7.39 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 15.9 Hz, 1H), 4.64 (d, J = 6.1 Hz, 1H), 4.58–4.47 (m, 3H), 4.35 (d, J = 15.5 Hz, 1H), 3.90 (d, J = 11.2 Hz, 1H), 3.81-3.78 (m, 1H), 3.73-3.68 (m, 3H), 3.63 (d, J = 10.5 Hz, 1H), 3.55 (d, J = 17.9 Hz, 2H), 3.45-3.44 (m, 1H), 3.35 –3.32 (m, 6H), 3.17-3.16 (m, 1H), 2.47 (s, 3H), 2.31–2.17 (m, 4H), 2.10–2.02 (m, 2H), 1.59 (br, 10H), 1.28 (br, 25H), 1.03 (s, 9H). HRMS (ESI) C 66 H 94 N9O7S + [M+H] + , calculated 1156.6991; found, 1156.6995.

[0740] Example 43: Preparation of (E)-N-(4-(1-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)butyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631020)

[0741] The target compound (SIAIS631020) (white solid, 6.8 mg, yield 22%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1222171; 3-(4-(4-bromobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2641288-70-0) by referring to the method of Example 15. 1 HNMR (500MHz, CD3OD) δ 8.90 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 5.4, 1.5 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 8.1, 5.3 Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 15.8 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.51 (d, J = 17.3 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.23 (t, J = 5.8 Hz, 2H), 4.01 - 3.79 (m, 3H), 3.70 (br, 2H), 3.35 - 3.32 (m, 4H), 3.29 - 3.21 (m, 6H), 2.96-2.86 (m, 1H), 2.81-2.76 (m, 1H), 2.56-2.47 (m, 1H), 2.24-2.15 (m, 1H), 2.10 - 2.01 (m, 2H), 2.01 - 1.92 (m, 2H), 1.84 - 1.69 (m, 2H), 1.59 (p, J = 7.1 Hz, 3H), 1.47 - 1.39 (m, 2H), 1.38 - 1.27 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 45 H 56 N7O6 + [M+H] + , calculated 790.4287; found, 790.4289.

[0742] Example 44: Preparation of (E)-N-(4-(1-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)hexyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631024)

[0743] The target compound (SIAIS631024) (white solid, 5.4 mg, 16%) was prepared according to Scheme 16, by the method of Example 15, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS1222063). 1 HNMR (500MHz, DMSO-d6) δ 11.10 (s, 1H), 10.97 (s, 1H), 9.03 (s, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.37 (t, J = 5.6 Hz, 1H), 7.94 (t, J = 6.9 Hz, 1H), 7.54 (d, J = 15.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 10.4, 8.0 Hz, 3H), 7.24 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 15.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 (d, J = 17.3 Hz, 1H), 4.22 (d, J = 17.4 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.88 (d, J = 13.0 Hz, 2H), 3.53 (d, J = 11.8 Hz, 2H), 3.29 - 3.15 (m, 5H), 3.11 - 3.01 (m, 5H), 2.95-2.86 (m, 2H), 2.64 - 2.52 (m, 1H), 2.48 - 2.42 (m, 1H), 2.05-1.95 (m, 1H), 1.79 - 1.70 (m, 4H), 1.66 (br, 2H), 1.46 (p, J = 6.9 Hz, 5H), 1.39 - 1.29 (m, 9H), 1.27 - 1.19 (m, 2H), 1.10-1.00 (m, 2H).. HRMS (ESI) C 49 H 64 N7O6 + [M+H] + , calculated 846.4913; found, 846.4915.

[0744] Example 45: Preparation of (E)-N-(4-(4-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hept-6-yn-1-yl)piperazin-1-yl)benzoyl)piperazin-1-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631045)

[0745] The target compound (SIAIS631045) (white solid, 12.4 mg, yield 39%) was prepared according to Scheme 16, using dapansutrine derivative 2 (SIAIS630020) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1- yl methanesulfonate; CAS Registry Number 2570254-41-8)) following the procedure of Example 15. 1 H NMR (500 MHz, CD3OD) δ 9.00 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.96 (s, 1H), 7.75 (dd, J = 7.6, 1.1 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 14.5 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.54 (d, J = 17.4 Hz, 1H), 4.48 (d, J = 17.5 Hz, 1H), 3.99 (d, J = 12.8 Hz, 2H), 3.69 (d, J = 11.4 Hz, 2H), 3.63 (br, 1H), 3.40 (t, J = 6.9 Hz, 3H), 3.27 - 3.23 (m, 6H), 3.21 - 3.15 (m, 4H), 2.97 - 2.88 (m, 1H), 2.83 - 2.75 (m, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.53 (dd, J = 13.3, 4.6 Hz, 1H), 2.22 - 2.17 (m, 1H), 1.93 - 1.84 (m, 5H), 1.75 - 1.60 (m, 8H), 1.29 (br, 1H). HRMS (ESI) C 47 H 57 N8O5 + [M+H] + Calcd 813.4446; Found 813.4449.

[0746] Example 46: Preparation of (E)-N-(4-(1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)ethyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631068)

[0747] The target compound (SIAIS631068) (yellow solid, 11.6 mg, yield 37%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (4-((2-bromoethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione dioxopiperidine; CAS Registry Number 2378582-68-2) by referring to the method of Example 15. 1 H NMR (500MHz, CD3OD) δ 8.75 (s, 1H), 8.56 (s, 1H), 8.14 (s, 1H), 7.84 (d, J = 5.9 Hz, 2H), 7.78 (dd, J = 5.7, 2.4 Hz, 1H), 7.56 (d, J = 14.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 16.6 Hz, 1H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.50 (m, 12H), 3.35 (br, 4H), 2.85 (br, 2H), 2.87 - 2.85 (m, 1H), 2.25 - 2.04 (m, 1H), 1.89 (br, 1H), 1.68 - 1.55 (m, 4H), 1.42 (br, 2H), 1.39 - 1.27 (m, 3H), 1.22 - 1.11 (m, 2H). HRMS (ESI) C 43 H 50 N7O6S + [M+H] + , calculated 792.3538; found, 792.3539.

[0748] Example 47: Preparation of (E)-N-(4-(1-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)propyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631069)

[0749] The target compound (SIAIS631069) was prepared according to Scheme 16, using daprodustine derivative 1 (SIAIS630006) and intermediate LM (4-((3-bromopropyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS Registry Number 2378582-69-3) following the procedure of Example 15 (yellow solid, 6.9 mg, yield 22%). 1 H NMR (500 MHz, CD3OD) δ 8.86 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.83 - 7.77 (m, 3H), 7.72 - 7.66 (m, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 15.9 Hz, 1H), 5.14 (dd, J = 12.8, 5.5 Hz, 1H), 3.96 (br, 2H), 3.71 - 3.61 (m, 2H), 3.47 - 3.40 (m, 4H), 3.30-2.28 (m, 8H), 2.92-2.85 (m, 1H), 2.81 - 2.68 (m, 1H), 2.25-2.20 (m, 2H), 2.19 - 2.10 (m, 1H), 1.82 (br, 1H), 1.62-1.57 (m, 4H), 1.47 - 1.38 (m, 2H), 1.36-1.29 (m, 4H), 1.18 (br, 2H). HRMS (ESI) C 44 H 52 N7O6S + [M+H] + , calculated 806.3694; found 806.3699.

[0750] Example 48: Preparation of (E)-N-(4-(1-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)butyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS631070)

[0751] The target compound (SIAIS631070) was prepared according to Scheme 16, using daprodustine derivative 1 (SIAIS630006) and intermediate LM (4-((4-bromobutyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS Registry Number 2378582-70-6) following the procedure of Example 15 (yellow solid, 7.1 mg, yield 22%).1 H NMR (500 MHz, CD3OD) δ 8.75 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.66 (d, J = 4.6 Hz, 3H), 7.60 - 7.53 (m, 1H), 7.48 (d, J = 15.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.71 (d, J = 15.8 Hz, 1H), 5.03 (dd, J = 12.8, 5.5 Hz, 1H), 3.87 (br, 2H), 3.58 (br, 2H), 3.18 - 3.14 (m, 6H), 3.04 (br, 3H), 2.79 - 2.74 (m, 1H), 2.66 - 2.60 (m, 1H), 2.07 - 1.98 (m, 1H), 1.96 - 1.83 (m, 2H), 1.80-1.74 (m, 5H), 1.49 (p, J = 7.2 Hz, 4H), 1.33 - 1.30 (m, 3H), 1.28 - 1.17 (m, 4H), 1.07 (br, 3H). HRMS (ESI) C 45 H 54 N7O6S + [M+H] + , calculated 820.3851 ; found, 820.3856.

[0752] Example 49: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)pentyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631071)

[0753] The target compound (SIAIS631071) (yellow solid, 5.9 mg, yield 18%) was prepared according to Scheme 16, by reference to the method of Example 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (4-((5-bromopentyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS Registry Number 2378582-71-7). 1H NMR (500 MHz, CD3OD) δ 8.98 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.97 (s, 1H), 7.79 - 7.69 (m, 2H), 7.70 - 7.55 (m, 2H), 7.45 - 7.22 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 16.0 Hz, 1H), 5.12 (dd, J = 12.7, 5.5 Hz, 1H), 3.97 (d, J = 13.4 Hz, 2H), 3.68 (d, J = 12.1 Hz, 2H), 3.34 (dd, J = 8.1, 1.6 Hz, 6H), 3.27 - 3.06 (m, 9H), 2.88-2.84 (m, 1H), 2.78 - 2.66 (m, 1H), 2.19 - 2.06 (m, 1H), 1.86 (p, J = 7.8 Hz, 4H), 1.67-1.56 (m, 4H), 1.43 (br, 2H), 1.38 - 1.26 (m, 4H), 1.16 (br, 3H). HRMS (ESI) C 46 H 56 N7O6S + [M+H] + , calculated 834.4007; found, 834.4009.

[0754] Example 50: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)hexyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631072)

[0755] The target compound (SIAIS631072) (yellow solid, 6.9 mg, yield 21%) was prepared according to Scheme 16, by reference to the method of Example 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (4-((6-bromohexyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS Registry Number 2378586-19-5). 1H NMR (500 MHz, CD3OD) δ 8.81 (d, J = 2.2 Hz, 1H), 8.60 (dd, J = 5.2, 1.5 Hz, 1H), 8.28 (dt, J = 8.0, 1.9 Hz, 1H), 7.76 - 7.70 (m, 3H), 7.64 - 7.53 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 15.8 Hz, 1H), 5.12 (dd, J = 12.7, 5.5 Hz, 1H), 3.98 - 3.82 (m, 3H), 3.67 (br, 2H), 3.33 (d, J = 7.3 Hz, 2H), 3.24 - 3.15 (m, 12H), 2.91 - 2.81 (m, 1H), 2.81 - 2.71 (m, 1H), 2.19 - 2.08 (m, 1H), 1.86-1.79 (m 5H), 1.66-1.58 (m, 4H), 1.52-1.48 (m, 4H), 1.44-1.40 (m, 2H), 1.36-1.32 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 47 H 58 N7O6S + [M+H] + , calculated 848.4164; found, 848.4168.

[0756] Example 51: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)heptyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631078)

[0757] The target compound (SIAIS631078) (yellow solid, 7.1 mg, yield 21%) was prepared according to Scheme 16, by reference to the method of Example 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (4-((7-bromoheptyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS Reg. No. 2378586-22-0). 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.69 (s, 1H), 8.87 (s, 1H), 8.66 (d, J = 5.0 Hz, 1H), 8.30 - 8.17 (m, 2H), 7.83 - 7.71 (m, 2H), 7.70-7.61 (m, 2H), 7.48 (d, J = 15.9 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 16.0 Hz, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 3.89 (d, J = 12.9 Hz, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.25 - 3.03 (m, 10H), 2.94-2.85 (m, 1H), 2.64-2.56 (m 1H), 2.55-2.52 (m, 1H), 2.10-2.02 (m, 1H), 1.79 - 1.61 (m, 6H), 1.46 (h, J = 7.5 Hz, 5H), 1.39 - 1.20 (m, 9H), 1.12 - 0.98 (m, 2H). HRMS (ESI) C 48 H 60 N7O6S + [M+H] + , calculated 862.4320; found, 862.4324.

[0758] Example 52: Preparation of (E)-N-(4-(1-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)octyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631073)

[0759] The target compound (SIAIS631073) (yellow solid, 7.7 mg, yield 22%) was prepared according to Scheme 16, by the method of Reference Example 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS1224003). 1H NMR (500 MHz, CD3OD) δ 8.81 (d, J = 2.3 Hz, 1H), 8.60 (dd, J = 5.1, 1.5 Hz, 1H), 8.27 (dt, J = 8.0, 1.9 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.63 - 7.54 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 15.9 Hz, 1H), 5.12 (dd, J = 12.7, 5.5 Hz, 1H), 3.96 - 3.82 (m, 3H), 3.67 (br, 2H), 3.33 (d, J = 7.4 Hz, 2H), 3.24 - 3.10 (m, 11H), 2.89 - 2.84 (m, 1H), 2.77 - 2.75 (m, 1H), 2.75 - 2.66 (m, 1H), 2.16 - 2.11 (m, 1H), 1.79 (q, J = 7.3 Hz, 5H), 1.65 - 1.52 (m, 6H), 1.43 (s, 8H), 1.37 - 1.26 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 49 H 62 N7O6S + [M+H] + , calculated 876.4477; found, 876.4478.

[0760] Example 53: Preparation of (E)-N-(4-(1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632027)

[0761] The target compound (SIAIS632027) (yellow solid, 8.7 mg, yield 32%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151045; 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)acetic acid; CAS Registry Number 2378582-26-2). 1H NMR (500MHz, CD3OD) δ 9.01 (s, 1H), 8.77 (d, J = 4.6 Hz, 1H), 8.71 (dt, J = 8.3, 1.7 Hz, 1H), 8.02 (dd, J = 8.3, 5.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.69 - 7.60 (m, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 15.8 Hz, 1H), 5.12 (dd, J = 12.7, 5.5 Hz, 1H), 4.20 (s, 2H), 3.79 (dt, J = 42.2, 5.4 Hz, 5H), 3.38 (t, J = 5.2 Hz, 2H), 3.34 (d, J = 7.0 Hz, 3H), 3.27 (t, J = 5.4 Hz, 2H), 2.93 - 2.83 (m, 2H), 2.79 - 2.66 (m, 3H), 2.18 - 2.10 (m, 1H), 1.76 (br, 2H), 1.59 (p, J = 7.3 Hz, 3H), 1.47 - 1.39 (m, 2H), 1.36 - 1.31 (m, 2H), 1.21 - 1.10 (m, 2H). HRMS (ESI) C 43 H 48 N7O7S + [M+H] + , calc. 806.3330; found, 806.3335.

[0762] Example 54: Preparation of (E)-N-(4-(1-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)propionyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632028)

[0763] The target compound (SIAIS632028) (yellow solid, 8.6 mg, 27% yield) was prepared according to Scheme 15, referring to the method of Example 1, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS151138B; 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)propanoic acid; CAS Registry Number 2378582-27-3). 1H NMR (500MHz, DMSO-d6) δ 11.12 (s, 1H), 9.03 (s, 1H), 8.79 (d, J=5.4 Hz, 1H), 8.53 (d, J=7.8 Hz, 1H), 8.34 (s, 1H), 7.95 - 7.85 (m, 1H), 7.85 - 7.76 (m, 2H), 7.64 (dd, J=6.3, 1.7 Hz, 1H), 7.54 (d, J=15.9 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 6.90 (d, J=15.9 Hz, 1H), 5.11 (dd, J=12.9, 5.4 Hz, 1H), 3.60 (d, J=25.7 Hz, 6H), 3.35 (t, J=7.1 Hz, 2H), 3.25 - 3.15 (m, 6H), 2.95 - 2.80 (m, 5H), 2.63 - 2.55 (m, 1H), 2.52 (br, 1H), 2.07 - 1.96 (m, 1H), 1.66 (d, J=12.4 Hz, 2H), 1.51 - 1.40 (m, 3H), 1.35 - 1.20 (m, 4H), 1.10 - 0.95 (m, 2H). HRMS (ESI) C 44 H 50 N7O7S + [M+H] + , calculated 820.3487; found, 820.3489.

[0764] Example 55: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)pentanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632029)

[0765] The target compound (SIAIS632029) (yellow solid, 9.1 mg, yield 28%) was prepared according to Scheme 15, using dapansutrile derivative 1 (SIAIS630006) and intermediate LM (SIAIS151140B; 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)pentanoic acid; CAS Registry Number 2378582-29-5) following the procedure of Example 1. 1H NMR (500MHz, DMSO-d6) δ 11.12 (s, 1H), 8.97 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.29 (t, J=5.7 Hz, 1H), 7.83 (t, J=6.7 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.62 (dd, J=6.3, 1.8 Hz, 1H), 7.52 (d, J=15.8 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.86 (d, J=15.9 Hz, 1H), 5.11 (dd, J=12.8, 5.4 Hz, 1H), 3.63 - 3.57 (m, 5H), 3.29 - 3.12 (m, 8H), 2.96-2.81 (m, 3H), 2.64-2.67 (m, 1H), 2.54-2.51 (m, 1H), 2.45 - 2.41 (m, 2H), 2.08-2.00 (m, 1H), 1.73 - 1.67 (m, 7H), 1.51 - 1.43 (m, 3H), 1.36 - 1.28 (m, 2H), 1.26-1.20 (m, 2H), 1.10-0.98 (m, 2H). HRMS (ESI) C 46 H 54 N7O7S + [M+H] + , calculated 848.3800; found, 848.3806.

[0766] Example 56: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632030)

[0767] The target compound (SIAIS632030) (yellow solid, 8.8 mg, yield 26%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151141B; 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)hexanoic acid; CAS Registry Number 2378582-30-8). 1H NMR (500MHz, DMSO-d6) δ 11.12 (s, 1H), 9.01 (d, J = 9.5 Hz, 1H), 8.78 (t, J = 5.6 Hz, 1H), 8.55 - 8.45 (m, 1H), 8.37 - 8.29 (m, 1H), 7.97 - 7.86 (m, 1H), 7.83 - 7.72 (m, 2H), 7.61 (d, J = 6.9 Hz, 1H), 7.54 (dd, J = 15.9, 2.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 8.9, 3.1 Hz, 2H), 6.94 - 6.86 (m, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 3.59 (d, J = 5.4 Hz, 5H), 3.25-3.17 (m, 6H), 3.13 (t, J = 7.3 Hz, 2H), 2.95-2.82 (m, 3H), 2.63-2.57 (m, 1H), 2.53-2.51 (m, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.08-2.03 (m, 1H), 1.75 - 1.62 (m, 4H), 1.56 (q, J = 7.4 Hz, 2H), 1.51-1.45 (m, 5H), 1.36 - 1.18 (m, 4H), 1.08-0.97 (m, 2H). HRMS (ESI) C 47 H 56 N7O7S + [M+H] + , calculated 862.3956; found, 862.3959.

[0768] Example 57: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)heptanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632031)

[0769] The target compound (SIAIS632031) (yellow solid, 10.1 mg, yield 29%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (SIAIS151142B; 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)heptanoic acid; CAS Registry Number 2378582-31-9). 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.00 (s, 1H), 8.76 (t, J = 5.1 Hz, 1H), 8.47 (br, 1H), 8.31 (br, 1H), 7.87 (br, 1H), 7.76 (dt, J = 15.9, 8.0 Hz, 2H), 7.62 (d, J = 6.9 Hz, 1H), 7.53 (d, J = 15.9 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 7.4 Hz, 1H), 6.91 - 6.82 (m, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.58 (d, J = 5.5 Hz, 5H), 3.25 - 3.15 (m, 6H), 3.13 (t, J = 7.3 Hz, 2H), 2.95 - 2.79 (m, 3H), 2.62 - 2.57 (m, 1H), 2.53 (d, J = 4.6 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.08 - 2.04 (m, 1H), 1.66 (q, J = 7.2 Hz, 4H), 1.56 - 1.42 (m, 8H), 1.40 - 1.28 (m, 4H), 1.26 - 1.22 (m, 2H), 1.08 - 1.00 (m, 2H). HRMS (ESI) C 48 H 58 N7O7S + [M+H] + , calculated 876.4113; found, 876.4116.

[0770] Example 58: Preparation of (E)-N-(4-(1-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)thio)octanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632032)

[0771] The target compound (SIAIS632032) (yellow solid, 10 mg, yield 28%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)thio)octanoic acid; CAS Reg. No. 2378585-62-5). 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.03 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 5.3 Hz, 1H), 7.98 - 7.90 (m, 1H), 7.84 - 7.69 (m, 2H), 7.62 (d, J = 6.9 Hz, 1H), 7.54 (d, J = 15.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 15.9 Hz, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 3.59 (t, J = 5.2 Hz, 5H), 3.26 - 3.17 (m, 5H), 3.12 (t, J = 7.3 Hz, 2H), 2.94 - 2.79 (m, 3H), 2.64-2.56 (m, 1H), 2.53 (d, J = 4.8 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), 2.09-2.00 (m, 1H), 1.72 - 1.58 (m, 4H), 1.55-1.41 (m, 8H), 1.37 - 1.19 (m, 8H), 1.09-1.00 (m, 2H). HRMS (ESI) C 49 H 60 N7O7S + [M+H] + , calculated 890.4269; found 890.4275.

[0772] Example 59: Preparation of (E)-N-(4-(1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632033)

[0773] The target compound (SIAIS632033) (pale yellow solid, 7.3 mg, yield 24%) was prepared according to the procedure of Example 1, according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetic acid; CAS Registry Number 1061605-21-7). 1HNMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.01 (s, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.51 (d, J = 7.3 Hz, 1H), 8.33 (t, J = 5.6 Hz, 1H), 7.90 (p, J = 4.0 Hz, 1H), 7.78 (dd, J = 8.6, 7.2 Hz, 1H), 7.54 (d, J = 15.9 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.89 (dd, J = 15.8, 1.9 Hz, 1H), 5.24 (s, 2H), 5.10 (dd, J = 12.8, 5.5 Hz, 1H), 3.61 (d, J = 5.1 Hz, 5H), 3.41 - 3.12 (m, 7H), 2.95-2.78 (m, 3H), 2.64-2.57 (m, 1H), 2.54 (d, J = 4.3 Hz, 1H), 2.06-1.99 (m, 1H), 1.67 (br, 2H), 1.52-1.40 (m, 3H), 1.36-1.28 (m, 2H), 1.28-1.20 (q, J = 6.9 Hz, 2H), 1.08-1.00 (m, 2H). HRMS (ESI) C 43 H 48 N7O8 + [M+H] + , calculated 790.3559; found, 790.3562.

[0774] Example 60: Preparation of (E)-N-(4-(1-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)pentanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632034)

[0775] The target compound (SIAIS632034) (pale yellow solid, 8.7 mg, yield 26%) was prepared according to the procedure of Reference Example 1, according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)pentanoic acid; CAS Registry Number 2169266-67-3). 1HNMR (500 MHz, CD3OD) δ 8.99 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 5.5 Hz, 1H), 8.67 (dt, J = 8.3, 1.7 Hz, 1H), 7.98 (dd, J = 8.2, 5.5 Hz, 1H), 7.77 (dd, J = 8.5, 7.3 Hz, 1H), 7.62 (d, J = 15.8 Hz, 1H), 7.44 (dd, J = 7.9, 6.7 Hz, 2H), 7.39 - 7.30 (m, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 15.9 Hz, 1H), 5.07 (dd, J = 12.5, 5.5 Hz, 1H), 4.28 (t, J = 5.7 Hz, 2H), 3.79 - 3.60 (m, 4H), 3.35-3.30 (m, 6H), 3.24-3.22 (m, 4H), 2.88 - 2.77 (m, 2H), 2.71 - 2.60 (m, 3H), 2.13 - 2.05 (m, 1H), 1.98 - 1.86 (m, 4H), 1.77 (br, 2H), 1.59 (p, J = 7.2 Hz, 3H), 1.47 - 1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 46 H 54 N7O8 + [M+H] + , calculated 832.4028; found 832.4029.

[0776] Example 61: Preparation of (E)-N-(4-(1-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)hexanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632035)

[0777] The target compound (SIAIS632035) (pale yellow solid, 7.2 mg, yield 21%) was prepared according to the procedure of Example 1, according to Scheme 15, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)hexanoic acid; CAS Registry Number 2087490-48-8). 1HNMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.97 (d, J = 10.8 Hz, 1H), 8.74 (q, J = 5.5 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J = 7.5 Hz, 1H), 7.80 (dd, J = 8.5, 7.2 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.97 - 6.93 (m, 2H), 6.84 (d, J = 15.1 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.62 - 3.56 (m, 7H), 3.25 - 3.15 (m, 6H), 2.90 - 2.85 (m, 2H), 2.62 - 2.55 (m, 1H), 2.53 - 2.51 (m, 1H), 2.38 (t, J = 7.4 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.81 - 1.76 (m, 2H), 1.71 - 1.55 (m, 4H), 1.53 - 1.42 (m, 5H), 1.35 - 1.21 (m, 4H), 1.09 - 1.00 (m, 2H). HRMS (ESI) C 47 H 56 N7O8 + [M+H] + , calculated 846.4185; found, 846.4189.

[0778] Example 62: Preparation of (E)-N-(4-(1-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)heptanoyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632036)

[0779] The target compound (SIAIS632036) (pale yellow solid, 9.6 mg, yield 26%) was prepared according to Scheme 15, referring to the method of Example 1, using dapelimab derivative 1 (SIAIS630006) and intermediate LM (7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)heptanoic acid; CAS Reg. No. 2169266-69-5). 1HNMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.97 (d, J = 5.4 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.33 - 8.24 (m, 1H), 7.81 (dd, J = 8.6, 7.3 Hz, 2H), 7.60 - 7.49 (m, 2H), 7.44 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 15.9 Hz, 1H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.21 (t, J = 6.4 Hz, 2H), 3.62 - 3.57 (m, 7H), 3.26 - 3.13 (m, 6H), 2.92 - 2.83 (m, 1H), 2.61 - 2.55 (m, 1H), 2.54 - 2.52 (m, 1H), 2.36 (t, J = 7.4 Hz, 2H), 2.06 - 1.98 (m, 1H), 1.80 - 1.74 (m, 2H), 1.71 - 1.64 (m, 2H), 1.57 - 1.43 (m, 7H), 1.42 - 1.28 (m, 4H), 1.27 - 1.21 (m, 2H), 1.11 - 0.99 (m, 2H). HRMS (ESI) C 48 H 58 N7O8 + [M+H] + , calculated 860.4341; found, 860.4346.

[0780] Example 63: Preparation of (E)-N-(4-(1-(4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hepta-6-yn-1-yl)piperidin-4-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631139)

[0781] The target compound (SIAIS631139) (white solid, 7.7 mg, yield 23%) was prepared according to Scheme 16, by following the procedure of Example 15, using daprodustat derivative 3 (SIAIS631127) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hepta-6-yn-1- yl methanesulfonate; CAS Registry Number 2570254-41-8). 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.62 (s, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.34 - 8.27 (m, 1H), 7.80 (dd, J = 8.2, 5.3 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.36 - 7.23 (m, 4H), 6.86 (d, J = 15.9 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.33 (d, J = 17.7 Hz, 1H), 3.57-3.52 (m, 2H), 3.18 (q, J = 6.6 Hz, 2H), 3.09 - 2.81 (m, 8H), 2.72 (br, 1H), 2.63 - 2.55 (m, 1H), 2.53 (t, J = 7.1 Hz, 2H), 2.48 - 2.43 (m, 1H), 2.10 (d, J = 12.6 Hz, 1H), 2.06-2.00 (m, 1H), 1.99 - 1.94 (m, 1H), 1.85 - 1.76 (m, 2H), 1.62 (q, J = 7.2 Hz, 3H), 1.53-1.43 (m, 5H), 1.35-1.22 (m, 4H), 1.05 (br, 2H). HRMS (ESI) C 49 H 59 N6O5 + [M+H] + , calculated 811.4541; found 811.4544.

[0782] Example 64: Preparation of (E)-N-(4-(1-(4-(1-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)piperidin-4-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631140)

[0783] The target compound (SIAIS631140) (white solid, 10.1 mg, yield 31%) was prepared according to Scheme 16, by following the procedure of Example 15, using daprodustat derivative 3 (SIAIS631127) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl methanesulfonate; CAS Registry Number 2570254-42-9).1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.90 (s, 1H), 8.69 (s, 1H), 8.27 (s, 2H), 7.71 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.36 - 7.25 (m, 4H), 6.82 (d, J = 16.2 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.7 Hz, 1H), 4.33 (d, J = 17.7 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.18 (q, J = 6.6 Hz, 2H), 3.09 - 2.80 (m, 8H), 2.73 (br, 1H), 2.65 - 2.57 (m, 1H), 2.52 (br, 2H), 2.49 - 2.42 (m, 1H), 2.12 - 2.01 (m, 2H), 1.97 (d, J = 13.6 Hz, 1H), 1.76 (br, 2H), 1.61 (p, J = 7.1 Hz, 3H), 1.53 - 1.42 (m, 5H), 1.40-1.27 (m, 4H), 1.27-1.21 (m, 2H), 1.05 (br, 2H). HRMS (ESI) C 50 H 61 N6O5 + [M+H] + , calculated 825.4698; found 825.4702.

[0784] Example 65: Preparation of (E)-N-(4-(l-(4-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)thio)butyl)piperidin-4-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631141)

[0785] The target compound (SIAIS631141) (white solid, 9.7 mg, yield 30%) was prepared according to Scheme 16, by reference to the method of Example 15, using daprodustat derivative 3 (SIAIS631127) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-l-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-59-1). 1HNMR (500MHz, CD3OD) δ 8.96 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8.2, 5.4 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.63 - 7.52 (m, 2H), 7.37 (s, 4H), 6.90 (d, J = 15.9 Hz, 1H), 5.18 (dd, J = 13.4, 5.2 Hz, 1H), 4.50 (d, J = 17.4 Hz, 1H), 4.43 (d, J = 17.4 Hz, 1H), 3.75 - 3.63 (m, 4H), 3.34 (d, J = 7.0 Hz, 2H), 3.23 - 3.04 (m, 7H), 3.02 - 2.91 (m, 1H), 2.86 - 2.76 (m, 1H), 2.59 - 2.51 (m, 1H), 2.25-2.17 (m, 1H), 2.14 - 1.93 (m, 7H), 1.87 (br, 1H), 1.78-1.72 (m, 2H), 1.71 - 1.64 (m, 1H), 1.59 (p, J = 7.2 Hz, 4H), 1.47 - 1.38 (m, 3H), 1.37 - 1.28 (m, 3H), 1.26 - 1.08 (m, 2H). HRMS (ESI) C 46 H 57 N6O5S+ + [M+H] + , calculated 805.4106; found, 805.4107.

[0786] Example 66: Preparation of (E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hept-6-yn-1-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3- carbonyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632005)

[0787] The target compound (SIAIS631139) (white solid, 8.3 mg, yield 24%) was prepared according to Scheme 16, by reference to the method of Example 15, using the dapansutrile derivative 5 (SIAIS631135) and the intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS Registry Number 2570254-41-8). 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.00 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.88 (br, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.7, 1.1 Hz, 2H), 7.58 (br, 1H), 7.55 - 7.53 (m, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 15.2 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 13.1 Hz, 2H), 4.47 (d, J = 17.7 Hz, 2H), 4.33 (d, J = 17.7 Hz, 1H), 3.94 (d, J = 13.0 Hz, 2H), 3.72 (br, 5H), 3.52 (br, 2H), 3.25 - 2.98 (m, 8H), 2.96-2.87 (m, 1H), 2.78 (t, J = 12.6 Hz, 1H), 2.67 - 2.55 (m, 1H), 2.52 (d, J = 7.3 Hz, 2H), 2.49 - 2.46 (m, 1H), 2.23 (d, J = 11.6 Hz, 2H), 2.05-1.97 (m, 1H), 1.82-1.72 (m, 5H), 1.67-1.54 (m, 4H), 1.53-1.43 (m, 4H), 1.36-1.29 (m, 2H), 1.28–1.22 (m, 2H), 1.16 -1.05 (m, 2H). HRMS (ESI) C 51 H 65 N 10 O5 + [M+H] + , calculated 897.5134; found, 897.5138.

[0788] Example 67: Preparation of (E)-N-(4-(l-(6-(4-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)oct-7-yn-l-yl)piperazin-l-yl)piperidin-l-yl)pyridazine-3- carbonyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632006)

[0789] The target compound (SIAIS632006) (white solid, 9.3 mg, yield 26%) was prepared according to Scheme 16, using dapansutrile derivative 5 (SIAIS631135) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl methanesulfonate; CAS Registry Number 2570254-42-9) according to the method of Example 15. 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.97 (s, 1H), 8.74 (s, 1H), 8.38 (d, J = 49.8 Hz, 2H), 7.83 (br, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.56 - 7.48 (m, 3H), 6.88 (d, J = 16.3 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 13.1 Hz, 2H), 4.47 (dd, J = 16.0, 10.9 Hz, 2H), 4.32 (d, J = 17.6 Hz, 1H), 3.95 (d, J = 13.5 Hz, 2H), 3.73 (br, 5H), 3.52 (br, 2H), 3.23 - 2.98 (m, 8H), 2.95- 2.85 (m, 1H), 2.83 - 2.74 (m, 1H), 2.70 - 2.58 (m, 1H), 2.49 (br, 2H), 2.47 - 2.43 (m, 1H), 2.22 (br, 2H), 2.10-1.96 (m, 1H), 1.83-1.70 (m, 5H), 1.67 - 1.50 (m, 4H), 1.47 (p, J = 7.2 Hz, 4H), 1.37-1.29 (m, 4H), 1.28-1.21 (m, 2H), 1.18-1.05 (m, 2H). HRMS (ESI): C 52 H 67 N 10 O5 + [M+H] + , calculated 911.5290; found, 911.5294.

[0790] Example 68: Preparation of (E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)butyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carbonyl)piperidin-4- yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632007)

[0791] The target compound (SIAIS632007) was prepared according to Scheme 16, using dapansutrine derivative 5 (SIAIS631135) and intermediate LM (SIAIS213134; 3-(4-(4- bromobutylsulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-59-1) following the procedure of Example 15 (white solid, 9.7 mg, 28% yield). 1 HNMR (500MHz, DMSO-d6) δ 10.99 (s, 1H), 8.99 (s, 1H), 8.76 (d, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.91 - 7.76 (m, 1H), 7.71 - 7.61 (m, 2H), 7.62 - 7.48 (m, 4H), 6.89 (d, J = 15.9 Hz, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.62 (d, J = 13.1 Hz, 2H), 4.48 (d, J = 12.9 Hz, 1H), 4.39 (d, J = 17.4 Hz, 1H), 4.25 (d, J = 17.4 Hz, 1H), 3.95 (d, J = 13.2 Hz, 2H), 3.65 (br, 7H), 3.22 - 3.12 (m, 6H), 3.03 (t, J = 13.0 Hz, 2H), 2.95 - 2.86 (m, 1H), 2.78 (t, J = 12.6 Hz, 1H), 2.63 - 2.56 (m, 1H), 2.55 - 2.51 (m, 2H), 2.49 - 2.43 (m, 1H), 2.23 (d, J = 11.6 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.87 (t, J = 8.0 Hz, 2H), 1.77 (br, 3H), 1.68 - 1.62 (m, 3H), 1.54 (br, 1H), 1.46 (q, J = 7.2 Hz, 2H), 1.38 - 1.30 (m, 2H), 1.28 - 1.22 (m, 2H), 1.16 - 1.06 (m, 2H). HRMS (ESI) C 48 H 63 N 10 O5S + [M+H] + , calculated 891.4698; found, 891.4603.

[0792] Example 69: Preparation of (E)-N-(4-(1-(6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hepta-6-yn-1-yl)piperazin-1-yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)- 3-(pyridin-3-yl)acrylamide (SIAIS632010)

[0793] The target compound (SIAIS632010) (white solid, 7.7 mg, yield 24%) was prepared according to Scheme 16, using dapansutrine derivative 4 (SIAIS632004) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hepta-6-yn-1- yl methanesulfonate; CAS Registry Number 2570254-41-8) following the procedure of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.94 (s, 1H), 8.71 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 15.8 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.53 (d, J = 17.5 Hz, 1H), 4.47 (d, J = 17.5 Hz, 1H), 3.93 (d, J = 13.2 Hz, 2H), 3.71 (s, 2H), 3.51 - 3.37 (m, 2H), 3.34 (d, J = 7.1 Hz, 2H), 3.27 - 3.22 (m, 3H), 3.20 - 3.13 (m, 2H), 2.95-2.87 (m, 2H), 2.85-2.76 (m, 1H), 2.57 (t, J = 6.9 Hz, 2H), 2.54 - 2.47 (m, 1H), 2.25-2.15 (m, 1H), 1.95-1.86 (m, 3H), 1.79-1.70 (m, 3H), 1.65-1.55 (m, 5H), 1.46-1.40 (m, 2H), 1.39-1.30 (m, 2H), 1.29-1.16 (m, 3H). HRMS (ESI) C 46 H 56 N9O5 + [M+H] + , calculated 814.4399; found 814.4403.

[0794] Example 70: Preparation of (E)-N-(4-(1-(6-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)piperazin-1-yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)- 3-(pyridin-3-yl)acrylamide (SIAIS632011)

[0795] The target compound (SIAIS632011) (white solid, 9.2 mg, yield 28%) was prepared according to Scheme 16, using dapansutrine derivative 4 (SIAIS632004) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl methanesulfonate; CAS Registry Number 2570254-42-9) following the procedure of Example 15. 1 H NMR (500 MHz, CD3OD) δ 9.06 (d, J = 1.8 Hz, 1H), 8.82 - 8.79 (m, 2H), 8.09 (dd, J = 7.8, 6.0 Hz, 1H), 7.75 (dd, J = 7.7, 1.0 Hz, 1H), 7.70 (d, J = 9.5 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.53 - 7.49 (m, 2H), 6.95 (d, J = 15.8 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.63 (d, J = 12.5 Hz, 2H), 4.53 (d, J = 17.5 Hz, 1H), 4.47 (d, J = 17.4 Hz, 1H), 3.93 (d, J = 13.3 Hz, 1H), 3.72 (s, 2H), 3.54 - 3.42 (m, 2H), 3.36-3.34 (m, 3H), 3.25 - 3.19 (m, 3H), 3.18-3.14 (m, 1H), 2.96-2.87 (m, 3H), 2.85-2.76 (m, 1H), 2.59 - 2.45 (m, 3H), 2.25-2.15 (m, 1H), 1.93-1.81 (m, 3H), 1.78 - 1.66 (m, 3H), 1.65-1.59 (m, 5H), 1.54-1.47 (m, 2H), 1.47 - 1.40 (m, 2H), 1.37-1.31 (m, 2H), 1.31 - 1.20 (m, 3H). HRMS (ESI) C 47 H 58 N9O5 + [M+H] + , calculated 828.4555; found 828.4559.

[0796] Example 71: Preparation of (E)-N-(4-(1-(6-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)butyl)piperazin-1-yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632012)

[0797] The target compound (SIAIS632012) (white solid, 8.7 mg, yield 27%) was prepared according to Scheme 16, using dapansutrile derivative 4 (SIAIS632004) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Registry Number 2378582-59-1) following the procedure of Example 15. 1 HNMR (500MHz, CD3OD) δ 9.04 (s, 1H), 8.81-8.75 (m, 2H), 8.07 (dd, J = 8.2, 5.6 Hz, 1H), 7.73-7.61 (m, 4H), 7.56 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 6.93 (d, J = 15.8 Hz, 1H), 5.19 (dd, J = 13.4, 5.2 Hz, 1H), 4.63 (d, J = 13.1 Hz, 2H), 4.50 (d, J = 17.4 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 3.94 (d, J = 13.7 Hz, 1H), 3.67 (s, 1H), 3.48-3.41 (m, 1H), 3.34 (d, J = 7.7 Hz, 3H), 3.24-3.12 (m, 6H), 2.96-2.88 (m, 2H), 2.84-2.77 (m, 1H), 2.61-2.49 (m, 1H), 2.22-2.19 (m, 1H), 2.00-1.86 (m, 3H), 1.78-1.70 (m, 3H), 1.64-1.58 (m, 3H), 1.50-1.41 (m, 2H), 1.40-1.34 (m, 3H), 1.33-1.22 (m, 4H). HRMS (ESI) C 43 H 54 N9O5S + [M+H] + , calculated 808.3963; found, 808.3967.

[0798] Example 72: Preparation of (E)-N-(4-(1-(6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hepta-6-yn-1-yl)piperazin-1-yl)nicotinoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632039)

[0799] The target compound (SIAIS632039) (white solid, 6.5 mg, 20%) was prepared according to Scheme 16, using dapansutrine derivative 6 (SIAIS632025) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hepta-6-yn-1- yl methanesulfonate; CAS Registry Number 2570254-41-8) in reference to the method of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.70 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 8.2, 5.4 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 8.8, 2.4 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 15.8 Hz, 1H), 5.19 (dd, J = 13.4, 5.2 Hz, 1H), 4.62 - 4.51 (m, 3H), 4.47 (d, J = 17.4 Hz, 1H), 3.85 - 3.60 (m, 2H), 3.34 (d, J = 7.3 Hz, 6H), 3.26 - 3.20 (m, 3H), 3.19 - 3.13 (m, 2H), 2.96 - 2.87 (m, 1H), 2.84 - 2.78 (m, 1H), 2.57 (t, J = 6.9 Hz, 3H), 2.26 - 2.10 (m, 1H), 1.88 - 1.85 (m, 3H), 1.75 (q, J = 7.3 Hz, 2H), 1.63 - 1.59 (m, 5H), 1.50 - 1.39 (m, 2H), 1.36 - 1.32 (m, 4H), 1.32 - 1.28 (m, 2H). HRMS (ESI) C 47 H 57 N8O5 + [M+H] + , calculated 813.4446; found, 813.4449.

[0800] Example 73: Preparation of (E)-N-(4-(1-(6-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)piperazin-1-yl)nicotinoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632040)

[0801] The target compound (SIAIS632040) (white solid, 7.4 mg, 22%) was prepared according to Scheme 16, using dapansutrine derivative 6 (SIAIS632025) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl methanesulfonate; CAS Registry Number 2570254-42-9) by the method described in Example 15. 1 H NMR (500 MHz, CD3OD) δ 9.07 (s, 1H), 8.87 - 8.78 (m, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.1, 5.8 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.67 - 7.59 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 15.9 Hz, 1H), 5.18 (dd, J = 13.3, 5.2 Hz, 1H), 4.62 - 4.50 (m, 3H), 4.47 (d, J = 17.5 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.40 - 3.32 (m, 6H), 3.24 - 3.16 (m, 5H), 2.97 - 2.87 (m, 1H), 2.83 - 2.75 (m, 1H), 2.53 (t, J = 6.8 Hz, 3H), 2.24 - 2.15 (m, 1H), 1.91 - 1.75 (m, 4H), 1.72 - 1.68 (m, 2H), 1.65 - 1.56 (m, 5H), 1.52 - 1.40 (m, 4H), 1.39 - 1.28 (m, 3H), 1.21 - 1.14 (m, 2H). HRMS (ESI) C 48 H 59 N8O5 + [M+H] + , calculated 827.4603; found 827.4608.

[0802] Example 74: Preparation of (E)-N-(4-(1-(6-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)thio)butyl)piperazin-1-yl)nicotinoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS632041)

[0803] The target compound (SIAIS632041) (white solid, 7.6 mg, 24%) was prepared according to Scheme 16, by reference to the method of Example 15, using dapansutrile derivative 6 (SIAIS632025) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; CAS Reg. No. 2378582-59-1). 1 H NMR (500 MHz, CD3OD) δ 9.05 (s, 1H), 8.87-8.71 (m, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.2, 5.7 Hz, 1H), 7.74-7.66 (m, 3H), 7.63 (d, J = 15.8 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.95 (d, J = 15.9 Hz, 1H), 5.18 (dd, J = 13.3, 5.2 Hz, 1H), 4.59-4.47 (m, 3H), 4.43 (d, J = 17.4 Hz, 1H), 3.86 (s, 1H), 3.71-3.56 (m, 2H), 3.34 (t, J = 7.2 Hz, 6H), 3.24-3.07 (m, 6H), 3.25-3.10 (m, 1H), 2.97-2.86 (m, 1H), 2.60-2.50 (m, 1H), 2.25-2.15 (m, 1H), 1.96 (p, J = 7.3 Hz, 2H), 1.83-1.69 (m, 4H), 1.60 (p, J = 7.3 Hz, 3H), 1.48-1.27 (m, 5H), 1.23-1.10 (m, 2H). HRMS (ESI) C 44 H 55 N8O5S + [M+H] + , calculated 807.4011; found 807.4016.

[0804] Example 75: Preparation of (E)-N-(4-(1-(4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)propionyl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631079)

[0805] The target compound (SIAIS631079) (yellow solid, 8.9 mg, yield 27%) was prepared according to Scheme 15, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS151001; 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoic acid; CAS Registry Number 2139348-60-8) following the procedure of Example 1. 1 H NMR (500 MHz, CD3OD) δ 8.94 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.55 (dt, J = 8.2, 1.8 Hz, 1H), 7.89 (dd, J = 8.2, 5.4 Hz, 1H), 7.60 (d, J = 15.9 Hz, 1H), 7.51 (dd, J = 8.6, 7.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.02 (dd, J = 15.3, 7.8 Hz, 2H), 6.88 (dd, J = 12.4, 3.5 Hz, 3H), 5.01 (dd, J = 12.5, 5.4 Hz, 1H), 3.82 (t, J = 5.9 Hz, 2H), 3.79 - 3.66 (m, 6H), 3.52-3.43 (m, 3H), 3.40 - 3.33 (m, 5H), 3.26 - 3.15 (m, 4H), 2.81 - 2.75 (m, 1H), 2.75 - 2.68 (m, 3H), 2.67 - 2.59 (m, 1H), 2.07 - 1.99 (m, 1H), 1.77 (br, 2H), 1.59 (p, J = 7.1 Hz, 3H), 1.47 - 1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.16 (br, 2H). HRMS (ESI) C 43 H 48 N7O7S + [M+H] + , calculated 847.4137; found, 847.4139.

[0806] Example 76: Preparation of (E)-N-(4-(1-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperazin-1-yl)benzoyl)piperidin-4- yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS631109)

[0807] The target compound (SIAIS631109) was prepared according to Scheme 15, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS151004; 3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid; CAS Reg. No. 2140807-17-4) according to the procedure of Example 1 (yellow solid, 9.6 mg, 27% yield). 1 H NMR (500 MHz, CD3OD) δ 9.02 (s, 1H), 8.76 (d, J = 21.8 Hz, 2H), 8.04 (s, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.97 - 6.89 (m, 2H), 5.05 (dd, J = 12.4, 5.5 Hz, 1H), 3.77 - 3.69 (m, 7H), 3.67 - 3.60 (m, 8H), 3.50 (t, J = 5.3 Hz, 3H), 3.47 - 3.42 (m, 1H), 3.38 (dd, J = 6.6, 3.9 Hz, 2H), 3.27-3.20 (m, 1H), 2.88 - 2.81 (m, 2H), 2.76 (dt, J = 5.3, 2.7 Hz, 1H), 2.75 - 2.72 (m, 1H), 2.72 - 2.68 (m, 1H), 2.54 (t, J = 6.3 Hz, 3H), 2.18 - 2.03 (m, 1H), 1.59 (p, J = 7.1 Hz, 3H), 1.42 (br, 2H), 1.39 - 1.28 (m, 3H), 1.25 - 1.09 (m, 2H). HRMS (ESI) C 48 H 59 N8O9 + [M+H] + , calculated 891.4400; found, 891.4403.

[0808] Example 77: Preparation of (E)-N-(4-(1-(4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)pent-4-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631119)

[0809] The target compound (SIAIS631119) (white solid, 8.7 mg, yield 28%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS292006; 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pent-4-yn-1- yl methanesulfonate; CAS Registry Number 2570254-45-2) following the procedure of Example 15. 1 H NMR (500 MHz, DMSO-d6) d 11.14 (s, 1H), 11.08 (s, 1H), 8.88 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 5.1, 1.5 Hz, 1H), 8.26 (q, J = 8.2, 6.9 Hz, 2H), 8.00 - 7.88 (m, 3H), 7.68 (dd, J = 8.1, 5.0 Hz, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 15.8 Hz, 1H), 5.16 (dd, J = 12.9, 5.4 Hz, 1H), 3.92 (d, J = 12.4 Hz, 2H), 3.62 (d, J = 11.5 Hz, 2H), 3.34 - 3.14 (m, 8H), 2.94 - 2.85 (m, 1H), 2.67 (t, J = 6.9 Hz, 2H), 2.63 - 2.58 (m, 1H), 2.57 - 2.52 (m, 1H), 2.15 - 2.01 (m, 3H), 1.67 (br, 2H), 1.46 (q, J = 7.3 Hz, 3H), 1.35 - 1.18 (m, 5H), 1.10 - 1.00 (m, 2H). HRMS (ESI) C 46 H 52 N7O6 + [M+H] + , calculated 798.3974; found, 798.3977.

[0810] Example 78: Preparation of (E)-N-(4-(1-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)hex-5-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631120)

[0811] The target compound (SIAIS631120) (white solid, 8.9 mg, yield 28%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS292007; 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1- yl methanesulfonate; CAS Registry Number 2641288-61-9) following the procedure of Example 15. 1 H NMR (500 MHz, CD3OD) δ 8.72 (s, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.78 - 7.72 (m, 3H), 7.57 (dd, J = 8.1, 5.1 Hz, 1H), 7.47 (d, J = 15.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 15.9 Hz, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.46 (s, 1H), 3.87 (s, 2H), 3.72 (s, 1H), 3.61 (s, 2H), 3.23 (d, J = 7.2 Hz, 2H), 3.22 - 3.16 (m, 4H), 3.10 - 3.02 (m, 2H), 2.82 - 2.73 (m, 2H), 2.71 - 2.60 (m, 2H), 2.54 (t, J = 6.8 Hz, 2H), 2.09 - 2.02 (m, 1H), 1.98 - 1.87 (m, 2H), 1.67 (p, J = 7.1 Hz, 4H), 1.49 (p, J = 7.4 Hz, 4H), 1.35 - 1.27 (m, 2H), 1.28 - 1.17 (m, 2H), 1.07 (br, 2H). HRMS (ESI) C 47 H 54 N7O6 + [M+H] + , calculated 812.4130; found, 812.4132.

[0812] Example 79: Preparation of (E)-N-(4-(1-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)hept-6-yn-1-yl)piperazin-1-yl)benzoyl)piperidin-4-yl)butyl)-3- (pyridin-3-yl)acrylamide (SIAIS631108)

[0813] The target compound (SIAIS631108) (white solid, 7.7 mg, yield 23%) was prepared according to Scheme 16, using dapansutrine derivative 1 (SIAIS630006) and intermediate LM (SIAIS292016; 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hept-6-yn-1- yl methanesulfonate; CAS Registry Number 2641288-62-0) by referring to the method of Example 15. 1 H NMR (500 MHz, DMSO-d6) d 11.14 (s, 1H), 11.10 (s, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H), 8.36 (t, J = 5.6 Hz, 1H), 7.94 - 7.83 (m, 4H), 7.53 (d, J = 15.9 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 15.9 Hz, 1H), 5.16 (dd, J = 12.9, 5.4 Hz, 1H), 3.90 (d, J = 13.0 Hz, 2H), 3.56 (d, J = 11.8 Hz, 2H), 3.27 - 3.07 (m, 8H), 2.95 - 2.85 (m, 1H), 2.65 - 2.57 (m, 1H), 2.56 (t, J = 6.9 Hz, 3H), 2.10 - 2.03 (m, 1H), 1.88 - 1.75 (m, 2H), 1.70 - 1.60 (m, 4H), 1.52 - 1.43 (m, 5H), 1.35 - 1.21 (m, 4H), 1.05 (m, 2H). HRMS (ESI) C 48 H 56 N7O6 + [M+H] + , calculated 862.4287; found, 862.428.

[0814] Example 80: Preparation of (E)-N-(4-(1-(4...

Claims

1. A compound of formula (I): ###0001### (I) or a salt thereof; wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linking moiety, the remainder of the molecule of formula (I) is a nicotinamide phosphoribosyl transferase (NAMPT) ligand, and ULM is covalently linked to the NAMPT ligand via LIN; wherein ring A is a group: ###0002### m represents an integer of 1 ; and Y is n linked rings D represented by the following structural formula: ###0003### n is an integer of 1 or 2, wherein when n represents an integer of 2, each ring D can be the same or different; ULM represents a structure of formula (III-1): ###0004### wherein R represents S, and W represents a bond; LIN represents a formula: ###0005### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and 2. The compound of formula (I) or a salt thereof of claim 1, wherein Y represents the following structure: ###0006### wherein the symbol ** indicates the point of attachment to ring C.

3. The compound of formula (I) or a salt thereof of claim 1, wherein ULM represents a structure of the following formula: ###0007### (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R a is independently halo, and m1 represents an integer of 0; R 1 and R 2 are the same or different and independently of each other H, cyano or methyl; L1represents a substituted or unsubstituted straight chain C 3-6 alkylene, said straight chain C 3-6 alkylene is selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl or any combination thereof; Ring B is a piperidinylene or piperazinylene group, (R b ) m2 represents that ring B is optionally substituted with m2 R b groups, each R b is independently C 1-3 alkyl, halo, C 1-3 alkoxy, haloC 1-3 alkyl or cyano, and m2 represents an integer 0, 1, 2, 3, 4 or 5; Ring C is phenylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, (R c ) m3 represents a ring C optionally replaced by m3 R c Group substitution, each R c Independently C 1-3 Alkyl, halogen, C 1-3 Alkoxy, halogenated C 1-3 alkyl or cyano, and m3 represents an integer of 0, 1, 2, 3, 4 or 5; 4. The compound of formula (I) or a salt thereof of any one of claims 1-3, wherein LIN represents a formula: ###0008### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and 5. The compound of formula (I) or a salt thereof of any one of claims 1-3, wherein LIN represents a formula: ###0009### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and each ring D is independently piperidinylene or piperazinylene, (R d ) m4 represents that each ring D is optionally and independently substituted with m4 R d groups, each R d is independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halo, oxo, C 1-3 alkoxy, C 1-3 alkylamino, haloC 1-3 alkyl, amino-substituted C 1-3 alkylene, or cyano, and m4 represents an integer 0, 1, 2, 3, 4, or 5; 6. The compound of formula (I) or a salt thereof of claim 1, wherein LIN represents a group: # -U- (CH2)2-, # -U- (CH2)3-, # -U- (CH2)4-, # -U- (CH2)5-, # -U- (CH2)6-, # -U- (CH2)7-, # -U- (CH2)8-, or # -U- (CH2)9-; wherein one or more hydrogens of CH2 of said group are optionally further replaced by a substituent selected from the group consisting of C1-C3 alkyl, halo, C1-C3 alkoxy, halo C1-C3 alkyl, and cyano, and U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y.

7. A compound of formula (I): ###0010### (I) or a salt thereof; wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linking moiety, the remainder of the molecule of formula (I) is a nicotinamide phosphoribosyl transferase (NAMPT) ligand, and ULM is covalently linked to the NAMPT ligand via LIN; wherein ring A is a group: ###0011### m represents an integer of 1 ; and Y is n linked rings D represented by the following structural formula: ###0012### n is an integer of 1 ; ULM represents a structure of formula (III-1): ###0013### LIN represents a formula: ###0014### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y; and 8. The compound of formula (I) or a salt thereof of claim 7, wherein Y represents the following structure: ###0015### wherein the symbol ** indicates the point of attachment to ring C. (R f ) m5 The phenyl ring of formula (III-1) is optionally substituted with m5 R f groups, each R f is independently halogen, m5 represents an integer 0, 1, 2 or 3; and Z represents CH2; and 9. The compound of formula (I) or a salt thereof of claim 7, wherein ULM represents a structure of the following formula: ###0016### ​ ​ said alkylene is a straight chain or branched C 2-9 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ wherein (R f ) m5 represents that the phenyl ring is optionally substituted with m5 R f groups, each R f is independently halo, and m5 represents an integer 0, 1, 2, or 3. ​ ​ ​ said alkylene is a straight chain or branched C 2-8 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ said alkylene is a straight chain or branched C 3-7 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ ​ (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R a is independently halo, and m1 represents an integer of 0; R 1 and R 2 are the same or different and independently of each other H, cyano or methyl; L1represents a substituted or unsubstituted straight chain C 3-6 alkylene, said straight chain C 3-6 alkylene is selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl or any combination thereof; Ring B is a piperidinylene or piperazinylene group, (R b ) m2 represents that ring B is optionally substituted with m2 R b groups, each R b is independently C 1-3 alkyl, halo, C 1-3 alkoxy, haloC 1-3 alkyl, or cyano, and m2 represents an integer 0, 1, 2, 3, 4, or 5; Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkenyl, (R c ) m3 represents that ring C is optionally substituted with m3 R c groups, each R c is independently C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl, or cyano, and m3 represents an integer 0, 1, 2, 3, 4, or 5; ​ ​ each ring D is independently a piperazinyl group, (R d ) m4 represents that each ring D is optionally and independently substituted with m4 R d groups, each R d is independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, halogenated C 1-3 alkyl, amino-substituted C 1-3 alkylene, or cyano, and m4 represents an integer 0, 1, 2, 3, 4, or 5; ​ ​ wherein R represents N(R 4 ), wherein R 4 represents H or C 1-3 alkyl, and W represents a bond; (R f ) m5 The phenyl ring of formula (III-1) is optionally substituted with m5 R f groups, each R f is independently halogen, m5 represents an integer 0, 1, 2, or 3; and Z represents C(O); and ​ ​ ​ said alkylene is a straight chain or branched C 1-10 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ wherein R 4 represents H or C 1-3 alkyl; (R f ) m5 represents that the phenyl ring is optionally substituted with m5 R f groups, each R f is independently halo, and m5 represents an integer 0, 1, 2, or 3.

10. The compound of formula (I) according to any one of claims 7 to 9, wherein LIN represents the following formula: ###0005### or a salt thereof. #-U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and said alkylene is a straight chain or branched C 1-9 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano.

11. The compound of formula (I) according to any one of claims 7 to 9, wherein LIN represents the following formula: ###0006### or a salt thereof. #-U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and said alkylene is a straight chain or branched C 1-8 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano.

12. The compound of formula (I) according to any one of claims 7 to 9, wherein LIN represents the following formula: ###0007### or a salt thereof. #-U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and said alkylene is a straight chain or branched C 2-8 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano.

13. A compound of formula (I) or a salt thereof as claimed in claim 7, wherein LIN represents the following group: #-U-CH2-, #-U-(CH2)2-, #-U-(CH2)3-, #-U-(CH2)4-, #-U-(CH2)5-, #-U-(CH2)6-, #-U-(CH2)7-, #-U-(CH2)8-, #-U-(CH2)9-, or #-U-(CH2) 10 -; wherein the hydrogen of one or more CH2 of the group may be further replaced by a substituent selected from the group consisting of C1-C3 alkyl, halogen, C1-C3 alkoxy, halo-C1-C3 alkyl and cyano, and U represents C(O) or U represents a bond, and the symbol # represents the point of attachment to the group Y.

14. The compound of formula (I): ###0008### or a salt thereof, wherein ULM is an E3 ubiquitin ligase ligand moiety, LIN is a linker moiety, the remainder of the molecule of formula (I) is a nicotinamide phosphoribosyl transferase (NAMPT) ligand, ULM is covalently linked to the NAMPT ligand via LIN; wherein ring A is the following group: ###0009### m represents the integer 1 ; and (R a ) m1 represents that ring A is optionally substituted with m1 R a groups, each R a is independently halo, and m1 represents an integer of 0; R 1 and R 2 are identical or different and independently of each other H, cyano or methyl; L1represents a substituted or unsubstituted straight chain C 3-6 alkylene, said straight chain C 3-6 alkylene is selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, halogenated C 1-3 alkyl or any combination thereof; Ring B is a piperidino group, (R b ) m2 represents that ring B is optionally substituted with m2 R b groups, each R b is independently C 1-3 alkyl, halo, C 1-3 alkoxy, haloC 1-3 alkyl or cyano, and m2 represents an integer 0, 1, 2, 3, 4 or 5; Ring C is phenylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, (R c ) m3 represents a ring C optionally replaced by m3 R c Group substitution, each R c Independently C 1-3 Alkyl, halogen, C 1-3 Alkoxy, halogenated C 1-3 alkyl or cyano, and m3 represents an integer of 0, 1, 2, 3, 4 or 5; Y is n connected rings D represented by the following structural formula: ###0010### n is the integer 1 or 2, wherein when n represents the integer 2, each ring D can be the same or different; each ring D is independently piperidinylene or piperazinylene, (R d ) m4 represents that each ring D is optionally and independently substituted with m4 R d groups, each R d is independently C 1-3 alkyl, C 3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, oxo, C 1-3 alkoxy, C 1-3 alkylamino, haloC 1-3 alkyl, amino-substituted C 1-3 alkylene, or cyano, and m4 represents an integer 0, 1, 2, 3, 4, or 5; ULM represents the structure of formula (III-1): ###0011### wherein R represents ethynylene, and W represents a bond; LIN represents the following formula: ###0012### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and (R f ) m5 The phenyl ring of formula (III-1) is optionally substituted with m5 R f groups, each R f is independently halogen, m5 represents an integer 0, 1, 2 or 3; and Z represents CH2; and 15. The compound of formula (I) according to claim 14, wherein Y represents the following structure: ###0013### wherein the symbol ** indicates the point of attachment to ring C.

16. The compound of formula (I) according to claim 14, wherein ULM represents the structure of the following formula: ###0014### 17. The compound of formula (I) according to any one of claims 14 to 16, wherein LIN represents the following formula: ###0015### -U-alkylene, said alkylene is a straight chain or branched C 1-6 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and 18. The compound of formula (I) according to any one of claims 14 to 16, wherein LIN represents the following formula: ###0016### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and wherein (R f ) m5 represents that the phenyl ring is optionally substituted with m5 R f groups, each R f is independently halo, and m5 represents an integer 0, 1, 2, or 3.

19. The compound of formula (I) according to any one of claims 14 to 16, wherein LIN represents the following formula: ###0017### -U-alkylene, wherein U represents C(O) or U represents a bond, and the symbol # indicates the point of attachment to the group Y; and ​ said alkylene is a straight chain or branched C 2-6 alkylene, optionally substituted by a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ said alkylene is a straight chain or branched C 1-5 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano. ​ ​ ​ said alkylene is a straight chain or branched C 1-4 alkylene, optionally substituted with a substituent selected from the group consisting of C1-C3alkyl, halogen, C1-C3alkoxy, halogenated C1-C3alkyl and cyano.

20. A compound of formula (I) or a salt thereof as claimed in claim 14, wherein LIN represents a group: #-U-CH2-, #-U-(CH2)2-, #-U-(CH2)3-, #-U-(CH2)4-, #-U-(CH2)5- or #-U-(CH2)6-; wherein the hydrogen of one or more CH2 of said group is optionally further replaced by a substituent selected from the group consisting of C1-C3 alkyl, halogen, C1-C3 alkoxy, halo C1-C3 alkyl and cyano, and U represents C(O) or U represents a key, and the symbol # represents a point of attachment to the group Y.

21. The compound of formula (I) or a salt thereof according to claim 1, which is selected from:

22. The compound of formula (I) or a salt thereof according to claim 7, which is selected from:

23. The compound of formula (I) or a salt thereof according to claim 14, which is selected from:

24. A compound of formula (I) or a salt thereof as described in any one of claims 1, 7, 14 and 21-23, which is a hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate or p-toluenesulfonate salt of the compound of formula (I).

25. A pharmaceutical composition comprising as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, and at least one pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25, further comprising at least one additional therapeutic agent.

27. A pharmaceutical kit or test kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 24 or a pharmaceutical composition as claimed in claim 25 or 26.

28. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, or a pharmaceutical composition according to claim 25 or 26, for preparing a medicament for preventing and / or treating a disease or condition associated with nicotinamide phosphoribosyltransferase (NAMPT).

29. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 24, or a pharmaceutical composition as claimed in claim 25 or 26, for preparing a pharmaceutical composition for preventing and / or treating a disease or condition selected from the group consisting of tumors, autoimmune diseases, inflammatory diseases, pregnancy-induced hypertension, cardiovascular and cerebrovascular diseases, obesity and diabetic nephropathy.

30. The use according to claim 28 or 29, wherein the disease or condition is selected from: Colorectal cancer; breast cancer; astrocytoma; pancreatic cancer; gastric cancer; prostate cancer; melanoma; leukemia; ovarian cancer; Liver cancer; lung cancer; glioblastoma; multiple myeloma; esophageal cancer; bladder cancer; thyroid cancer; endometrial cancer; lymphoma; neuroendocrine tumor; renal cancer; pediatric glioma; rhabdomyosarcoma; leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; oral squamous cell carcinoma; autoimmune disease; cardiovascular and cerebrovascular disease; inflammatory disease; pregnancy-induced hypertension syndrome; obesity and diabetic nephropathy.

31. The use of claim 28 or 29, wherein the disease or disorder is selected from: triple-negative breast cancer, invasive breast cancer, infiltrating breast cancer, acute myeloid leukemia, acute lymphoblastic leukemia, non-small cell lung cancer, small cell lung cancer, diffuse large B-cell tumor, follicular B-cell lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma, renal oncocytoma, renal clear cell carcinoma, renal urothelial carcinoma; rheumatoid arthritis, autoimmune encephalitis, coronary atherosclerosis, acute myocardial infarction, myocardial ischemia-reperfusion injury, and ischemic stroke.

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