Patent Application
20250144223
The present disclosure relates to protein degradation compounds of Formula (I) designed based on nicotinamide phosphoribosyltransferase (NMPRTase; NAMPT) target protein or salts, enantiomers, stereoisomers, solvates, prodrugs or polymorphs thereof, as well as theirs use in the treatment or prevention of diseases or disorders associated with NAMPT.
Nicotinamide adenine dinucleotide (NAD+) as an enzyme cofactor for transferring hydrogen participates in various physiological functions such as energy synthesis, cellular metabolism, DNA repair, etc[1]. As an important small-molecule metabolite, nicotinamide adenine dinucleotide (NAD+) is widely involved in a series of biochemical reactions in cell energy metabolism, such as glycolysis, oxidative phosphorylation, and fatty acid oxidation. Therefore, NAD+ is crucial for human health[2].
There are three biosynthetic pathways for NAD+[3]:
1. De novo pathway. This pathway starts with indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), which catalyze the conversion of tryptophan into N-formylkynurenine. Then, N-formylkynurenine is converted by formamidase (KFase) to kynurenine which is then hydroxylated by kynurenine 3-hydroxylase (K3H) to produce 3-hydroxykynurenine. The product 3-hydroxykynurenine is further converted into 3-hydroxyanthranilic acid which is then converted into 2-amino-3-carboxymuconate-6-semialdehyde (ACMS) by kynureninase (Kyase) and 3-hydroxyanthranilate 3,4-dioxygenase[4]. ACMS then cyclizes to form quinolinic acid (QA) that participates in NAMN biosynthesis with quinolinate phosphoribosyltransferase (QPRT)[5,6].
2. Preiss-Handler pathway. This pathway starts with the conversion of nicotinic acid (NA) to nicotinamide mononucleotide (NAMN) by Nicotinate Phosphoribosyltransferase (NAPRT)[7]. NAMN is then used for the biosynthesis of nicotinic acid adenine dinucleotide (NAAD) by nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT). Finally, NAD+ synthase (NADS) transforms the NAAD into NAD+ with ammonia and ATP action[8-9].
3. Salvage pathway. Rather than generated de novo pathway, most NAD+ is recycled from NAM, NA, NR and NMN in the salvage pathway to maintain the cellular NAD+ levels. Rather than generated de novo pathway, most NAD+ is recycled from NAM, NA, NR and NMN in the salvage pathway to maintain the cellular NAD+ levels. Therefore, the salvage pathway is the primary source of NAD+ in mammalian cells. NAM could be recycled from NAD+ consumption reactions, including both NAD+-dependent deacylation and ADP-ribosylation, into NMN by NAMPT, which catalyzes the rate-limiting reaction in the salvage pathway[10]. The precursor NR is transformed to NMN by NRK1/2. Ultimately, NMN is adenylated by NMNAT to yield NAD+[2].
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme that catalyzes the synthesis of nicotinamide adenine dinucleotide (NAD+).
Cancer cells have different metabolic demands and increased NAD+ turnover as compared to normal cells[11]. Therefore, the salvage pathway is of major importance to cancer cells. In fact, many types of cancer cells have been shown to highly express NAMPT, reflecting potentially increased dependence on this pathway due to high NAD+ utilization and in some cases, loss of expression of other key NAD+ biosynthetic enzymes[12-15]. The types of cancers reported to have high NAMPT expression include, but are not limited to, colorectal cancer (CRC), breast cancer, osteosarcoma, chondrosarcoma, pancreatic ductal adenocarcinoma, oral squamous cell carcinoma, prostate cancer, rhabdomyosarcoma, leiomyosarcoma, esophagogastric junction adenocarcinomas, thyroid cancer, leukemia, lymphoma, ovarian cancer, and some renal cancer, and in many of these, higher NAMPT expression correlated with worse outcomes[16-32]. NMN may also be produced from nicotinamide riboside via nicotinamide riboside kinase[13]. Currently, however, NAMPT is the only NAD+ production enzyme that has been targeted in the clinic.
NAMPT exists in two forms in mammals: intracellular NAMPT (iNAMPT) in the cytoplasm and nucleus and extracellular NAMPT (eNAMPT) in the plasma or extracellular space.
NAMPT is overexpressed in several human malignancies such as colorectal cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, endometrial cancer, melanoma, multiple myeloma, astrocytoma, liver cancer, thyroid cancer, malignant lymphoma, and others. Given its role in promoting various aspects of the malignant phenotype, inhibiting NAMPT may have anticancer effects. NAMPT inhibition also leads to ATP depletion, reduced PARP-1 and SirT1 activity, and ultimately cell death[34-36]. Tumor cells are more sensitive to iNAMPT inhibition than normal cells due to increased NAD+ and ATP catabolism[37]. The highly specific NAMPT inhibitor FK866 can induce apoptosis in human hepatocellular carcinoma cells (HepG2) by depleting NAD+, which could be partially reversed by adding NAM or nicotinic acid[33]. NAMPT inhibitors have potential therapeutic applications in treating triple-negative breast cancer, liver cancer, gastric cancer, non-small cell lung cancer with epidermal growth factor receptor gene mutations, glioblastoma, melanoma, etc.
eNAMPT can be released by various types of cells and acts as a cytokine on multiple cell types. It is able to activate downstream intracellular pathways by stimulating the subsequent release of other cytokines.
Plasma eNAMPT levels are elevated in various human malignancies, including astrocytoma, myeloma, male oral squamous cell carcinoma, gastric cancer, endometrial cancer, hepatocellular carcinoma, colorectal cancer, and invasive breast cancer, etc[38-46]. In astrocytoma, plasma eNAMPT levels increase with tumor staging and are considered a prognostic marker. Similarly, eNAMPT levels are elevated in tumor later stages of male oral squamous cell carcinoma, hepatocellular carcinoma, endometrial cancer, and infiltrating breast cancer. In patients with endometrial cancer, higher eNAMPT levels are associated with endometrial infiltrating and shorter patient survival. Higher eNAMPT levels in infiltrating breast cancer are associated with lymph node metastasis and the loss of estrogen and progesterone receptors. Myocardial cells treated with H2O2 or incubated in the condition of serum starvation will secrete eNAMPT[47]. Pretreatment of human chondrocytes with eNAMPT may inhibit IGF-1-stimulated proteoglycan synthesis and AKT and insulin receptor substrate-1 phosphorylation while activating ERK[48]. Researchers have found that eNAMPT treatment rapidly induces the production of IL-6 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.
NAMPT is also closely related to the occurrence and development of various diseases.
Diabetic nephropathy is one of the most severe diabetic microvascular complications and a risk factor for death in diabetes patients, posing a serious threat to human health. The pathogenesis of diabetic nephropathy is complex and diverse, mainly involving renal inflammation and fibrosis. Studies have found that the renal inflammatory and fibrotic process is closely related to NAMPT. On the one hand, in glomerular mesangial cells, NAMPT can promote the expression and translocation of GLUT-1 to the cell membrane, thereby mediating intracellular glucose transport, leading to increased glucose metabolism and extracellular matrix synthesis, which causes renal parenchymal damage[52,53]. On the other hand, diabetic patients are in an obvious imbalance state of oxidative stress. By detecting the patient's serum, it is found that serum levels of NAMPT are directly proportional to lipid peroxidation metabolite levels and inversely proportional to antioxidant enzyme SOD levels, indicating a close relationship between NAMPT and oxidative stress in vivo[54]. The interaction of these two factors together promotes the occurrence of diabetic nephropathy.
NAMPT is closely related to the occurrence and development of cardiovascular and cerebrovascular diseases. NAMPT expression is significantly increased in carotid plaques of patients with unstable coronary atherosclerosis and ruptured plaques in patients with acute myocardial infarction[55,56]. Studies have found that NAMPT can enhance the enzymatic activity of MMP-2 and MMP-9, while MMP can degrade the extracellular matrix, which leads to a thin fibrous cap and plaque rupture, suggesting that NAMPT plays an important role in the instability of atherosclerotic plaques[57]. NAMPT inhibitors can reduce myocardial infarction size, neutrophil infiltration, and the production of reactive oxygen species generation within a mouse model of myocardial ischemia-reperfusion injury[58]. Therefore, as an effective therapeutic drug, NAMPT pharmacological inhibitors can reduce oxidative stress-mediated tissue damage in myocardial infarction.
NAMPT is overexpressed in placental tissue from women with gestational hypertension, and the expression levels of both are significantly positively correlated, suggesting a close relationship with gestational hypertension.
Clinical studies have shown that the concentration of NAMPT is significantly increased in chronic inflammatory diseases. As a pro-inflammatory adipokine, NAMPT promotes the expression of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 protein[59]. NAMPT can induce CD14+ monocytes to produce inflammatory cytokines such as interleukin-1β, tumor necrosis factor-α, and interleukin-6, and increase the surface expression of co-stimulatory molecules CD54, CD40, and CD80[60]. eNAMPT can activate NF-κB, leading to upregulation of inducible nitric oxide synthase expression and promotion of inflammatory responses[61].
NAMPT also plays a role as an immune regulatory 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 thymocyte numbers and 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].
The high expression of NAMPT in blood and gastric adipose tissue is positively correlated with overweight or obesity. NAMPT is a necessary factor for overweight or obesity, and downregulating NAMPT in adipose tissue can help alleviate obesity[65].
Currently, the NAMPT inhibitor FK866 is in the clinical stage. It can exert antitumor effects in cell models and animal models, especially in hematological tumors. FK866 can clear tumor cells to undetectable levels, resulting in long-term survival of 80% of mice[66]. However, there are some issues with FK866. Clinical trial results have shown that FK866 treatment can cause dose-limiting toxicities such as thrombocytopenia, as well as gastrointestinal reactions such as diarrhea and constipation[67]. This is also the reason why the phase II clinical trial utilizing FK866 was halted. In addition, NAMPT exists in both enzymatically active and inactive forms. FK866, as an enzyme inhibitor, cannot inhibit the non-enzymatically active form of NAMPT (eNAMPT) in plasma and extracellular spaces. eNAMPT has been shown to contribute to carcinogenesis and tumor growth, which may affect the therapeutic effect of FK866. Therefore, there is a need to improve existing inhibitors or develop new drugs to overcome the deficiencies of existing inhibitors.
Designing degraders targeting specific proteins is a new model for drug development. We utilize the Proteolysis Targeting Drug (PROTAD) technology platform for the development of antitumor drugs. PROTAD can label target proteins for degradation through specially designed bispecific protein regulators, and degrade target proteins by activating intracellular protein degradation pathways. Therefore, we hope to develop protein modulators that can degrade disease-related pathogenic proteins using the protein degradation technology platform, thereby treating cancer patients and prolonging their survival.
Therefore, there is an urgent need for a series of novel protein degraders designed based on NAMPT target protein for the treatment and/or prevention of diseases or disorders associated with NAMPT.
The present disclosure provides series of novel NAMPT target protein based-protein degraders, salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof, which can target and degrade NAMPT protein, effectively treating and/or preventing diseases or disorders associated with NAMPT. The diseases or disorders associated with NAMPT include but are not limited to tumors, autoimmune diseases, inflammatory diseases, gestational hypertension, cardiovascular and cerebrovascular diseases, obesity and diabetic nephropathy.
In some embodiments, the present disclosure provides a compound of Formula (I) or a salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof:
wherein ULM is a E3 ligase ligand moiety, LIN is a linker moiety, the remaining moiety of the compound of Formula (I) is a nicotinamide phosphoribosyltransferase (NAMPT) ligand, and ULM is covalently bonded to NAMPT ligand through LIN;
wherein ring A is the following groups:
and
In some embodiments, the present disclosure provides a pharmaceutical composition comprising as active ingredient the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.
In some embodiments, the present disclosure provides a medicine kit or reagent kit comprising the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof of the present disclosure, or the pharmaceutical composition of the present disclosure.
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 enantiomer), or mixture of stereoisomers thereof for use as a medicament.
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 enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure for use in the prevention and/or treatment of a disease or disorder associated with NAMPT.
In some embodiments, the present disclosure provides use of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure for the manufacture of a medicament for the prevention and/or treatment of a disease or disorder associated with NAMPT.
In some embodiments, the present disclosure provides a method for treating or preventing a disease or disorder associated with 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 enantiomer), or mixture of stereoisomers thereof, or the pharmaceutical composition of the present disclosure.
The following detailed description is provided as exemplary specific embodiments to assist those skilled in the art in understanding and practicing the present disclosure. It should be appreciated, however, that such description is not intended to limit the scope of the present disclosure, and that various modifications and changes may be made to the specific embodiments described in the present disclosure without departing from the spirit and scope of the present disclosure. Such changes and modifications are to be understood as being included within the scope of the present invention as defined by the appended claims.
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 enantiomer), or mixture of stereoisomers thereof:
wherein ULM is a E3 ligase ligand moiety, LIN is a linker moiety, the remaining moiety of the compound of Formula (I) is a nicotinamide phosphoribosyltransferase (NAMPT) ligand, and ULM is covalently bonded to NAMPT ligand through LIN;
and
In some embodiments, L1 represents substituted or unsubstituted linear C3-6 alkylene group. Exemplary examples of linear C3-6 alkylene group include, but are not limited to, propylene, butylene, pentylene, and hexylene. The linear C3-6 alkylene group is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halo-substituted C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 in any way, or is automatically limited by the size of the building unit.
In some embodiments, L1 represents substituted or unsubstituted linear C3-6 alkenylene group. Exemplary examples of linear C3-6 alkenylene group include, but are not limited to,
The linear C3-6 alkenylene is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halo-substituted C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 in any way, or is automatically limited by the size of the building unit.
In some embodiments, ring B is a 5- to 11-membered heterocyclylene containing from 1 to 3 heteroatoms independently selected from sulfur, oxygen, and nitrogen.
In some embodiments, ring B is a 5- to 11-membered heterocyclylene group containing 1 nitrogen atom and optionally containing from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
In some embodiments, exemplary examples of ring B include, but are not limited to, the following groups: piperidinylene, piperazinylene, morpholinylene, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, dioxanylene, diazepanylene, or C7-11 spiroheterocyclylene.
In some embodiments, when ring B represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene may be the following groups:
As used herein, the wording “ . . . represents a bond” used alone or in combination means that the referenced group is a bond linker (that is, the referenced group is absent). For example, the wording “X represents a bond” means that X is a bond linker. In other words, when X presents a bond, the two adjacent carbon atoms on both sides of X are directly connected to each other.
In some embodiments, when ring B represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene may be the following groups:
In some embodiments, ring B is optionally further substituted by m2 Rb groups, wherein m2 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rb is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
include, but are not limited to, the following groups:
In some embodiments, ring C is a 5- to 10-membered heteroarylene group or a 6-membered arylene group. Exemplary examples of ring C include, but are not limited to, the following groups: phenylene, pyridylene, pyrimidinylene, 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]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, 4H-fluoro[3,2b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, or imidazo[2,1-b]thiazolylene.
In some embodiments, the ring C is optionally further substituted by m3 Rc groups, wherein m3 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rc is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
include, but are not limited to, the following groups:
wherein the symbol *** indicates the point of attachment to Y, or the symbol *** indicates the point of attachment to carbonyl.
In some embodiments, Y represents —N(R3)—, where R3 is H or C1-3 alkyl.
In some embodiments, Y represents —O—.
In some embodiments, Y is n connected rings D represented by the following formula:
wherein n represents 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, and each ring D is independently a 5- to 11-membered heterocyclylene group, and (Rd)m4 indicates that each ring D is optionally independently substituted by m4 Rd groups, wherein m4 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rd is independently C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, oxo, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, or cyano.
In some embodiments, exemplary examples of ring D include, but are not limited to, the following groups: piperidinylene, piperazinylene, morpholinylene, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, dioxanylene, diazepanylene, or C7-11 spiroheterocyclylene.
In some embodiments, when ring D represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene can be the following groups:
In some embodiments, when ring D represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene can be the following groups:
wherein the symbol ** indicates the point of attachment to ring C.
In some embodiments, ring D is optionally further substituted by m4 Rd groups, wherein m4 represents an integer of 0, 1, 2, 3, 4, or 5; and each Rd is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), oxo, C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
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 ** can also indicate the point of attachment to LIN.
In some embodiments, m is 0, n is 1. In some embodiments, m is 0, n is 2. In some embodiments, m is 0, n is 3. In some embodiments, m is 1, n is 0. In some embodiments, m is 1, n is 1. In some embodiments, m is 1, n is 2. In some embodiments, m is 1, n is 3.
In some embodiments, exemplary examples of
include, but are not limited to, the following groups:
wherein the symbol ##indicates the point of attachment to LIN.
In some embodiments, ULM represents a structure of Formula (III):
In some embodiments, the structure of Formula (III) also can be of the structure of the following formula:
In some embodiments, Z represents C(O).
In some embodiments, Z represents CH2.
In some embodiments, R represents O.
In some embodiments, R represents N(R4), where R4 represents H or C1-3 alkyl (e.g., methyl, ethyl, or propyl).
In some embodiments, R represents a bond. In some embodiments, when R represents a bond, W represents a bond.
In some embodiments, R represents alkynylene, e.g., ethynylene
or butynylene
In some embodiments, R represents alkenylene, e.g., vinylene
In some embodiments, R represents S.
In some embodiments, R represents triazolylene.
In some embodiments, W represents optionally substituted phenylene, and exemplary examples of optional substituents include, but are not limited to, halogen (e.g., fluorine, chlorine, bromine, or iodine). The number of the optional substituents can be 0, 1, 2, or 3.
In some embodiments, W represents a bond.
In some embodiments, ULM represents the structure of the following formula:
In some embodiments, ULM represents a structure of Formula (IV):
In some embodiments, ULM represents the structure of the following formula:
In some embodiments, LIN is represented by the following formula:
#-U-alkylene,
or butynylene
alkenylene (e.g., vinylene
or any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are each independently optionally substituted by a substituent selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 some sub-embodiments, the backbone carbon chain of the alkylene (e.g., substituted or unsubstituted linear or branched C2-60 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) fragments “—CH2—R5—CH2—” 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) fragments “—CH2—R6—CH2—” 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) fragments “—CH2—R5—R6—CH2—”, wherein each R5 are the same or different, each R6 are the same or different, and are as defined herein.
In some embodiments, LIN is represented by the following formula:
#-U-alkylene,
In some embodiments, the alkylene in LIN can be substituted linear or branched C1-60 alkylene, e.g., linear or branched C1-60 alkylene (e.g., C1-55 alkylene, C1-50 alkylene, C1-45 alkylene, C1-40 alkylene, C1-35 alkylene, C1-30 alkylene, C1-25 alkylene, C1-23 alkylene, C1-22 alkylene, C1-21 alkylene, C1-20 alkylene, C2-20 alkylene, C1-19 alkylene, C2-19 alkylene, C1-18 alkylene, C2-18 alkylene, C1-17 alkylene, C2-17 alkylene, C1-16 alkylene, C2-16 alkylene, C1-15 alkylene, C2-15 alkylene, C1-14 alkylene, C2-14 alkylene, C1-13 alkylene, C2-13 alkylene, C1-12 alkylene, C2-12 alkylene, C1-11 alkylene, C2-11 alkylene, C1-10 alkylene, C2-10 alkylene, C3-10 alkylene, C1-9 alkylene, C2-9 alkylene, C3-9 alkylene, C1-8 alkylene, C2-8 alkylene, C3-8 alkylene, C1-7 alkylene, C2-7 alkylene, C3-7 alkylene, C1-6 alkylene, C2-6 alkylene, C3-6 alkylene, C1-5 alkylene, C2-5 alkylene, C3-5 alkylene, C1-4 alkylene, C1-3 alkylene, C1-2 alkylene, methylene) substituted by one or more identical or different substituents, wherein the substituents are optionally selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., F3C—, FCH2—, F2CH—, ClCH2—, Cl2CH—, CF3CF2—, CF3CHF—, CHF2CF2—, CHF2CHF—, CF3CH2—, and CH2ClCH2—), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 C1-60 alkylene is optionally substituted by 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 in any way, or is automatically limited by the size of the building unit.
In some embodiments, LIN represents the following groups: #—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—; wherein a hydrogen atom of one or more CH2 groups of the groups is optionally replaced with a substituent selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., F3C—, FCH2—, F2CH—, ClCH2—, Cl2CH—, CF3CF2—, CF3CHF—, CHF2CF2—, CHF2CHF—, CF3CH2—, and CH2ClCH2—), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 #indicates the point of attachment to Y.
In some embodiments, LIN represents is represented by the following formula:
#-U-alkylene,
Herein, when one or more groups R5 and/or one or more groups R6 and/or one or more any combination of R5 and R6 are inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group, the resulting backbone chain group conforms to the 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) fragments “—CH2—R5—CH2—” 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) fragments “—CH2—R6—CH2—” 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) fragments “—CH2—R5—R6—CH2—”, wherein each R5 are the same or different, each R6 are the same or different, and are as defined herein.
In some embodiments, LIN can be represented by the following formula:
#-U—(C(Ra1)(Ra2))n4—(R5(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(R5(C(Ra3)(Ra4))n5)m6—(R5(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(R5(C(Ra3)(Ra4))n5)m6—(R5(C(Ra5)(Ra6))n6)m7—(R5(C(Ra7)(Ra8))n7)m8—;
#-U—(C(Ra1)(Ra2))n4—(R6(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(R6(C(Ra3)(Ra4))n5)m6—(R6(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(R6(C(Ra3)(Ra4))n5)m6—(R6(C(Ra5)(Ra6))n6)m7—(R6(C(Ra7)(Ra5))n7)m8—;
#-U—(C(Ra1)(Ra2))n4—(R5-R6—(CRa3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(R5(C(Ra3)(Ra4))n5)m6—(R6(CRa5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(R6—R5—(C(Ra3)(Ra4))n5)m6—; or
#-U—(C(Ra1)(Ra2))n4—(R6(C(Ra3)(Ra4))n5)m6—(R5(C(Ra5)(Ra6))n6)m7—;
In some embodiments, LIN can be represented by the following formula:
#-U—(C(Ra1)(Ra2))n4—(O(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(O(C(Ra3)(Ra4))n5)m6—(O(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(O(C(Ra3)(Ra4))n5)m6—(O(C(Ra5)(Ra6))n6)m7—(O(C(Ra7)(Ra8))n7)m8—;
#-U—(C(Ra1)(Ra2))n4—(N(R7)(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(N(R7)(C(Ra3)(Ra4))n5)m6—(N(R7)(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(N(R7)(C(Ra3)(Ra4))n5)m6—(N(R7)(C(Ra5)(Ra6))n6)m7—(N(R7)(C(Ra7)(Ra8))n7)m8;
#-U—(C(Ra1)(Ra2))n4—(C(O)N(R7)—(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(C(O)N(R7)—(C(Ra3)(Ra4))n5)m6—(C(O)N(R7)—(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—(C(O)N(R7)—(C(Ra3)(Ra4))n5)m6—(C(O)N(R7)—(C(Ra5)(Ra6))n6)m7—(C(O)N(R7)—(C(Ra7)(Ra8))n7)m8—;
#-U—(C(Ra1)(Ra2))n4—(C(O)N(R7)—(C((Ra3)(Ra4))n5)m6—(O—(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4—C(O)N(R7)—(C(Ra3)(Ra4))n5—(O(C(Ra5)(Ra6))n6)m6—;
#-U—(C(Ra1)(Ra2))n4—(N(R7)C(O)—(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4—(N(R7)C(O)—(C(Ra3)(Ra4))n5)m6—(O(C(Ra5)(Ra6))n6)m7;
#-U—(C(Ra1)(Ra2))n4—(N(R7)C(O)—(C(Ra3)(Ra4))n5)m6—(O—(C(Ra5)(Ra6))n6)m7—(O—(C(Ra7)(Ra8))n7)m8—;
#-U—(C(Ra1)(Ra2))n4—N(R7)C(O)—(C(Ra3)(Ra4))n5—(O(C(Ra5)(Ra6))n6)m6—;
#-U—(C(Ra1)(Ra2))n4—N(R7)C(O)N(R7)—(C(Ra3)(Ra4))n5—;
#-U—(C(Ra1)(Ra2))n4—C(O)—(C(Ra3)(Ra4))n5—;
#-U—(C(Ra1)(Ra2))n4—CH═CH—(C(Ra3)(Ra4))n5—;
#-U—(C(Ra1)(Ra2))n4—C≡C—(C(Ra3)(Ra4))n5—;
#-U—(C(Ra1)(Ra2))n4—C≡C—C≡C—(C(Ra3)(Ra4))n5—;
#-U—(C(Ra1)(Ra2))n4-(arylene-(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4-(arylene-(C(Ra3)(Ra4))n5)m6-arylene-(C(Ra5)(Ra6))n6—;
#-U—(C(Ra1)(Ra2))n4-(heterocyclylene-(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4-(heterocyclylene-(C(Ra3)(Ra4))n5)m6-(heterocyclylene-(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4-(heteroarylene-(C(Ra3)(Ra4))n5)m6—;
#-U—(C(Ra1)(Ra2))n4-(heteroarylene-(C(Ra3)(Ra4))n5)m6-(heteroarylene-(C(Ra5)(Ra6))n6)m7—;
#-U—(C(Ra1)(Ra2))n4-(cycloalkylene-(C(Ra3)(Ra4))n5)m6—; or
#-U—(C(Ra1)(Ra2))n4-(cycloalkylene-(C(Ra3)(Ra4))n5)m6-(cycloalkylene-(C(Ra5)(Ra6))n6)m7—;
In some embodiments, the cycloalkylene in LIN is optionally selected from the group consisting of:
In some embodiments, the arylene in LIN is optionally selected from the group consisting of: phenylene or naphthylene, wherein the arylene is optionally substituted by one or more (e.g., 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., F3C—, FCH2—, F2CH—, ClCH2—, Cl2CH—, CF3CF2—, CF3CHF—, CHF2CF2—, CHF2CHF—, CF3CH2—, and CH2ClCH2—), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 some embodiments, the heterocyclylene in LIN is optionally selected from the group consisting of:
In some embodiments, the heteroarylene in LIN is optionally selected from the group consisting of:
In some embodiments, LIN represents the structure of the following formula:
#-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)9—, #-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)9—, #-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—, #-U—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—(O(CH2)2)1—OCH2—, #-U—CH2—(O(CH2)2)2—OCH2—, #-U—CH2—(O(CH2)2)3—OCH2—, #-U—CH2—(O(CH2)2)4—OCH2—, #-U—CH2—(O(CH2)2)5—OCH2—, #-U—CH2—(O(CH2)2)6—OCH2—, #-U—CH2—(O(CH2)2)7—OCH2—, #-U—CH2—(O(CH2)2)8—OCH2—, #-U—CH2—(O(CH2)2)9—OCH2—, #- U—CH2—(O(CH2)2)10—OCH2—, #-U—(CH2)2—(O(CH2)2)2—, #-U—(CH2)2—(O(CH2)2)3—, #-U—(CH2)2—(O(CH2)2)4—, #-U—(CH2)2—(O(CH2)2)5—, #-U—(CH2)2—(O(CH2)2)6—, #-U—(CH2)2—(O(CH2)2)7—, #-U—(CH2)2—(O(CH2)2)8—, #-U—(CH2)2—(O(CH2)2)9—, #-U—(CH2)2—(O(CH2)2)10—, #-U—(CH2)3—(O(CH2)2)2—, #-U—(CH2)3—(O(CH2)2)3—, #-U—(CH2)3—(O(CH2)2)4—, #-U—(CH2)3—(O(CH2)2)5—, #-U—(CH2)3—(O(CH2)2)6—, #-U—(CH2)3—(O(CH2)2)7—, #-U—(CH2)3—(O(CH2)2)8—, #-U—(CH2)3—(O(CH2)2)9—, #-U—(CH2)3—(O(CH2)2)10—, #-U—(CH2)4—(O(CH2)2)2—, #-U—(CH2)4—(O(CH2)2)3—, #-U—(CH2)4—(O(CH2)2)4—, #-U—(CH2)4—(O(CH2)2)5—, #-U—(CH2)4—(O(CH2)2)6—, #-U—(CH2)4—(O(CH2)2)7—, #-U—(CH2)4—(O(CH2)2)8—, #-U—(CH2)4—(O(CH2)2)9—, #-U—(CH2)4—(O(CH2)2)10—, #-U—CH2—(O(CH2)3)2—, #-U—CH2—(O(CH2)3)3—, #-U—CH2—(O(CH2)3)4—, #-U—CH2—(O(CH2)3)5—, #-U—CH2—(O(CH2)3)6—, #-U—CH2—(O(CH2)3)7—, #-U—CH2—(O(CH2)3)8—, #-U—CH2—(O(CH2)3)9—, #- U—CH2—(O(CH2)3)10—, #-U—(CH2)2—(O(CH2)3)2—, #-U—(CH2)2—(O(CH2)3)3—, #-U—(CH2)2—(O(CH2)3)4—, #-U—(CH2)2—(O(CH2)3)5—, #-U—(CH2)2—(O(CH2)3)6—, #-U—(CH2)2—(O(CH2)3)7—, #-U—(CH2)2—(O(CH2)3)8—, #-U—(CH2)2—(O(CH2)3)9—, #-U—(CH2)2—(O(CH2)3)10—, #-U—(CH2)3—(O(CH2)3)2—, #-U—(CH2)3—(O(CH2)3)3—, #-U—(CH2)3—(O(CH2)3)4—, #-U—(CH2)3—(O(CH2)3)5—, #-U—(CH2)3—(O(CH2)3)6—, #-U—(CH2)3—(O(CH2)3)7—, #-U—(CH2)3—(O(CH2)3)8—, #-U—(CH2)3—(O(CH2)3)9—, #-U—(CH2)3—(O(CH2)3)10—, #-U—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)2O—CH2—, #-U—(CH2)2—O—(CH2)2O—CH2—, #-U—(CH2)2—(O(CH2)2)2—O—(CH2)3—, #-U—(CH2)2—(O(CH2)2)3—O—(CH2)3—, #-U—(CH2)2—(O(CH2)2)4—O—(CH2)3—, #-U—(CH2)5—(O(CH2)2)2—O—(CH2)5—, #-U—(CH2)5—(O(CH2)2)2—O—(CH2)6—, #-U—(CH2)1—N(R7)—(CH2)1—, #-U—(CH2)1—N(R7)—(CH2)2—, #-U—(CH2)1—N(R7)—(CH2)3—, #-U—(CH2)1—N(R7)—(CH2)4—, #-U—(CH2)1—N(R7)—(CH2)5—, #- U—(CH2)1—N(R7)—(CH2)6—, #-U—(CH2)1—N(R7)—(CH2)7—, #-U—(CH2)1—N(R7)—(CH2)8—, #-U—(CH2)1—N(R7)—(CH2)9—, #-U—(CH2)1—N(R7)—(CH2)10—, #-U—(CH2)2—N(R7)—(CH2)1—, #-U—(CH2)2—N(R7)—(CH2)2—, #- U—(CH2)2—N(R7)—(CH2)3—, #-U—(CH2)2—N(R7)—(CH2)4—, #-U—(CH2)2—N(R7)—(CH2)5—, #-U—(CH2)2—N(R7)—(CH2)6—, #-U—(CH2)2—N(R7)—(CH2)7—, #-U—(CH2)2—N(R7)—(CH2)8—, #-U—(CH2)2—N(R7)—(CH2)9—, #- U—(CH2)2—N(R7)—(CH2)10—, #-U—(CH2)2—N(R7)—(CH2)11—, #-U—(CH2)2—N(R7)—(CH2)12—, #-U—(CH2)3—N(R7)—(CH2)1—, #-U—(CH2)3—N(R7)—(CH2)2—, #-U—(CH2)3—N(R7)—(CH2)3—, #-U—(CH2)4—N(R7)—(CH2)1—, #- U—(CH2)4—N(R7)—(CH2)2—, #-U—(CH2)4—N(R7)—(CH2)3—, #-U—(CH2)4—N(R7)—(CH2)4—, #-U—(CH2)5—N(R7)—(CH2)1—, #-U—(CH2)5—N(R7)—(CH2)2—, #-U—(CH2)5—N(R7)—(CH2)3—, #-U—(CH2)5—N(R7)—(CH2)4—, #- U—(CH2)5—N(R7)—(CH2)5—, #-U—(CH2)6—N(R7)—(CH2)1—, #-U—(CH2)6—N(R7)—(CH2)2—, #-U—(CH2)6—N(R7)—(CH2)3—, #-U—(CH2)7—N(R7)—(CH2)1—, #-U—(CH2)7—N(R7)—(CH2)2—, #-U—(CH2)7—N(R7)—(CH2)3—, #- U—(CH2)8—N(R7)—(CH2)1—, #-U—(CH2)8—N(R7)—(CH2)2—, #-U—(CH2)8—N(R7)—(CH2)3—, #-U—CH(CH3)—N(R7)—(CH2)1—, #-U—CH(CH3)—N(R7)—(CH2)2—, #-U—CH(CH3)—N(R7)—(CH2)3—, #-U—CH(CH3)—N(R7)—(CH2)4—, #-U—CH(CH3)—N(R7)—(CH2)5—, #-U—CH(CH3)—N(R7)—(CH2)6—, #-U—CH(CH3)—N(R7)—(CH2)7—, #-U—CH(CH3)—N(R7)—(CH2)8—, #-U—CH(CH3)—N(R7)—(CH2)9—, #-U—CH(CH3)—N(R7)—(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)10C(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)10NHC(O)(CH2)10—, #-U—(CH2)4NHC(O)(CH2)8—, #-U—(CH2)2NHC(O)(CH2)2—O—(CH2)2—, #-U—(CH2)4NHC(O)CH2—, #-U—CH2-phenylene-CH2—, #-U—CH2-phenylene-(CH2)2—, #-U—CH2-phenylene-(CH2)3—, #-U—CH2-phenylene-(CH2)4—, #-U—CH2-phenylene-(CH2)5—, #-U—CH2-phenylene-(CH2)6—, #-U—CH2-phenylene-(CH2)7—, #-U—CH2-phenylene-(CH2)8—, #-U—(CH2)2-phenylene-(CH2)1—, #-U—(CH2)2-phenylene-(CH2)2—, #-U—(CH2)2-phenylene-(CH2)3—, #-U—(CH2)2-phenylene-(CH2)4—, #-U—(CH2)2-phenylene-(CH2)5—, #-U—(CH2)2-phenylene-(CH2)6—, #-U—(CH2)2-phenylene-(CH2)7—, #-U—(CH2)2-phenylene-(CH2)8—, #-U—(CH2)3-phenylene-CH2—, #-U—(CH2)3-phenylene-(CH2)2—, #-U—(CH2)3-phenylene-(CH2)3—, #-U—(CH2)3-phenylene-(CH2)4—, #-U—(CH2)3-phenylene-(CH2)5—, #-U—(CH2)3-phenylene-(CH2)6—, #-U—(CH2)3-phenylene-(CH2)7—, #-U—(CH2)3-phenylene-(CH2)8—, #-U—(CH2)4-phenylene-CH2—, #-U—(CH2)4-phenylene-(CH2)2—, #-U—(CH2)4-phenylene-(CH2)3—, #-U—(CH2)4-phenylene-(CH2)4—, #-U—(CH2)4-phenylene-(CH2)5—, #-U—(CH2)4-phenylene-(CH2)6—, #-U—(CH2)4-phenylene-(CH2)7—, #-U—(CH2)4-phenylene-(CH2)8—, #-U—(CH2)5-phenylene-(CH2)1—, #-U—(CH2)5-phenylene-(CH2)2—, #-U—(CH2)5-phenylene-(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)1—, #-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)1—, #-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(R7)—CH2-phenylene-CH2—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)2—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)3—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)4—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)5—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)6—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)7—, #-U—CH2—N(R7)—CH2-phenylene-(CH2)8—, #-U—CH2—N(R7)—(CH2)2-phenylene-CH2—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)2—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)3—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)4—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)5—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)6—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)7—, #-U—CH2—N(R7)—(CH2)2-phenylene-(CH2)8—, #-U—(CH2)2—N(R7)—CH2-phenylene-CH2—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)2—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)4—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)5—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)6—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)7—, #-U—(CH2)2—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)3—N(R7)—CH2-phenylene-CH2—, #-U—(CH2)3—N(R7)—CH2-phenylene-(CH2)2—, #-U—(CH2)3—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)3—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)4—N(R7)—CH2-phenylene-CH2—, #-U—(CH2)4—N(R7)—CH2-phenylene-(CH2)2—, #-U—(CH2)4—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)4—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)5—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)5—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)6—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)6—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)7—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)7—N(R7)—CH2-phenylene-(CH2)8—, #-U—(CH2)8—N(R7)—CH2-phenylene-CH2—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)2—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)3—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)4—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)5—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)6—, #-U—(CH2)8—N(R7)—CH2-phenylene-(CH2)7—, #-U—(CH2)8—N(R7)—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)1—, #-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)1—, #-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—, #-U—(CH2)7-piperazinylene-(CH2)1—, #-U—(CH2)7-piperazinylene-(CH2)2—, #-U—(CH2)7-piperazinylene-(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—;
In some embodiments, the compound of Formula (I) of the present disclosure is also of Formula (II):
or salts (including pharmaceutically acceptable salts), solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof,
and
In some embodiments, L1 of the compound of Formula (II) represents substituted or unsubstituted linear C3-6 alkylene group. Exemplary examples of linear C3-6 alkylene group include, but are not limited to, propylene, butylene, pentylene, and hexylene. The linear C3-6 alkylene group is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halo-substituted C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 in any way, or is automatically limited by the size of the building unit.
In some embodiments, L1 of the compound of Formula (II) represents substituted or unsubstituted linear C3-6 alkenylene group. Exemplary examples of linear C3-6 alkenylene group include, but are not limited to,
The linear C3-6 alkenylene is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl (e.g., methyl, ethyl, or propyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), halo-substituted C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 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 in any way, or is automatically limited by the size of the building unit.
In some embodiments, ring B of the compound of Formula (II) is a 5- to 11-membered heterocyclylene containing from 1 to 3 nitrogen atoms.
In some embodiments, ring B of the compound of Formula (II) is piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, diazepanylene, or C7-11 spiroheterocyclylene containing 1 nitrogen atom and optionally containing from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
In some embodiments, when ring B of the compound of Formula (II) is C7-11 spiroheterocyclylene containing 1 nitrogen atom and optionally containing from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, the C7-11 spiroheterocyclylene is the following groups:
wherein the symbol * indicates the point of attachment to L1, X represents O, N(Re), S, or CH2, or X represents a bond, where Re represents H or methyl, and n1, n2, and n3 are each independently an integer of 1 or 2.
In some embodiments, when ring B of the compound of Formula (II) is C7-11 spiroheterocyclylene containing 1 nitrogen atom and optionally containing from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, the C7-11 spiroheterocyclylene is the following groups:
wherein the symbol * indicates the point of attachment to L1.
In some embodiments, ring B of the compound of Formula (II) is optionally further substituted by m2 Rb groups, wherein m2 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rb is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
of the compound of Formula (II) include, but are not limited to, the following groups:
wherein the symbol * indicates the point of attachment to L1.
In some embodiments, ring C of the compound of Formula (II) is a 5- to 10-membered heteroarylene group or a 6-membered arylene group. Exemplary examples of ring C include, but are not limited to, the following groups: phenylene, pyridylene, pyrimidinylene, 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]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, 4H-fluoro[3,2b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, or imidazo[2,1-b]thiazolylene.
In some embodiments, ring C of the compound of Formula (II) is optionally further substituted by m3 Rc groups, wherein m3 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rc is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
of the compound of Formula (II) include, but are not limited to, the following groups:
wherein the symbol *** indicates the point of attachment to Y, or the symbol *** indicates the point of attachment to carbonyl.
In some embodiments, Y of the compound of Formula (II) represents —N(R3)—, where R3 is H or C1-3 alkyl.
In some embodiments, Y of the compound of Formula (II) represents —O—.
In some embodiments, Y of the compound of Formula (II) is n connected rings D represented by the following formula:
wherein n represents 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, and each ring D is independently a 5- to 11-membered heterocyclylene group, and (Rd)m4 indicates that each ring D is optionally independently substituted by m4 Rd groups, wherein m4 represents an integer of 0, 1, 2, 3, 4, or 5, and each Rd is independently C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, oxo, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, or cyano.
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, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, dioxanylene, diazepanylene, or C7-11 spiroheterocyclylene.
In some embodiments, when ring D of the compound of Formula (II) represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene can be the following groups:
wherein the symbol ** indicates the point of attachment to ring C, X represents O, N(Re), S, or CH2, or X represents a bond, where Re represents H or methyl, and n1, n2, and n3 are each independently an integer of 1 or 2.
In some embodiments, when ring D of the compound of Formula (II) represents C7-11 spiroheterocyclylene, the C7-11 spiroheterocyclylene can be the following groups:
wherein the symbol ** indicates the point of attachment to ring C.
In some embodiments, ring D of the compound of Formula (II) is optionally further substituted by m4 Rd groups, wherein m4 represents an integer of 0, 1, 2, 3, 4, or 5; and each Rd is independently C1-3 alkyl (e.g., methyl, ethyl, or propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyl, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine, or iodine), oxo, C1-3 alkoxy (e.g., methoxy, ethoxy, or propoxy), C1-3 alkylamino (e.g., C1-3 alkyl-NH—, e.g., CH3NH—, CH3CH2NH—, or CH3CH2CH2NH—), halogenated C1-3 alkyl (e.g., —CF3, —CH2F, —CHF2, —CH2Cl, —CHCl2, —CF2CF3, —CHFCF3, —CF2CHF2, —CHFCHF2, —CH2CF3, and —CH2CH2Cl), amino-substituted C1-3 alkylene (NH2—C1-3 alkylene-, e.g., NH2CH2—, NH2CH2CH2—, and NH2CH2CH2CH2—), C1-3 alkyl-NHC(O)— (e.g., CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—), C1-3 alkyl-C(O)NH— (e.g., CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—), or cyano.
In some embodiments, exemplary examples of
of the compound 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 ** can also indicate the point of attachment to LIN.
In some embodiments, exemplary examples of
of the compound of Formula (II) include, but are not limited to, the following groups:
wherein the symbol ##indicates the point of attachment to LIN.
ULM and LIN of the compound of Formula (II) of the present disclosure are as defined in the embodiments or sub-embodiments of the compounds of Formula (I) herein.
In some embodiments, the compound of Formula (I) of the present disclosure is also of Formula (V):
or salts (including pharmaceutically acceptable salts), solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof,
In some embodiments, the compound of Formula (I) of the present disclosure is also of Formula (VI):
or salts (including pharmaceutically acceptable salts), solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof,
In some embodiments, the compound of Formula (I) of the present disclosure is also of Formula (VII):
or salts (including pharmaceutically acceptable salts), solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof,
In some embodiments, the compound of Formula (I) of the present disclosure is also of Formula (VIII):
or salts (including pharmaceutically acceptable salts), solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixture of stereoisomers thereof,
It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features of one embodiment with technical features or preferred technical features of another embodiment are also encompassed within the scope of the present invention as defined by the appended claims.
In some embodiments, the compounds of the present invention and their salts (especially pharmaceutically acceptable salts, such as hydrochloride, etc.), prodrugs, solvates, isotopically enriched analogs, polymorphs, stereoisomers (including enantiomers and diastereomers), or mixture of stereoisomers thereof in Table 1 are provided.
The compounds of the present disclosure have the structures of any one of Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), or Formula (VIII). Unless otherwise specified, all references to the compound of the present disclosure also include compounds of any one of Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), or Formula (VIII) and specific compounds within the scope of these general formulae.
It should be recognized that compounds of the present disclosure (including Formula (I), Formula (II), Formula (V), Formula (VI), Formula (VII), and Formula (VIII)) may have a stereo-configuration and thus can exist in more than one stereoisomeric form. The present disclosure also relates to optically enriched compounds having a stereo-configuration, e.g., greater than about 90% enantiomeric/diastereomeric excess (“ee”), such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. As used herein, “optically enriched” means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer, and can be described by enantiomeric excess (ee %). Purification of isomers and separation of mixtures of isomers can be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates) and/or or chiral resolution, etc.).
In some embodiments, polymorph forms or salts of the compounds of the present disclosure are also provided. Salts of the compounds of the present disclosure can be pharmaceutically acceptable salts including, but not limited to, hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate, or p-toluenesulfonate, etc. The compounds of the present disclosure can exist as non-solvated or solvated forms in pharmaceutically acceptable solvents such as water, ethanol, and the like. In some embodiments, compounds of the present disclosure can be prepared as prodrugs or precursor drugs. Prodrugs can be converted into parent drugs in the body to play their role. In some embodiments, isotopically-labeled compounds of the present disclosure are also provided, examples of which include deuterium (D or 2H).
In some embodiments, the present disclosure provides a pharmaceutical composition comprising as active ingredient the compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.
In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; polyethylene oxide, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other common non-toxic compatible substances used in pharmaceutical formulations.
The pharmaceutical composition of the present disclosure can further comprise at least one second therapeutic agent for treating or preventing diseases or disorders associated with nicotinamide phosphoribosyltransferase (NAMPT). The second therapeutic agent may be used in combination with the compound of Formula (I) described in the present disclosure to treat the diseases or disorders associated with NAMPT. The second therapeutic agent includes, but is not limited to, chemotherapeutic agents, immunotherapeutic agents, gene therapy agents, and the like. In some embodiments, the diseases or disorders associated with NAMPT include tumors, autoimmune diseases, inflammatory diseases, gestational hypertension, cardiovascular and cerebrovascular diseases, obesity and diabetic nephropathy.
In some embodiments, the diseases or disorders associated with NAMPT comprises: colorectal cancer; breast cancer (including triple negative breast cancer, invasive breast cancer, infiltrating breast cancer); astrocytoma; pancreatic cancer; gastric cancer; prostate cancer; melanoma; leukemia (such as acute myeloid leukemia, acute lymphocytic leukemia); ovarian cancer; liver cancer; lung cancer (such as non-small cell lung cancer and small cell lung cancer); glioblastoma; multiple myeloma; esophageal cancer; bladder cancer; thyroid cancer; endometrial cancer; lymphoma (such as diffuse large B-cell carcinoma, follicular B-cell lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma); neuroendocrine tumors; renal cancer (such as renal oncocytoma, clear cell renal cell carcinoma, renal urothelial carcinoma); pediatric gliomas; rhabdomyosarcoma; leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; oral squamous cell carcinoma; autoimmune diseases (such as rheumatoid arthritis, autoimmune encephalitis); cardiovascular and cerebrovascular diseases (including coronary atherosclerosis, acute myocardial infarction, myocardial ischemia-reperfusion injury, ischemic stroke); inflammatory diseases; gestational hypertension; obesity; and diabetic nephropathy.
The pharmaceutical composition of the present invention comprising, as an active ingredient, the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof can be formulated into any suitable formulations such as sprays, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-coated capsules), dragees, troches, powders, granules, powder injections, suppositories, or liquid formulations (such as suspensions (e.g., aqueous or oily suspensions), solutions, emulsions, or syrups), or conventional injection dosage forms such as injectable solutions (e.g., sterile injectable solutions formulated according to methods known in the art using water, Ringer's solution, or isotonic sodium chloride solution or the like as a vehicle or solvent) or lyophilized injectable formulation and the like, depending upon a suitable route of administration (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration). Those skilled in the art can also formulate the compound of formula (I) of the present disclosure into conventional, dispersible, chewable, orally disintegrating or rapidly dissolving formulations, or sustained-release capsules or controlled-release capsules as needed.
The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof is used as a medicament. In some embodiments, the medicament of the present disclosure or the composition of the present disclosure may be presented in a kit/packaged product. The kit/packaged product may include a package or container including, but not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, and the like. The kit/packaged product may contain instructions for use of the product.
The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof can be used as a medicament. Especially the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof can be used for the manufacture of a medicament for the prevention and/or treatment of a disease or disorder associated with NAMPT.
The present disclosure provides a method for treating or preventing a disease or disorder associated with NAMPT in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure. In some embodiments, the disease or disorder associated with NAMPT comprises: tumors, autoimmune diseases, inflammatory diseases, gestational hypertension, cardiovascular and cerebrovascular diseases, obesity and diabetic nephropathy. In some embodiments, the disease or disorder associated with NAMPT comprises: colorectal cancer; breast cancer (including triple negative breast cancer, invasive breast cancer, infiltrating breast cancer); astrocytoma; pancreatic cancer; gastric cancer; prostate cancer; melanoma; leukemia (such as acute myeloid leukemia, acute lymphocytic leukemia); ovarian cancer; liver cancer; lung cancer (such as non-small cell lung cancer and small cell lung cancer); glioblastoma; multiple myeloma; esophageal cancer; bladder cancer; thyroid cancer; endometrial cancer; lymphoma (such as diffuse large B-cell carcinoma, follicular B-cell lymphoma, Hodgkin's lymphoma, peripheral T-cell lymphoma); neuroendocrine tumors; renal cancer (such as renal oncocytoma, clear cell renal cell carcinoma, renal urothelial carcinoma); pediatric gliomas; rhabdomyosarcoma; leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; oral squamous cell carcinoma; autoimmune diseases (such as rheumatoid arthritis, autoimmune encephalitis); cardiovascular and cerebrovascular diseases (including coronary atherosclerosis, acute myocardial infarction, myocardial ischemia-reperfusion injury, ischemic stroke); inflammatory diseases; gestational hypertension; obesity; and diabetic nephropathy.
In the method for treating or preventing a disease or disorder associated with NAMPT in a subject, the compound of Formula (I) or the pharmaceutical composition of the present disclosure is administered to the subject through at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration.
The term “treatment” or “treating” refers to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure, or the pharmaceutical composition containing, as an active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof, to a subject to mitigate (alleviate) undesirable diseases or conditions, such as the development of a cancer or tumor. The beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, slowing down or delaying the progression of the disease, improving or alleviating the condition, and alleviating the disease.
A “therapeutic effective amount” of the compound of the present disclosure depends on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, the age, sex and weight of the patient, the patient's current medical condition, the route and duration of administration, the excretion rate, the combined administration of additional drugs, and the progression of the diseases or conditions of the patient being treated. Those skilled in the art will be able to determine appropriate dosages based on these and other factors.
It is to be understood that the choice of using one or more active compounds and/or compositions and their dosage depends on the basic situations of the individual (which should generally render the individual situation to achieve the best effect). Dosing and dosing regimens should be within the ability of those skilled in the art, and the appropriate dosage depends on many factors including the knowledge and ability of the physicians, veterinarians or researchers (Jun Li (chief editor), “Clinical Pharmacology”, 4th edition, People's Public Health Press, 2008).
As used herein, the term “patient” or “subject” refers to animal, for example mammal, including but not limited to primate (such as human being), cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mice, etc.
Unless otherwise specified, the following words, phrases and symbols used herein generally have the meanings as described below.
In general, the nomenclature used herein (including the IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, and pharmacology, etc.) are those well-known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in connection with the present disclosure described herein have the same meaning as commonly understood by one skill in the art. In addition, the use of the word “a” or “an” when used in conjunction with the term “comprising” or a noun in the claims and/or the specification may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the terms “another” or “other” can mean at least a second or more.
It should be understood that whenever the term “comprise” or “include” is used herein to describe various aspects, other similar aspects described by “consisting of” and/or “consisting essentially of” are also provided.
As used herein, the term “about” used alone or in combination refers to approximately, roughly, nearly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. In general, the term “about” can modify a numerical value above and below the stated value by an upward or downward (increasing or decreasing) variation, e.g., 10%, 5%, 2%, or 1%.
As used herein, the wording “ . . . represents a bond” used alone or in combination means that the referenced group is a bond linker (that is, the referenced group is absent). For example, the wording “R represents a bond” means that R is a bond linker. In other words, when R presents a bond, the group W in the structure of Formula (III) is directly connected to phenyl ring in the structure of Formula (III).
As used herein, the term “inserted” of the expression “one or more groups R5 and/or one or more groups R6 and/or any combination of one or more groups R5 and R6 are inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group”, used alone or in combination, has a known definition in the art, which can mean that carbon-carbon bond between one or more pairs of adjacent carbon atoms in the referenced backbone carbon chain is interrupted by the groups R5, R6, or a combination of R5 and R6. Herein, non-limiting examples of the above-mentioned expression “one or more groups . . . are inserted into” may include, but are not limited to, that one or more (e.g., 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 R5 as defined herein and/or one or more (e.g., 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 R6 as defined herein and/or one or more (e.g., 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) combinations of R5 with R6 are inserted into the backbone carbon chain, and the resulting backbone chain group conforms to the covalent bond theory. For example, the expression “one or more groups R5 and/or one or more groups R6 and/or any combination of one or more groups R5 and R6 are inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group” can refer to that 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) groups R5 and/or R6 and/or one or more combinations of R5 with R6 are inserted between one or more pairs of any two adjacent carbon atoms of the backbone carbon chain of the linear or branched C2-60 alkylene group, resulting in the formation of 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) fragments “—CH2—R5—CH2—” 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) fragments “—CH2—R6—CH2—” 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) fragments “—CH2—R5—R6—CH2—”, where each R5 are the same or different, each R6 are the same or different, and are as defined herein.
Herein, it should be understood that the expression “one or more groups R5 and/or one or more groups R6 and/or any combination of one or more groups R5 and R6 are optionally inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group” includes embodiments where “one or more groups R5 and/or one or more groups R6 and/or any combination of one or more groups R5 and R6 are inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group”, as well as embodiments where “no one or more groups R5 and/or one or more groups R6 and/or any combination of one or more groups R5 and R6 are optionally inserted into the backbone carbon chain of the linear or branched C2-60 alkylene group”.
Herein, a bond interrupted by a wavy line shows the point of attachment of the depicted group to the rest of the molecule. For example, the group of ULM depicted below
As used herein, the expression “a hydrogen atom of one or more CH2 of the linear or branched Cx-y alkylene is replaced by . . . ”, used alone or in combination, means that a hydrogen atom of any one or more CH2 of the linear or branched Cx-y alkylene is replaced by a substituent(s) as defined herein. Herein, the term “one or more” of “a hydrogen atom of one or more CH2 of groups #-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—” may include part or all hydrogen atoms of each referenced alkylene group, including but not limited to 1-80 hydrogens. In some embodiments, the expression “a hydrogen atom of one or more CH2” may refer to part or all of the hydrogen atoms of the referenced alkylene group, 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 atoms. In some embodiments, the expression “a hydrogen atom of one or more CH2” may include 1-3 of the plurality of hydrogen atoms of the referenced alkylene group. The number of hydrogens to be replaced is in principle not limited in any way, or is automatically limited by the size of the building unit.
As used herein, the wordings “optionally substituted” and “unsubstituted or substituted” can be used interchangeably. The term “substituted” usually means that one or more hydrogen atoms in the structure referenced are replaced by the same or different specific substituents.
As used herein, the term “oxo” or “oxo group” refers to ═O.
As used herein, the term “C(O)” or “C(═O)” or “C═O” used alone or in combination refers to a carbonyl group.
As used herein, the term “nicotinoyl” refers
As used herein, the term “halogen atom” or “halogen”, used alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
As used herein, the term “alkyl”, used alone or in combination, refers to a linear or branched alkyl group. The term “Cx-Cy alkyl” or “Cx-y alkyl” (x and y each being an integer) refers to a linear or branched alkyl group containing from x to y carbon atoms. The term “C1-10 alkyl” used alone or in combination in the present disclosure refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms. Non-limiting examples of the C1-10 alkyl of the present disclosure may include a C1-9 alkyl, C1-8 alkyl, C2-8 alkyl, C1-7 alkyl, C1-6 alkyl, C1-5 alkyl, and C1-4 alkyl. 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 “C1-3 alkyl” in the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms, and representative examples thereof include methyl, ethyl, n-propyl, and isopropyl. In the present disclosure, the “alkyl” is optionally substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, heterocyclyl, or a combination thereof.
As used herein, the term “halogenated alkyl” or “haloalkyl”, used alone or in combination, refers to a linear or branched alkyl group substituted with one or more halogens, wherein one or more hydrogen atom(s) of the alkyl group is replaced with one or more halogens. The term “halogenated Cx-Cy alkyl” or “halogenated Cx-y alkyl” (x and y are each an integer) refers to a linear or branched alkyl containing from x to y carbon atoms substituted with one or more halogens. The term “halogenated C1-10 alkyl” used alone or in combination in the present invention refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms substituted with one or more halogens. Examples of the halogenated C1-10 alkyl group of the present disclosure include halogenated C1-9 alkyl group, e.g., halogenated C1-8 alkyl group, halogenated C2-8 alkyl group, C1-7 alkyl group, halogenated C1-6 alkyl, halogenated C1-5 alkyl, or halogenated C1-4 alkyl. Representative examples include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl, halo-sec-butyl, halo-tert-butyl, halopentyl, haloisoamyl, haloneopentyl, halo-tert-pentyl, halohexyl, haloheptyl, halooctyl, halononyl, and halodecyl. The term “halo-C1-3 alkyl” of the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms substituted by one or more halogens, and its representative examples include halomethyl, haloethyl, halo-n-propyl and haloisopropyl.
As used herein, the term “alkylene” (which is used interchangeably with “alkylene chain”), used alone or in combination, refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term “Cx-Cy alkylene” or “Cx-y alkylene” (x and y each being an integer) refers to a linear or branched alkylene group containing from x to y carbon atoms. Examples of the C1-C60 alkylene in the present disclosure may include C1-C55 alkylene, C1-C50 alkylene, C1-C45 alkylene, C1-C40 alkylene, C1-C35 alkylene, C1-C30 alkylene, C1-C29 alkylene, C1-C28 alkylene, C1-C27 alkylene, C1-C26 alkylene, C1-C25 alkylene, C1-C24 alkylene, C1-C23 alkylene, C1-C22 alkylene, C1-C21 alkylene, C1-C20 alkylene, C1-C19 alkylene, C1-C18 alkylene, C1-C17 alkylene, C1-C16 alkylene, C1-C15 alkylene, C1-C14 alkylene, C1-C13 alkylene, C1-C12 alkylene, C1-C11 alkylene, C1-C10 alkylene, C1-C9 alkylene, C1-C8 alkylene, C1-C7 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylidene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene. In the present disclosure, the “alkylene” is optionally substituted by one or more substituents selected from C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “alkoxy”, used alone or in combination, refers to a linear or branched alkoxy group having structural formula of —O-alkyl. Optionally, the alkyl portion of the alkoxy group may contain 1-10 carbon atoms. Representative examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. The term “C1-C3 alkoxy” or “C1-3 alkoxy” refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Representative examples of C1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.
As used herein, the term “alkylamino”, used alone or in combination, refers to a linear or branched alkylamino group having structural formula of alkyl-NH—. Optionally, the alkyl portion of the alkylamino group may contain 1-10 carbon atoms. Representative examples of “alkylamino” include, but are not limited to, methyl-NH—, ethyl-NH—, n-propyl-NH—, isopropyl-NH—, n-butyl-NH—, isobutyl-NH—, tert-butyl-NH—, pentyl-NH—, and hexyl-NH—, etc. The term “C1-C3 alkyl-NH—” or “C1-3 alkyl-NH—” refers to a linear or branched alkyl-NH— group containing from 1 to 3 carbon atoms. Representative examples of C1-3 alkyl-NH— include, but are not limited to, methyl-NH—, ethyl-NH—, n-propyl-NH—, and isopropyl-NH—.
As used herein, the term “amino-substituted alkylene”, used alone or in combination, refers to a linear or branched alkylene group substituted by amino having structural formula of NH2-alkylene. Optionally, the alkylene portion of the amino-substituted alkylene group may contain 1-10 carbon atoms. The term “amino-substituted C1-3 alkylene” or “NH2—C1-3 alkyl” refers to a linear or branched alkylene group substituted by amino containing from 1 to 3 carbon atoms. Representative examples of amino-substituted C1-3 alkylene include, but are not limited to, NH2—CH2—, NH2—CH2CH2—, and NH2—CH2CH2CH2—.
As used herein, the term “alkyl-NHC(O)—”, used alone or in combination, refers to a linear or branched alkyl-NHC(O)— group having structural formula of alkyl-NHC(O)—. Optionally, the alkyl portion of the alkyl-NHC(O)— group may contain 1-10 carbon atoms. The term “C1-3 alkyl-NHC(O)—” or “C1-C3 alkyl-NHC(O)—” refers to a linear or branched alkyl-NHC(O)— group containing from 1 to 3 carbon atoms. Representative examples of C1-3 alkyl-NHC(O)— include, but are not limited to, CH3—NHC(O)—, CH3CH2—NHC(O)—, and CH3CH2CH2—NHC(O)—.
As used herein, the term “alkyl-C(O)NH—”, used alone or in combination, refers to a linear or branched alkyl-C(O)NH— group having structural formula of alkyl-C(O)NH—. Optionally, the alkyl portion of the alkyl-C(O)NH— group may contain 1-10 carbon atoms. The term “C1-3 alkyl-C(O)NH—” or “C1-C3 alkyl-C(O)NH—” refers to a linear or branched alkyl-C(O)NH— group containing from 1 to 3 carbon atoms. Representative examples of C1-3 alkyl-C(O)NH— include, but are not limited to, CH3—C(O)NH—, CH3CH2—C(O)NH—, and CH3CH2CH2—C(O)NH—.
As used herein, the term “heteroaryl”, used alone or in combination, refers to a 5- to 20-membered (e.g., 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, bicyclic, or polycyclic aromatic ring group containing at least one aromatic ring having one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic or tetracyclic heteroaryl groups, which contain one aromatic ring having one or more heteroatoms independently selected from O, S and N, and the remaining rings may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring 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, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridyl, furopyridyl, pteridyl, purinyl, pyridopyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 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 xanthyl. The heteroaryl group may be unsubstituted or substituted. A substituted heteroaryl refers to heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) by a substituent(s) optionally selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “heteroarylene”, used alone or in combination, refers to a 5- to 20-membered (e.g., 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, bicyclic, or polycyclic bivalent aromatic ring group containing at least one aromatic ring having one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene groups include bicyclic, tricyclic or tetracyclic heteroarylene groups, which contain one aromatic ring having one or more heteroatoms independently selected from O, S and N, and the remaining ring(s) may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring 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, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylene groups include, but are not limited to, indolylene, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, oxazolopyridylene, furopyridylene, pteridylene, purinylene, pyridopyridylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. Examples of tricyclic heteroarylene groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, and xanthylene. The heteroarylene group may be unsubstituted or substituted. A substituted heteroarylene refers to heteroarylene substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) by a substituent(s) optionally selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “aryl”, used alone or in combination, refers to a monovalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl group, naphthyl group, or fluorenyl group. As used herein, the “aryl” is optionally substituted. A substituted aryl group refers to an aryl group substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent(s). For example, aryl is mono-, di-, or tri-substituted by a substituent(s) optionally selected from e.g., C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “arylene”, used alone or in combination, refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene, naphthylene, or fluorenylene. As used herein, the “arylene” is optionally substituted. A substituted arylene refers to an arylene group optionally substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent(s). For example, arylene is mono-, di-, or tri-substituted by a substituent(s) optionally selected from e.g., C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “cycloalkyl”, used alone or in combination, refers to a saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic or bicyclic or polycyclic cyclic hydrocarbon radical, which in some embodiments contains from 3 to 20 carbon atoms (i.e., C3-20 cycloalkyl), or from 3 to 15 carbon atoms (i.e., C3-15 cycloalkyl), or from 3 to 12 carbon atoms (i.e., C3-12 cycloalkyl), or from 3 to 11 carbon atoms (i.e., C3-11 cycloalkyl), or from 3 to 10 carbon atoms (i.e., C3-10 cycloalkyl), or from 3 to 8 carbon atoms (i.e., C3-8 cycloalkyl), or from 3 to 7 carbon atoms (i.e., C3-7 cycloalkyl), or from 3 to 6 carbon atoms (i.e., C3-6 cycloalkyl). The term “cycloalkyl” includes monocyclic, bicyclic, or tricyclic cyclic hydrocarbon radical having from 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 cycloalkyl and spiro-cycloalkyl groups such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl, adamantanyl, noradamantanyl, bornyl, norbornyl (also named as bicyclo[2.2.1]heptyl by the IUPAC system). As used herein, the “cycloalkyl” is optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted “cycloalkyl” can be optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof. Examples of “C3-6 cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.
As used herein, the term “cycloalkylene”, used alone or in combination, refers to a saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic or bicyclic or polycyclic divalent cyclic hydrocarbon radical containing from 3 to 12 carbon atoms (e.g., 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms). The term “cycloalkylene” includes monocyclic, bicyclic or tricyclic cycloalkylene having from 3 to 12 carbon atoms. Representative examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic and tricyclic cycloalkylene groups include bridged cycloalkylene, fused cycloalkylene and spiro-cycloalkylene groups such as, but not limited to, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spiro-cycloalkylene, adamantanylene, noradamantanylene, and norbornylene (also named as bicyclo[2.2.1]heptylene by the IUPAC system). As used herein, the “cycloalkylene” is optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexylene. The substituents of the substituted “cycloalkylene” can be optionally one or more substituents selected from C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “Cx-y spiro-cycloalkylene” (x and y each being an integer), used alone or in combination, refers to a spiro-cycloalkylene group containing from x to y carbon atoms. As used herein, the term “C7-11 spiro-cycloalkylene”, used alone or in combination, refers to a spiro-cycloalkylene group containing from 7 to 11 carbon atoms (e.g., 7-10, 7-9 carbon atoms). Representative examples of “C7-11 spiro-cycloalkylene” include, but are not limited to, spiro[3.3]heptylene, spiro[2.5]octylene, spiro[3.5]nonylene, spiro[4.4]nonylene, spiro[4.5]decylene, or spiro[5.5]undecylene. The “C7-11 spiro-cycloalkylene” is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “Cx-y spiro-heterocyclylene” (x and y each being an integer), used alone or in combination, refers to a spiro-heterocyclylene group containing from x to y carbon atoms and one or more (e.g., from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. As used herein, the term “C7-11 spiro-heterocyclylene”, used alone or in combination, refers to a spiro-heterocyclylene group containing from 7 to 11 carbon atoms (e.g., 7-10, or 7-9 carbon atoms) and one or more (e.g., from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of “C7-11 spiro-cycloalkylene” include (but are not limited to):
The “C7-11 spiro-heterocyclylene” is optionally further substituted with one or more substituents selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “heterocyclyl” or “heterocyclic group”, used alone or in combination, refers to a 3- to 20-membered saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic, bicyclic, or tricyclic cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, “heterocyclyl” may refer to a 3- to 15-membered (e.g., 3- to 14-membered, 3- to 12-membered, 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, or 3- to 5-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of the monocyclic heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptan-1-yl), and diazacyclooctyl. Bicyclic and tricyclic heterocyclyl groups include bridged heterocyclyl, fused heterocyclyl and spiro-heterocyclyl groups such as, 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 azaspirocycloalkyl (including 3-azaspiro[5.5]undecan-3-yl). The heterocyclyl may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) by a substituent(s) optionally selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “heterocyclylene”, used alone or in combination, refers to a 3- to 20-membered saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic, bicyclic, or tricyclic bivalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, “heterocyclylene” may refer to a 3- to 15-membered (e.g., 3- to 14-membered, 3- to 12-membered, 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, or 3- to 5-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of the monocyclic heterocyclylene include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxacyclohexylene, and diazacycloheptanylene (e.g., 1,4-diazacycloheptanylene, 4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene). Bicyclic and tricyclic heterocyclylene groups include bridged heterocyclylene, fused heterocyclylene and spiro-heterocyclylene groups such as, but not limited to, 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptanylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, and azaspirocycloalkylene (e.g., 3-azaspiro[5.5]undecanylene). The heterocyclylene may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) by a substituent(s) optionally selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C1-3 alkoxy, C1-3 alkylamino, halogenated C1-3 alkyl, amino-substituted C1-3 alkylene, C1-3 alkyl-NHC(O)—, C1-3 alkyl-C(O)NH—, cyano, or any combination thereof.
As used herein, the term “alkynylene”, used alone or in combination, refers to a linear or branched divalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, or preferably 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynylene include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.
As used herein, the term “alkenylene”, used alone or in combination, refers to a linear or branched divalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, from 2 to 3, or 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene groups include, but are not limited to, vinylene (e.g., —CH═CH—), 1-propenylene, allylidene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-pent-2,4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.
As used herein, “bornylane” or “bornane” (also known as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; bornylane) has a definition known to those skilled in the art. As used herein, “camphanyl” or “bornyl” refers to a monovalent group of bornane, i.e., the group remaining after any one of the hydrogens in bornane is removed. Representative examples of “bornyl” include, but are not limited to, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-5-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-6-yl,
As used herein, “bicyclo[2.2.1]heptane” also known as “norbornane”, has a definition known to those skilled in the art. As used herein, “bicyclo[2.2.1]heptyl” or “norbornyl” refers to a monovalent group of bicyclo[2.2.1]heptane, i.e., the group remaining after any hydrogen in bicyclo[2.2.1]heptane is removed. Representative examples of “bicyclo[2.2.1]heptyl” include, but are not limited to, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-3-yl, bicyclo[2.2.1]heptan-4-yl, bicyclo[2.2.1]heptan-5-yl, or bicyclo[2.2.1]heptan-6-yl.
As used herein, the term “bicyclo[2.2.1]heptene” has a definition known to those skilled in the art. As used herein, “bicyclo[2.2.1]heptenyl” refers to a monovalent group of bicyclo[2.2.1]heptene, i.e., the group remaining after any hydrogen in bicyclo[2.2.1]heptene is removed. Representative examples of “bicyclo[2.2.1]heptenyl” include, but are not limited to, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]hept-5-en-3-yl, or bicyclo[2.2.1]hept-5-en-7-yl.
As used herein, “adamantane” (also known as tricyclo[3.3.1.13,7]decane) has a definition known to those skilled in the art, and its structural formula is e.g., as follows:
As used herein, “adamantanyl” refers to a monovalent group of adamantane, that is, the group remaining after any hydrogen in adamantane is removed. Representative examples of “adamantanyl” include, but are not limited to, 1-adamantanyl, 2-adamantanyl, 3-adamantanyl, 4-adamantanyl, 5-adamantanyl, 6-adamantanyl, 7-adamantanyl, 8-adamantanyl, 9-adamantanyl, or 10-adamantanyl.
As used herein, “noradamantane” (also known as octahydro-2,5-methanopentalene) has a definition known to those skilled in the art, and its structural formula is e.g., as follows:
As used herein, “noradamantanyl” refers to a monovalent group of noradamantane, that is, the group remaining after any hydrogen in noradamantane is removed. Representative examples of “noradamantanyl” include, but are not limited to, 1-noradamantanyl, 2-noradamantanyl, 3-noradamantanyl, 4-noradamantanyl, 5-noradamantanyl, 6-noradamantanyl, 7-noradamantanyl, 8-noradamantanyl or 9-noradamantanyl.
As used herein, “adamantanamine” has the definitions known to those skilled in the art, namely referring to an adamantane having an amino substituent, wherein the amino substituent can replace a hydrogen on a carbon at any position in the adamantane. An example of “adamantanamine” can be adamantan-1-amine (corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.13,7]decan-1-amine; CAS No.: 768-94-5), with the following structural Formula:
Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of Formula (I) of the present disclosure are also encompassed within the scope of the present invention.
In all embodiments of the present disclosure, the salts or pharmaceutically acceptable salts of the compounds of Formula (I) refer to non-toxic inorganic or organic acid and/or base addition salts. Examples include: sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate, or p-toluenesulfonate, etc.
“Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be “acceptable”. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other common non-toxic compatible substances used in pharmaceutical formulations.
As used herein, the term “room temperature” refers to the ambient temperature, such as 20-30° C.
As used herein, “stereoisomer” refers to a compound with the same chemical structural formula, but a different arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis/trans isomers), atropisomers, and so on.
As used herein, the term “solvate” refers to an association or complex formed by the interaction between one or more solvent molecules and compounds of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term “hydrate” means that a complex formed with water.
As used herein, the term “chiral” refers to a molecule that is nonsuperimposable on its mirror image; whereas “achiral” refers to a molecule that can be superimposed on its mirror image.
As used herein, the term “enantiomers” refers to two isomers of a compound that are nonsuperimposable mirror images.
As used herein, the term “diastereomers” refers to stereoisomers which have two or more chiral centers but which are non-mirror images. The diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. The diastereomeric mixture can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other cases, well-known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. Although the present disclosure will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present disclosure to these embodiments.
The following abbreviations are used throughout the specification and examples:
In the present disclosure, the 1H NMR spectrum was recorded on a Bruker-500 MHz nuclear magnetic resonance instrument, by using, as a solvent, CD3OD (δ=3.31 ppm) containing 0.1% TMS (as an internal standard); or using, as a solvent, CDCl3 (δ=7.26 ppm) containing 0.1% TMS (as an internal standard); or using, as a solvent, DMSO-d6 (δ=2.50 ppm) containing 0.03% TMS (as an internal standard). LRMS spectrum was recorded on an AB Triple 4600 mass spectrometer, HPLC preparation was measured on a SHIMADZU LC-20AP type instrument, and HPLC purity was measured on a SHIMADZU LC-30AP or Waters 1525 type instrument. Unless otherwise specified, all reactions were performed in the air atmosphere. The reactions were followed by TLC or LC-MS.
Solvents and reagents are processed as follows:
Compounds and/or pharmaceutically acceptable salts thereof of the present disclosure can be synthesized using commercially available raw materials by synthetic techniques known in the art. The synthetic schemes described below illustrate the preparation of most compounds. The starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art. One skilled in the art can prepare the salt, racemate, enantiomer, phosphate, sulfate, hydrochloride and prodrug forms of the compounds of formula (I) of the present disclosure according to routine techniques in the art.
General Synthesis Method for Intermediates LM (pomalidomide-N-Linker-COOH):
Step 1: a 30 mL microwave reaction tube was charged with 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1 equiv; CAS No.: 835616-60-9), the corresponding raw material amine (1.2 equiv), and N,N-diisopropylethylamine (5 equiv), followed by addition of NMP (8 mL). The resulting reaction mixture was stirred at room temperature for 10 minutes. Then argon gas was slowly blown into the microwave reaction tube. The microwave reaction tube was placed into a microwave reactor, and heated to 110° C. The reaction mixture was stirred for 2 h. The reaction solution was cooled to room temperature, and poured into 90% brine. The resulting mixture was extracted with ethyl acetate (4×50 mL). Organic phases were combined, washed with water (2×30 mL) and saturated brine (50 mL), and dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (eluent (v/v): petroleum ether/ethyl acetate=1:1) to give Boc protected intermediate.
Step 2: a 50 mL single-necked flask was charged with the Boc protected intermediate from step 1 and 20 mL of 88% formic acid. The reaction mixture was stirred at room temperature for 12 h, and evaporated under reduced pressure to remove the reaction solvent. The resulting residue was added with water and lyophilized to obtain the corresponding final target compound.
General Synthesis Method for Intermediates LM (lenalidomide-N-Linker-COOH):
A single-necked flask was charged with lenalidomide (1 equiv.), NMP (8 mL), corresponding raw material brominated tert butyl ester (1.2 equiv.) and N,N-diisopropylethylamine (3 equiv.). The reaction solution was reacted at 110° C. for 12 h, cooled to room temperature, and subjected to a C18 reverse phase column (eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%) for separation and purification, to give the corresponding intermediate tert butyl ester.
A single-necked flask was charged with the intermediate tert butyl ester from step 1, DCM (6 mL) and TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h, and evaporated under reduced pressure to remove the reaction solvent. The resulting residue was added with water and lyophilized to obtain the corresponding final target compound.
General Synthesis Method for Intermediates LM (pomalidomide-N-alkylene-I):
Step 1:
To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1 equiv.) in NMP (25 mL) were sequentially added corresponding tert-butyldimethylsilyloxy-protected primary amine (1.0 equiv) and N,N-diisopropylethylamine (1.5 equiv.). The reaction mixture was reacted at 100° C. for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature, and poured into saturated brine. The resulting mixture was extracted with ethyl acetate (4×50 mL). Organic phases were combined, washed with water (2×30 mL) and saturated brine (50 mL), and dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (eluent (v/v): petroleum ether/ethyl acetate=1:1) to give the intermediate. To a solution of the intermediate in THF (50 mL) was added tetrabutylammonium fluoride (1 equiv.). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, to the reaction solution was added saturated brine (200 mL). The resulting mixture was extracted with ethyl acetate (4×50 mL). Organic phases were combined, washed with water (2×30 mL) and saturated brine (50 mL), and dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The obtained crude product was used directly in the next step.
Step 2:
To a solution of the crude product from step 1 in 40 mL of mixed solvent (DCM/pyridine=3/1) were sequentially added triethylamine (3.0 equiv) and methanesulfonyl chloride (1.5 equiv) in ice water bath. The reaction mixture was reacted at room temperature for 12 h. After the reaction was complete, the reaction solution was washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography to give corresponding sulfonate intermediate.
Step 3: To a solution of the corresponding sulfonate intermediate from step 2 in acetone was added NaI. The reaction mixture was heated to 60° C. and reacted overnight to give the target compound.
General Synthesis Method for Intermediates LM (lenalidomide/pomalidomide-alkynyl-linker-OMs):
Step 1:
a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione or 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1 equiv.) in DMF (5 mL) was bubbled with argon gas for 5 min, followed by sequentially addition of corresponding alkynol substrate (2 equiv.), Pd(PPh3)2Cl2 (0.1 equiv.) and CuI (0.2 equiv.). The reaction mixture was stirred for 5 min, and then triethylamine (2.5 mL) was added thereto. The resulting mixture was heated to 80° C., and reacted overnight. The mixture was cooled to room temperature, quenched with 50 mL of water, and extracted with ethyl acetate (3×50 mL). Organic phases were combined, washed with water (2×30 mL) and saturated brine (50 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (eluent (v/v): DCM/MeOH=5/1) to give the corresponding alcohol intermediate.
Step 2:
To a solution of the corresponding alcohol intermediate from step 1 in DCM (15 mL) were sequentially added triethylamine (3 equiv.) and methanesulfonyl chloride (1.5 equiv.). The reaction system become clear and reacted overnight. The reaction solution was washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (eluent (v/v): DCM/MeOH=5/1) to give the corresponding target compound.
General Synthesis Method for Intermediates LM (lenalidomide/pomalidomide-alkylene-OMs):
Step 1: to a solution of the corresponding alkynol substrate (1 equiv.) in ethanol (10 mL) were added 10% Pd/C (5 mg) and PtO2 (5 mg) as catalysts under hydrogen atmosphere. The resulting mixture was reacted for 12 h at 50° C. under normal pressure under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The resulting crude product was directly used in the next step.
Step 2: to a solution of the reduction product from step 1 in DCM (15 mL) were sequentially added triethylamine (3 equiv.) and methanesulfonyl chloride (1.5 equiv.). The reaction system become clear and reacted overnight. The reaction solution was washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (eluent (v/v): DCM/MeOH=5/1) to give the corresponding target compound.
General Synthesis Method for Intermediates LM (pomalidomide-S-alkylene-COOH):
Step 1:
A 250 mL egg-shaped flask was charged with 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (20 g, 72.4 mmol) and anhydrous N,N-dimethylformamide (150 mL), followed by addition of sodium sulfide nonahydrate (28 g, 108.6 mmol) in portions under stirring at room temperature, and the mixture was stirred at room temperature for 6 h. Then the reaction solution was slowly poured into 400 mL ice-water mixture. With stirring, the pH of the reaction solution was adjusted slowly to pH 2-3 with 6N aqueous hydrochloric acid solution. The color of the solution changed from blood red to light yellow, and a large amount of off-white solids were precipitated out. After stirring at room temperature for 0.5 h, the solids were filtrated, and the filter cake was washed 3 times with water; then the filter cake was slurried with 100 mL of anhydrous acetone, filtered, and washed 3 times with acetone, and dried under reduced pressure to afford intermediate 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014).
Step 2:
A 100 mL egg-shaped flask was charged with the intermediate 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014) (1 equiv) from step 1, anhydrous N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (2 equiv), followed by slow addition of the corresponding brominated substrate (1.2 equiv) under stirring at room temperature. After the completion of addition, the mixture was stirred at room temperature for 0.5 h. After the reaction was complete, 50 mL of water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water (3×20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvents. The crude product was purified by column chromatography (eluent (v/v): dichloromethane/ethyl acetate=20:1) to give the corresponding tert-butyl ester intermediate compound. The corresponding tert-butyl ester intermediate compound and 88% formic acid (10 mL) were sequentially added to a 25 mL egg-shaped flask, and stirred at room temperature for 12 h, and then concentrated under reduced pressure to remove the solvent. The resulting residue was added with water and lyophilized to afford the corresponding target compound.
General Synthesis Method for Intermediates LM (pomalidomide-S-PEGn-COOH):
A 100 mL egg-shaped flask was charged with the 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (SIAIS151014) (1 equiv), anhydrous N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (2 equiv), followed by slow addition dropwise of the corresponding p-toluenesulfonate-protected PEG chain substrate (1.2 equiv), and the mixture was stirred at room temperature for 0.5 h. After the reaction was complete, 50 mL of water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water (3×20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvents. The crude product was purified by column chromatography (eluent (v/v): dichloromethane/ethyl acetate=20:1) to give the corresponding tert-butyl ester intermediate compound. A 25 mL egg-shaped flask was charged with the corresponding tert-butyl ester intermediate compound, followed by addition of DCM and TFA. The resulting mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure to remove the solvent. The resulting residue was added with water and lyophilized to afford the corresponding target compound.
General Synthesis Method for Intermediates LM (lenalidomide-S-alkylene-COOH):
Step 1: a 500 mL egg-shaped flask containing methanol (120 mL) and water (120 mL) was charged with 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). The mixture was slowly warmed up to 80° C. and stirred for 2 h. After cooling to room temperature, to the reaction solution was added 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (lenalidomide) (8.0 g, 30.9 mmol), followed by slow addition dropwise of tert-butyl nitrite (4.78 g, 46.4 mmol). After the completion of addition, the reaction solution was warmed up to 80° C. again and stirred for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, followed by addition of water (200 mL), and extraction with ethyl acetate (2×200 mL). The organic phases were combined, washed with water (2×50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (eluent (v/v): petroleum ether/ethyl acetate=1:2) to give the product (SIAIS171088).
Step 2: a 250 mL egg-shaped flask was charged with anhydrous aluminum trichloride (2.61 g, 19.6 mmol) and anhydrous toluene (70 mL), followed by slow addition of the compound SIAIS171088 (1.8 g, 4.9 mmol) with stirring. The mixture was stirred at 35° C. overnight. After the reaction was completed, 20% citric acid aqueous solution was slowly added to the reaction mixture with stirring, and a large amount of solids were precipitated out. After filtration, the filter cake was washed with water and ethyl acetate, respectively, and dried to give the product (SIAIS171095).
Step 3: a 100 mL egg-shaped flask was charged with the compound SIAIS171095 (1 equiv), anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (2 equiv), followed by slowly addition dropwise of the corresponding brominated substrate (1.2 equiv). The mixture was stirred at room temperature for 0.5 h. After the reaction was complete, 50 mL of water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water (3×20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was purified by a column chromatography (eluent (v/v): dichloromethane/ethyl acetate=20:1) to give the corresponding tert-butyl ester intermediate compound. The corresponding tert-butyl ester intermediate compound and 88% formic acid (10 mL) were sequentially added to a 25 mL egg-shaped flask, and stirred at room temperature for 12 h, and then concentrated under reduced pressure to remove the solvent. The resulting residue was treated by addition of water and lyophilized to afford the corresponding target compound.
General Synthesis Method for Intermediates LM (lenalidomide-S-PEGn-COOH):
A 100 mL egg-shaped flask was charged with the intermediate SIAIS171095 (1 equiv), anhydrous N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (2 equiv), followed by slow addition dropwise of the corresponding p-toluenesulfonate-protected PEG chain substrate (1.2 equiv) with stirring at room temperature. After the completion of addition, the mixture was stirred at room temperature for 0.5 h. After the reaction was complete, 50 mL of water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water (3×20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was purified by a column chromatography (eluent (v/v): dichloromethane/ethyl acetate=20:1) to give the corresponding tert-butyl ester intermediate compound. A 25 mL egg-shaped flask was charged with the corresponding tert-butyl ester intermediate compound, followed by addition of DCM (10 mL) and TFA (5 mL). The resulting mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure to remove the solvent. The resulting residue was added with water and lyophilized to afford the corresponding target compound.
General Synthesis Method for Intermediates LM (lenalidomide/pomalidomide-S-alkylene-Br):
To a solution of 3-(4-mercapto-1-oxoisoindolin-2-yl)piperidine-2,6-dione or 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione (1 equiv) in DMF (20 mL) was added K2CO3 (3 equiv.). The reaction mixture was stirred for 15 min, and the corresponding dibromide substrate (3 equiv) was added thereto. The reaction solution was reacted at room temperature for 12 h, and then was poured into 50 mL of water. The resulting mixture was extracted with dichloromethane twice. Organic phases were combined, washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the corresponding target compound.
General Synthesis Method for Intermediates LM (lenalidomide-O-alkylene-Br):
To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 equiv) in DMF (20 mL) was added K2CO3 (3 equiv.). The reaction mixture was stirred for 15 min, and the corresponding dibromide substrate (3 equiv) was added thereto. The reaction solution was heated to 80° C. and reacted for 12 h, and then poured into 50 mL of water. The resulting mixture was extracted with dichloromethane twice. Organic phases were combined, washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the corresponding target compound.
General Synthesis Method for Intermediates LM (pomalidomide-O-alkylene-COOH):
Step 1: to a solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1 equiv) in DMF (20 mL) were added K2CO3 (3 equiv.) and the corresponding tert-butyl-protected brominated alkyl chain acid substrate (1.2 equiv). The reaction solution was reacted at room temperature for 2 h, and then poured into 50 mL of water. The resulting mixture was extracted with dichloromethane twice. Organic phases were combined, washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the corresponding tert-butyl ester intermediate compound.
Step 2: a 25 mL egg-shaped flask was charged with the corresponding tert-butyl ester intermediate compound, followed by addition of DCM (10 mL) and TFA (5 mL). The resulting mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure to remove the solvent. The resulting residue was added with water and lyophilized to afford the corresponding target compound.
A 250 mL three-necked flask was charged with the corresponding raw material diacid (2.5 equiv), anhydrous DMF (10 mL) and anhydrous dichloromethane (150 mL), followed by addition of 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) with stirring in ice water bath. After the completion of addition, the reaction mixture was stirred in ice water bath for 5 h, and then warmed up to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with 1 mL of deionized water, and evaporated under reduced pressure to remove the dichloromethane. The resulting residue was subjected to a C18 reverse phase column (eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%) for separation and purification. The collected fractions were concentrated under reduced pressure to remove acetonitrile, and the resulting residue was lyophilized to give the corresponding target compound.
Depending upon the target compounds, the above schemes and their reaction substrates, reaction conditions (including reaction dosage, temperature, duration, etc.), work up, etc. can be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compounds. The obtained target compounds can be further modified by the substituents and the like to obtain subsequent target compounds through methods well known to those skilled in the art.
Referring to the method of Scheme 1, Daporinad derivative 1 (SIAIS630006) was prepared.
A 50 ml round-bottomed flask was sequentially charged with (E)-3-(pyridin-3-yl)acrylic acid (1 g, 1.5 equiv) and DCM (10 mL) at room temperature, followed by addition dropwise of oxalyl chloride (0.7 mL, 1.8 equiv) in ice bath. After the addition was complete, 2 drops of DMF were added to the reaction mixture to initiate the reaction, and the reaction mixture was reacted for 3 hours at 60° C. A small amount of the reaction solution was taken, dissolved in methanol, and analyzed by LC-MS to detect the formation of the corresponding methyl ester. The reaction solution was then evaporated to remove DCM for further use. Separately, another 50 mL round-bottomed flask was charged with tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate (860 mg, 0.75 equiv), 10 mL of DCM, and 1 mL of TEA (1.5 equiv), followed by slow addition dropwise of the acyl chloride solution dissolved in DCM under an ice bath. After the addition was complete, the reaction mixture was reacted for 1 hour at room temperature. The reaction was monitored by LC-MS, and upon completion, water was added to quench the reaction. To the mixture was added Silica gel, and the resulting mixture was then subjected to a column chromatography using an eluent system of 5% CH3OH/DCM to yield a yellow oily compound, which was directly used for the next reaction. To the solution of this yellow oily compound in 10 mL of DCM was added 2 mL of TFA, and the reaction mixture was reacted at room temperature for 2 hours. Once the reaction was complete as monitored by LC-MS, the reaction solution was rotary evaporated to remove the reaction solvent. The resulting residue was adjusted to a basic pH with a saturated solution of sodium bicarbonate, and then extracted three times with dichloromethane/methanol (10:1). The organic phases were combined, washed twice with a saturated NaCl solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness, and the resulting residue was subjected to C18 reverse-phase column chromatography using CH3CN and water as the eluent for separation. The collected fractions were evaporated to remove CH3CN, and the resulting residue was lyophilized to afford SIAIS524135 as white solid (823 mg, total yield for two steps: 64%). 1H 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) calcd for C17H26N3O+ [M+H]+, 288.2070; found, 288.2074.
A 50 ml round-bottomed flask was sequentially charged with 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 of DMF, and 1.6 mL of DIPEA (3 equiv) at room temperature. The reaction mixture was reacted at 60° C. overnight. Once the reaction was complete as monitored by LC-MS, the reaction mixture was filtered, and the filtrate was subjected to a C18 reverse-phase column using CH3CN and water as the eluent for separation. The collected fractions were evaporated to remove CH3CN, and the resulting residue was lyophilized to yield a yellow solid compound, which was directly used for the next reaction. To the solution of this yellow solid compound in 10 mL of DCM was added 2 mL of TFA, and the reaction mixture was reacted at room temperature for 2 hours. Once the reaction was complete as monitored by LC-MS, the reaction solution was rotary evaporated to remove the reaction solvent. The resulting residue was adjusted to a basic pH with a saturated solution of sodium bicarbonate, and then the organic phases were combined, extracted three times with dichloromethane/methanol (10:1), washed twice with a saturated NaCl solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness, and the resulting residue was subjected to C18 reverse-phase column chromatography using CH3CN and water as the eluent for separation. The collected fractions were evaporated to remove CH3CN, and the resulting residue was lyophilized to afford SIAIS630006 as yellow solid (1.1 g, total yield for two steps: 64%). 1H NMR (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) calcd for C28H38N5O2+ [M+H]+, 476.3020; found, 476.3024.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 2 was prepared, and the synthesis data and structural characterization data thereof are as follows:
(E)-N-(4-(4-(4-(piperazin-1-yl)benzoyl)piperazin-1-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS630020). (white solid, 258 mg, total yield for two steps: 63%). 1H 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) calcd for C27H37N6O2+ [M+H]+: 477.2973, found, 477.2975.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 3 was prepared, and the synthesis data and structural characterization data thereof are as follows:
(E)-N-(4-(1-(4-(piperidin-4-yl)benzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS631127) (yellow oily liquid, 359 mg, yield 73%). 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) calcd for C29H39N4O2+ [M+H]+: 475.3068, found, 475.3072.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 4 was prepared, and the synthesis data and structural characterization data thereof are as follows:
(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) calcd for C26H36N7O2+ [M+H]+: 478.2925, found, 478.2928.
Referring to Scheme 17, 6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxylic acid (SIAIS631145) was prepared.
To a solution of 6-chloropyridazine-3-carboxylic acid (1 equiv.) in DMF (20 mL) were added DIPEA (5 equiv) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2 equiv). The reaction mixture was reacted at 130° C. for 3 h, then was slowly poured into 50 mL of water. The resulting mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to remove the solvents. The resulting residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the intermediate compound SIAIS631145, ESI [M+H]+: 392.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 5 ((E)-N-(4-(1-(6-(4-(piperazin-1-yl)piperidin-1-yl)pyridazine-3-carbonyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS631135)) was prepared by using the intermediate SIAIS631145 from step 1. (yellow oily liquid, 359 mg, yield 73%). 1H 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) calcd for C31H45N8O2+ [M+H]+: 561.3660, found 561.3665.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 6 was prepared, and the synthesis data and structural characterization data thereof are as follows:
(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%). 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.92 (s, 1H), 8.73 (d, J=8.2 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.09 (s, 1H), 7.73-7.59 (m, 2H), 7.00 (d, J=9.0 Hz, 1H), 6.92 (d, J=15.8 Hz, 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) calcd for C27H37N6O2+ [M+H]+: 477.2973, found, 477.2976.
Referring to Scheme 17, 6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)piperidin-1-yl)nicotinic acid (SIAIS631147) was prepared.
To a solution of 6-chloronicotinic acid (1 equiv.) in DMF (20 mL) were added DIPEA (5 equiv) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2 equiv). The reaction mixture was reacted at 130° C. for 3 h, then was poured into 50 mL of water. The resulting mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to remove the solvents. The resulting residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the intermediate compound SIAIS631147, ESI [M+H]+: 391.
Referring to Scheme 1 and using a method similar to the preparation of the Daporinad derivative 1 in Intermediate Preparation Example 1, the Daporinad derivative 7 ((E)-N-(4-(1-(6-(4-(piperazin-1-yl)piperidin-1-yl)nicotinoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide (SIAIS632044)) was prepared by using the intermediate SIAIS631147 from step 1. (white solid, 132 mg, yield 30%). 1H 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) calcd for C32H46N7O2+ [M+H]+: 560.3708, found, 560.3711.
Referring to the method of Scheme 14, the compound SIAIS352066 was prepared under appropriate conditions that will be recognized by one skilled in the art, except that the raw material diacid used was malonic acid. The compound (SIAIS352066) was obtained as white solid (0.82 g, yield 68%). ESI [M+H]+: 517.
Referring to the method of Scheme 14, the compound SIAIS164189 was prepared under appropriate conditions that will be recognized by one skilled in the art, except that the raw material diacid used was hexadecanedioic acid. The compound (SIAIS164189) was obtained as white solid (0.88 g, yield 67%). ESI [M+H]+: 699.
Referring to Scheme 12, to a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.8 mmol) in DMF (20 mL) was added K2CO3 (0.27 g, 1.9 mmol). The reaction mixture was stirred for 15 min, and the 1,8-dibromooctane (2.0 g, 7.6 mmol) was added thereto. The reaction solution was heated to 80° C. and reacted for 12 h, and then poured into 50 mL of water. The resulting mixture was extracted with dichloromethane twice. Organic phases were washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by column chromatography (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the compound SIAIS1222063 as white powder (yield 32%). ESI [M+H]+: 451.
Referring to the method of Scheme 11, the compound SIAIS1224003 was prepared under appropriate conditions that will be recognized by one skilled in the art, except that the raw materials used were 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione and 1,8-dibromooctane. The compound (SIAIS1224003) was obtained as white solid (0.92 g, yield 71%). ESI [M+H]+: 481.
Referring to Scheme 15, a reaction flask was sequentially charged with Nampt inhibitor (i.e., Daporinad derivative 1 (SIAIS630006)) (0.02 mmol, 1 equiv), intermediate LM (SIAIS151026; 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propionic acid; CAS No.: 2225940-46-3) (0.02 mmol, 1 equiv), HATU (0.024 mmol, 1.2 equiv), 2 mL of DMF, and DIPEA (0.06 mmol, 3 equiv) at room temperature. The reaction mixture was reacted at room temperature overnight. Once the reaction was complete as monitored by LC-MS, the reaction mixture was filtered. The filtrate was subjected to preparative HPLC for separation. The collected fractions were evaporated to remove CH3CN, and the resulting residue was lyophilized to afford the target compound (SIAIS630009) as yellow solid (6.3 mg, yield 46%). 1H NMR (500 MHz, 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) calcd for C44H51N8O7+ [M+H]+, 803.3875; found, 803.3879.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630010) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151019; 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyric acid; CAS No.: 2225940-47-4). The compound (SIAIS630010) was obtained as yellow solid (6.8 mg, yield 49%). 1H NMR (500 MHz, 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) calcd for C45H53N8O7+ [M+H]+, 817.4032; found, 817.4038.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630011) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151020; 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid; CAS No.: 2225940-48-5). The compound (SIAIS630011) was obtained as yellow solid (6.0 mg, yield 43%). 1H NMR (500 MHz, CD3OD) δ 8.85 (s, 1H), 8.63 (d, J=5.1 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.77-7.70 (m, 1H), 7.63-7.48 (m, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.5 Hz, 1H), 6.99 (dd, J=17.8, 7.9 Hz, 3H), 6.81 (d, J=15.8 Hz, 1H), 5.03 (dd, J=12.6, 5.5 Hz, 1H), 3.70 (dt, J=16.9, 5.3 Hz, 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), 2.52-2.51 (m, 2H), 2.13-2.02 (m, 1H), 1.75 (t, J=3.3 Hz, 5H), 1.59 (p, J=6.9 Hz, 4H), 1.43 (br, 2H), 1.37-1.32 (m, 2H), 1.29 (br, 2H), 0.18 (br, 2H). HRMS (ESI) calcd for C46H55N8O7+ [M+H]+, 831.4188; found, 831.4190.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632014) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204057; (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid; CAS No.: 2103656-92-2). The compound (SIAIS632014) was obtained as white solid (5.2 mg, yield 17%). 1H NMR (500 MHz, 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) calcd for C43H51N8O6+ [M+H]+, 775.3926; found, 775.3928.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632015) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204085; 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyric acid; CAS No.: 1781226-49-0). The compound (SIAIS632015) was obtained as white solid (4.7 mg, yield 15%). 1H NMR (500 MHz, 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) calcd for C45H55N8O6+ [M+H]+, 803.4239; found, 803.4240.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632016) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1210133; 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid; CAS No.: 2338824-29-4). The compound (SIAIS632016) was obtained as white solid (4.1 mg, yield 14%). 1H NMR (500 MHz, 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) calcd for C46H57N8O6+ [M+H]+, 817.4396; found, 817.4398.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632017) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204061; 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoic acid; CAS No.: 2338824-30-7). The compound (SIAIS632017) was obtained as white solid (5.3 mg, yield 16%). 1H NMR (500 MHz, 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) calcd for C47H59N8O6+ [M+H]+, 831.4552; found, 831.4554.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632018) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204063; 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoic acid; CAS No.: 22338824-32-9). The compound (SIAIS632018) was obtained as white solid (5.7 mg, yield 17%). 1H NMR (500 MHz, 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) calcd for C48H61N8O6+ [M+H]+, 845.4709; found, 845.4711.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630012) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151086; 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid; CAS No.: 2225940-50-9). The compound (SIAIS630012) was obtained as yellow solid (6.1 mg, yield 44%). 1H NMR (500 MHz, 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) calcd for C48H59N8O7+ [M+H]+, 859.4501; found, 859.4505.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630013) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS171090; 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetic acid; CAS No.: 2378582-40-0). The compound (SIAIS630013) was obtained as white solid (3.1 mg, yield 24%). 1H NMR (500 MHz, 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) calcd for C43H50N7O6S+ [M+H]+, 792.3538; found, 792.3540.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630014) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS171079; 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentanoic acid; CAS No.: 2378582-43-3). The compound (SIAIS630014) was obtained as white solid (4.0 mg, yield 29%). 1H NMR (500 MHz, 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) calcd for C46H56N7O6S+ [M+H]+, 834.4007; found, 834.4011.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS6320037) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS171091; 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanoic acid; CAS No.: 2378582-44-4). The compound (SIAIS6320037) was obtained as white solid (4.6 mg, yield 33%). 1H NMR (500 MHz, 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) calcd for C47H58N7O6S+ [M+H]+, 848.4164; found, 848.4168.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630038) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)acetic acid; CAS No.: 2378582-21-7). The compound (SIAIS630038) was obtained as white solid (4.3 mg, yield 31%). 1H NMR (500 MHz, 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) calcd for C45H54N7O7S+ [M+H]+, 836.3800; found, 836.3805.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630039) was prepared by using Daporinad 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 No.: 2378582-22-8). The compound (SIAIS630039) was obtained as white solid (4.2 mg, yield 31%). 1H 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) calcd for C47H58N7O8S+ [M+H]+, 880.4062; found, 880.4065.
Referring to Scheme 16, a reaction flask was sequentially charged with Nampt inhibitor (i.e., Daporinad derivative 1 (SIAIS630006)) (0.04 mmol, 1 equiv), intermediate LM (SIAIS213137; 3-(4-(2-bromoethylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-57-9) (0.048 mmol, 1.2 equiv), 2 mL of DMF, and DIPEA (0.12 mmol, 3 equiv) at room temperature. The reaction mixture was reacted at 60° C. for 8 h. Once the reaction was complete as monitored by LC-MS, the reaction mixture was filtered. The filtrate was subjected to preparative HPLC for separation. The collected fractions were evaporated to remove CH3CN, and the resulting residue was lyophilized to afford the target compound (SIAIS630130) as white solid (6.2 mg, yield 20%). 1H 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) calcd for C43H52N7O5S+ [M+H]+, 778.3745; found, 778.3748.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630131) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS213132; 3-(4-(3-bromopropylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-58-0). The compound (SIAIS630131) was obtained as white solid (6.4 mg, yield 21%). 1H NMR (500 MHz, 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) calcd for C44H54N7O5S+ [M+H]+, 792.3902; found, 792.3905.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630123) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-59-1). The compound (SIAIS630123) was obtained as white solid (5.6 mg, yield 23%). 1H NMR (500 MHz, 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) calcd for C45H56N7O5S [M+H]+, 806.4058; found, 806.4061.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630132) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216049; 3-(4-((5-bromopentyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-60-4). The compound (SIAIS630132) was obtained as white solid (6.1 mg, yield 19%). 1H NMR (500 MHz, 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) calcd for C46H58N7O5S+ [M+H]+, 820.4215; found, 820.4217.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630133) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216133; 3-(4-((6-bromohexyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-61-5). The compound (SIAIS630133) was obtained as white solid (6.4 mg, yield 19%). 1H NMR (500 MHz, 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) calcd for C47H60N7O5S+ [M+H]+, 834.4371; found, 834.4375.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630134) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216135; 3-(4-(7-bromoheptylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-62-6). The compound (SIAIS630134) was obtained as white solid (6.7 mg, yield 20%). 1H NMR (500 MHz, 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) calcd for C48H62N7O5S+ [M+H]+, 848.4528; found, 848.4531.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630135) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1216137; 3-(4-((8-bromooctyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-63-7). The compound (SIAIS630135) was obtained as white solid (6.9 mg, yield 20%). 1H NMR (500 MHz, 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) calcd for C49H64N7O5S+ [M+H]+, 862.4684; found, 862.4689.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630136) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1220015; 3-(4-((11-bromoundecyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-66-0). The compound (SIAIS630136) was obtained as white solid (7.0 mg, yield 20%). 1H 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) calcd for C52H70N7O5S+ [M+H]+, 904.5154; found, 904.5155.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630129) was prepared by using Daporinad 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 No.: 2138441-31-1). The compound (SIAIS630129) was obtained as white solid (5.3 mg, yield 17%). 1H 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) calcd for C46H54N7O5+ [M+H]+, 784.4181; found, 784.4183.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630119) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS255119; 6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl methanesulfonate; CAS No.: 2570254-40-7). The compound (SIAIS630119) was obtained as white solid (5.6 mg, yield 24%). 1H 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) calcd for C47H56N7O5+ [M+H]+, 798.4337; found, 798.4339.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630120) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS630120) was obtained as white solid (5.8 mg, yield 25%). 1H 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) calcd for C48H58N7O5+ [M+H]+, 812.4494; found, 812.4496.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630121) was prepared by using Daporinad 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 No.: 2570254-42-9). The compound (SIAIS630121) was obtained as white solid (5.7 mg, yield 24%). 1H 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) calcd for C49H60N7O5+ [M+H]+, 826.4650; found, 826.4655.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS630122) was prepared by using Daporinad 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 No.: 2600734-35-6). The compound (SIAIS630122) was obtained as white solid (6.3 mg, yield 25%). 1H 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) calcd for C50H62N7O5+ [M+H]+, 840.4807; found, 840.4809.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631001) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS352066). The compound (SIAIS631001) was obtained as white solid (11.9 mg, yield 31%). 1H NMR (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) calcd for C53H68N9O7S+ [M+H]+, 974.4957; found, 974.4959.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631002) was prepared by using Daporinad 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 No.: 2172819-72-4). The compound (SIAIS631002) was obtained as white solid (11.5 mg, yield 30%). 1H 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) calcd for C54H70N9O7S+ [M+H]+, 988.5113; found, 988.5116.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631003) was prepared by using Daporinad 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 No.: 2172819-73-5). The compound (SIAIS631003) was obtained as white solid (12.8 mg, yield 33%). 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) calcd for C55H72N9O7S+ [M+H]+, 1002.5270; found, 1002.5273.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630007) was prepared by using Daporinad 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 No.: 2172819-74-6). The compound (SIAIS630007) was obtained as white solid (13.4 mg, yield 34%). 1H 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) calcd for C56H74N9O7S+ [M+H]+, 1016.5426; found, 1016.5428.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631004) was prepared by using Daporinad 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 No.: 2162120-87-6). The compound (SIAIS631004) was obtained as white solid (12.1 mg, yield 30%). 1H NMR (500 MHz, DMSO-d6) δ 9.08 (d, J=2.0 Hz, 1H), 9.06 (d, J=3.2 Hz, 1H), 8.83 (d, J=4.3 Hz, 1H), 8.64 (d, J=8.3 Hz, 1H), 8.58 (t, J=6.1 Hz, 1H), 8.40 (q, J=5.4 Hz, 1H), 8.01 (dd, J=8.2, 5.5 Hz, 1H), 7.85 (dd, J=9.4, 2.7 Hz, 1H), 7.56 (d, J=15.9 Hz, 1H), 7.44-7.34 (m, 4H), 7.27 (dd, J=8.8, 2.5 Hz, 2H), 7.05-6.91 (m, 3H), 4.53 (d, J=9.3 Hz, 1H), 4.45-4.40 (m, 3H), 4.36-4.32 (m, 1H), 4.21 (dd, J=15.9, 5.5 Hz, 1H), 3.71-3.56 (m, 6H), 3.45 (dd, J=6.5, 4.0 Hz, 1H), 3.25 (t, J=5.2 Hz, 1H), 3.23-3.15 (m, 5H), 2.95-2.65 (m, 2H), 2.44 (s, 3H), 2.33 (t, J=7.5 Hz, 1H), 2.26-2.21 (m, 1H), 2.19-2.08 (m, 1H), 2.06-1.99 (m, 1H), 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) calcd for C57H76N9O7S+ [M+H]+, 1030.5583; found, 1030.5585.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631005) was prepared by using Daporinad 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 No.: 2172819-75-7). The compound (SIAIS631005) was obtained as white solid (14.8 mg, yield 36%). 1H 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) calcd for C58H78N9O7S+ [M+H]+, 1044.5739; found, 1044.5741.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631006) was prepared by using Daporinad 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 No.: 2172819-76-8). The compound (SIAIS631006) was obtained as white solid (18 mg, yield 43%). 1H 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) calcd for C59H80N9O7S+ [M+H]+, 1058.5896; found, 1058.5898.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631007) was prepared by using Daporinad 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 No.: 2172819-77-9). The compound (SIAIS631007) was obtained as white solid (18.3 mg, yield 43%). 1H NMR (500 MHz, DMSO-d6) 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) calcd for C60H82N9O7S+ [M+H]+, 1072.6052; found, 1072.6055.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631008) was prepared by using Daporinad 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 No.: 2172819-78-0). The compound (SIAIS631008) was obtained as white solid (21 mg, yield 49%). 1H 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) calcd for C61H84N9O7S+ [M+H]+, 1086.6209; found, 1086.6211.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631010) was prepared by using Daporinad 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 No.: 2172820-08-3). The compound (SIAIS631010) was obtained as 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) calcd for C56H74N9O9S+ [M+H]+, 1048.5325; found, 1048.5327.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631011) was prepared by using Daporinad 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 No.: 2172820-09-4). The compound (SIAIS631011) was obtained as white solid (14.2 mg, yield 33%). 1H 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) calcd for C58H78N9O9S+ [M+H]+, 1076.5638; found, 1076.5641.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631012) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151003; (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid; CAS No.: 2140807-42-5). The compound (SIAIS631012) was obtained as white solid (14.8 mg, yield 34%). 1H 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) calcd for C60H82N9O10S+ [M+H]+, 1120.5900; found, 1120.5905.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631013) was prepared by using Daporinad 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-azaeicosanoic acid; CAS No.: 2172820-12-9). The compound (SIAIS631013) was obtained as white solid (15.2 mg, yield 33%). 1H NMR (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) calcd for C62H86N9O11S+ [M+H]+, 1164.6162; found, 1164.6165.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631014) was prepared by using Daporinad 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-azadocosanoic acid; CAS No.: 2172820-14-1). The compound (SIAIS631014) was obtained as white solid (17.6 mg, yield 36%). 1H 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) calcd for C64H90N9O12S+ [M+H]+, 1208.6424; found, 1208.6427.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS630008) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS164189). The compound (SIAIS630008) was obtained as white solid (7.0 mg, yield 37%). 1H NMR (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) calcd for C66H94N9O7S+ [M+H]+, 1156.6991; found, 1156.6995.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631020) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1222171; 3-(4-(4-bromobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2641288-70-0). The compound (SIAIS631020) was obtained as white solid (6.8 mg, yield 22%). 1H NMR (500 MHz, 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) calcd for C45H56N7O6+ [M+H]+, 790.4287; found, 790.4289.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631024) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1222063). The compound (SIAIS631024) was obtained as white solid (5.4 mg, 16%). 1H NMR (500 MHz, 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) calcd for C49H64N7O6+ [M+H]+, 846.4913; found, 846.4915.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631045) was prepared by using Daporinad 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 No.: 2570254-41-8). The compound (SIAIS631045) was obtained as white solid (12.4 mg, yield 39%). 1H 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) calcd for C47H57N8O5+ [M+H]+, 813.4446; found, 813.4449.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631068) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((2-bromoethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378582-68-2). The compound (SIAIS631068) was obtained as yellow solid (11.6 mg, yield 37%). 1H NMR (500 MHz, 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) calcd for C43H50N7O6S+ [M+H]+, 792.3538; found, 792.3539.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631069) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((3-bromopropyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378582-69-3). The compound (SIAIS631069) was obtained as yellow solid (6.9 mg, yield 22%). 1H 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) calcd for C44H52N7O6S+ [M+H]+, 806.3694; found, 806.3699.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631070) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((4-bromobutyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378582-70-6). The compound (SIAIS631070) was obtained as yellow solid (7.1 mg, yield 22%). 1H 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) calcd for C45H54N7O6S+ [M+H]+, 820.3851; found, 820.3856.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631071) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((5-bromopentyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378582-71-7). The compound (SIAIS631071) was obtained as yellow solid (5.9 mg, yield 18%). 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) calcd for C46H56N7O6S+ [M+H]+, 834.4007; found, 834.4009.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631072) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((6-bromohexyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378586-19-5). The compound (SIAIS631072) was obtained as yellow solid (6.9 mg, yield 21%). 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) calcd for C47H58N7O6S+ [M+H]+, 848.4164; found, 848.4168.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631078) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (4-((7-bromoheptyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CAS No.: 2378586-22-0). The compound (SIAIS631078) was obtained as yellow solid (7.1 mg, yield 21%). 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) calcd for C48H60N7O6S+ [M+H]+, 862.4320; found, 862.4324.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631073) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1224003). The compound (SIAIS631073) was obtained as yellow solid (7.7 mg, yield 22%). 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) calcd for C49H62N7O6S+ [M+H]+, 876.4477; found, 876.4478.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632027) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151045; 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)acetic acid; CAS No.: 2378582-26-2). The compound (SIAIS632027) was obtained as yellow solid (8.7 mg, yield 32%). 1H NMR (500 MHz, 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) calcd for C43H48N7O7S+ [M+H]+, 806.3330; found, 806.3335.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632028) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151138B; 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)propanoic acid; CAS No.: 2378582-27-3). The compound (SIAIS632028) was obtained as yellow solid (8.6 mg, yield 27%). 1H NMR (500 MHz, 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) calcd for C44H50N7O7S+ [M+H]+, 820.3487; found, 820.3489.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632029) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151140B; 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)valeric acid; CAS No.: 2378582-29-5). The compound (SIAIS632029) was obtained as yellow solid (9.1 mg, yield 28%). 1H NMR (500 MHz, 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) calcd for C46H54N7O7S+ [M+H]+, 848.3800; found, 848.3806.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632030) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151141B; 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)caproic acid; CAS No.: 2378582-30-8). The compound (SIAIS632030) was obtained as yellow solid (8.8 mg, yield 26%). 1H NMR (500 MHz, 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) calcd for C47H56N7O7S+ [M+H]+, 862.3956; found, 862.3959.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632031) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS151142B; 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)heptanoic acid; CAS No.: 2378582-31-9). The compound (SIAIS632031) was obtained as yellow solid (10.1 mg, yield 29%). 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) calcd for C48H58N7O7S+ [M+H]+, 876.4113; found, 876.4116.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632032) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)octanoic acid; CAS No.: 2378585-62-5). The compound (SIAIS632032) was obtained as yellow solid (10 mg, yield 28%). 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) calcd for C49H60N7O7S+ [M+H]+, 890.4269; found, 890.4275.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632033) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid; CAS No.: 1061605-21-7). The compound (SIAIS632033) was obtained as pale yellow solid (7.3 mg, yield 24%). 1H NMR (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) calcd for C43H48N7O8+ [M+H]+, 790.3559; found, 790.3562.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632034) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentanoic acid; CAS No.: 2169266-67-3). The compound (SIAIS632034) was obtained as pale yellow solid (8.7 mg, yield 26%). 1H NMR (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) calcd for C46H54N7O8+ [M+H]+, 832.4028; found, 832.4029.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632035) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexanoic acid; CAS No.: 2087490-48-8). The compound (SIAIS632035) was obtained as pale yellow solid (7.2 mg, yield 21%). 1H NMR (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) calcd for C47H56N7O8+ [M+H]+, 846.4185; found, 846.4189.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632036) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)heptanoic acid; CAS No.: 2169266-69-5). The compound (SIAIS632036) was obtained as pale yellow solid (9.6 mg, yield 26%). 1H NMR (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) calcd for C48H58N7O8+ [M+H]+, 860.4341; found, 860.4346.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631139) was prepared by using Daporinad derivative 3 (SIAIS631127) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS631139) was obtained as white solid (7.7 mg, yield 23%). 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) calcd for C49H59N6O5+ [M+H]+, 811.4541; found, 811.4544.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631140) was prepared by using Daporinad 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 No.: 2570254-42-9). The compound (SIAIS631140) was obtained as white solid (10.1 mg, yield 31%). 1H 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) calcd for C50H61N6O5+ [M+H]+, 825.4698; found, 825.4702.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631141) was prepared by using Daporinad derivative 3 (SIAIS631127) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-59-1). The compound (SIAIS631141) was obtained as white solid (9.7 mg, yield 30%). 1H NMR (500 MHz, 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) calcd for C46H57N6O5S++ [M+H]+, 805.4106; found, 805.4107.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631139) was prepared by using Daporinad derivative 5 (SIAIS631135) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS631139) was obtained as white solid (8.3 mg, yield 24%). 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) calcd for C51H65N10O5+ [M+H]+, 897.5134; found, 897.5138.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632006) was prepared by using Daporinad 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 No.: 2570254-42-9). The compound (SIAIS632006) was obtained as white solid (9.3 mg, yield 26%). 1H 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): calcd for C52H67N10O5+ [M+H]+, 911.5290; found, 911.5294.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632007) was prepared by using Daporinad derivative 5 (SIAIS631135) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-59-1). The compound (SIAIS632007) was obtained as white solid (9.7 mg, yield 28%). 1H NMR (500 MHz, 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) calcd for C48H63N10O5S+ [M+H]+, 891.4698; found, 891.4603.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632010) was prepared by using Daporinad derivative 4 (SIAIS632004) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS632010) was obtained as white solid (7.7 mg, yield 24%). 1H 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) calcd for C46H56N9O5+ [M+H]+, 814.4399; found, 814.4403.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632011) was prepared by using Daporinad 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 No.: 2570254-42-9). The compound (SIAIS632011) was obtained as white solid (9.2 mg, yield 28%). 1H 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) calcd for C47H58N9O5+ [M+H]+, 828.4555; found, 828.4559.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632012) was prepared by using Daporinad derivative 4 (SIAIS632004) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-59-1). The compound (SIAIS632012) was obtained as white solid (8.7 mg, yield 27%). 1H NMR (500 MHz, 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) calcd for C43H54N9O5S+ [M+H]+, 808.3963; found, 808.3967.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632039) was prepared by using Daporinad derivative 6 (SIAIS632025) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS632039) was obtained as white solid (6.5 mg, 20%). 1H 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) calcd for C47H57N8O5+ [M+H]+, 813.4446; found, 813.4449.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632040) was prepared by using Daporinad 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 No.: 2570254-42-9). The compound (SIAIS632040) was obtained as white solid (7.4 mg, 22%). 1H 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) calcd for C48H59N8O5+ [M+H]+, 827.4603; found, 827.4608.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS632041) was prepared by using Daporinad derivative 6 (SIAIS632025) and intermediate LM (SIAIS213134; 3-(4-(4-bromobutylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2378582-59-1). The compound (SIAIS632041) was obtained as white solid (7.6 mg, 24%). 1H 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) calcd for C44H55N8O5S+ [M+H]+, 807.4011; found, 807.4016.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631079) was prepared by using Daporinad 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 No.: 2139348-60-8). The compound (SIAIS631079) was obtained as yellow solid (8.9 mg, yield 27%). 1H 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) calcd for C43H48N7O7S+ [M+H]+, 847.4137; found, 847.4139.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631109) was prepared by using Daporinad 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 No.: 2140807-17-4). The compound (SIAIS631109) was obtained as yellow solid (9.6 mg, yield 27%). 1H 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) calcd for C48H59N8O9+ [M+H]+, 891.4400; found, 891.4403.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631119) was prepared by using Daporinad 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 No.: 2570254-45-2). The compound (SIAIS631119) was obtained as white solid (8.7 mg, yield 28%). 1H NMR (500 MHz, DMSO-d6) δ 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) calcd for C46H52N7O6+ [M+H]+, 798.3974; found, 798.3977.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631120) was prepared by using Daporinad 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 No.: 2641288-61-9). The compound (SIAIS631120) was obtained as white solid (8.9 mg, yield 28%). 1H 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) calcd for C47H54N7O6+ [M+H]+, 812.4130; found, 812.4132.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631108) was prepared by using Daporinad 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 No.: 2641288-62-0). The compound (SIAIS631108) was obtained as white solid (7.7 mg, yield 23%). 1H NMR (500 MHz, DMSO-d6) δ 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) calcd for C48H56N7O6+ [M+H]+, 862.4287; found, 862.428.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS631121) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS292008; 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oct-7-yn-1-yl methanesulfonate; CAS No.: 2641288-63-1). The compound (SIAIS631121) was obtained as white solid (7.1 mg, yield 23%). 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=2.1 Hz, 1H), 8.49 (d, J=3.7 Hz, 1H), 8.16 (dt, J=8.1, 1.9 Hz, 1H), 7.78-7.66 (m, 3H), 7.54 (dd, J=8.1, 5.0 Hz, 1H), 7.47 (d, J=15.8 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.6 Hz, 2H), 6.70 (d, J=15.9 Hz, 1H), 5.04 (dd, J=12.8, 5.5 Hz, 1H), 4.46 (s, 1H), 3.86 (s, 2H), 3.72 (br, 1H), 3.58 (s, 2H), 3.23 (d, J=7.3 Hz, 2H), 3.16-3.09 (m, 4H), 3.05 (br, 2H), 2.82-2.73 (m, 2H), 2.69-2.56 (m, 2H), 2.44 (t, J=6.9 Hz, 2H), 2.08-2.00 (m, 1H), 1.82-1.69 (m, 3H), 1.60 (p, J=6.9 Hz, 3H), 1.55-1.45 (m, 6H), 1.41 (q, J=7.6 Hz, 2H), 1.37-1.29 (m, 2H), 1.28-1.18 (m, 2H), 1.06 (br, 2H). HRMS (ESI) calcd for C49H58N7O6+ [M+H]+, 840.4443; found, 840.4447.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631111) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204137; 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)acetic acid; CAS No.: 2378582-16-0). The compound (SIAIS631111) was obtained as yellow solid (8.0 mg, yield 24%). 1H NMR (500 MHz, CD3OD) δ 8.98 (s, 1H), 8.74 (d, J=5.6 Hz, 1H), 8.65 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.2, 5.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.31 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 6.91 (d, J=15.9 Hz, 1H), 5.08 (dd, J=12.8, 5.5 Hz, 1H), 4.29 (s, 2H), 3.86 (t, J=6.0 Hz, 3H), 3.71-3.64 (m, 4H), 3.42-3.33 (m, 6H), 3.27-3.23 (m, 4H), 3.07 (br, 1H), 2.87-2.83 (m, 1H), 2.76-2.73 (m, 1H), 2.71-2.64 (m, 1H), 2.12-2.06 (m, 1H), 1.76 (br, 3H), 1.59 (p, J=7.2 Hz, 3H), 1.46-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.16 (s, 2H). HRMS (ESI) calcd for C45H52N7O8S+ [M+H]+, 850.3593; found, 850.3595.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631112) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204139; 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetic acid; CAS No.: 2378582-17-1). The compound (SIAIS631112) was obtained as yellow solid (8.7 mg, yield 23%). 1H NMR (500 MHz, CD3OD) δ 8.89 (d, J=19.8 Hz, 1H), 8.67 (dd, J=16.1, 5.2 Hz, 1H), 8.45 (dd, J=47.0, 8.4 Hz, 1H), 7.84-7.66 (m, 3H), 7.64-7.54 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 7.07 (d, J=8.9 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.83 (dd, J=15.8, 10.7 Hz, 1H), 5.11 (dd, J=12.4, 5.5 Hz, 1H), 4.30 (s, 1H), 4.10 (s, 1H), 3.83-3.79 (m, 4H), 3.69-1.67 (m, 8H), 3.54-3.47 (m, 2H), 3.39-3.33 (m, 8H), 2.89-2.83 (m, 1H), 2.80-2.76 (m, 1H), 2.73-2.64 (m, 1H), 2.15-2.10 (m, 1H), 1.74 (br, 2H), 1.60-1.56 (m, 3H), 1.42 (br, 2H), 1.38-1.30 (m, 2H), 1.15 (br, 2H). HRMS (ESI) calcd for C47H56N7O9S+ [M+H]+, 894.3855; found, 894.3857.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631113) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204141; 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetic acid; CAS No.: 2378582-18-2). The compound (SIAIS631113) was obtained as yellow solid (8.4 mg, yield 22%). 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.40 (dd, J=8.2, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 5.4 Hz, 1H), 7.67-7.55 (m, 2H), 7.53-7.43 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.9 Hz, 2H), 6.76 (d, J=15.8 Hz, 1H), 5.00 (dd, J=12.8, 5.5 Hz, 1H), 4.19 (s, 2H), 3.74-3.66 (m, 2H), 3.63-3.50 (m, 12H), 3.43-3.38 (m, 1H), 3.29-3.26 (m, 1H), 3.26-3.21 (m, 5H), 3.21-3.10 (m, 5H), 2.82-2.70 (m, 1H), 2.69-2.63 (m, 1H), 2.63-2.54 (m, 1H), 2.09-1.95 (m, 1H), 1.64 (br, 2H), 1.52-1.44 (m, 3H), 1.34-1.28 (m, 2H), 1.24-1.20 (m, 3H), 1.04 (br, 2H). HRMS (ESI) calcd for C49H60N7O10S+ [M+H]+, 938.4117; found, 938.4118.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631114) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204147; 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecanoic acid; CAS No.: 2378582-19-3). The compound (SIAIS631114) was obtained as yellow solid (11.3 mg, yield 29%). 1H NMR (500 MHz, CD3OD) δ 9.05 (s, 1H), 8.79 (d, J=6.4 Hz, 2H), 8.14-8.01 (m, 1H), 7.71 (q, J=7.8 Hz, 2H), 7.64-7.55 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.96 (d, J=15.8 Hz, 1H), 5.09 (dd, J=12.9, 5.5 Hz, 1H), 4.53 (br, 1H), 4.10 (s, 2H), 3.79 (t, J=6.2 Hz, 2H), 3.70-3.59 (m, 11H), 3.49 (dd, J=6.8, 3.8 Hz, 4H), 3.39-3.24 (m, 11H), 3.07 (br, 1H), 2.90-2.80 (m, 1H), 2.76-2.64 (m, 2H), 2.15-2.06 (m, 1H), 1.75 (d, J=45.8 Hz, 2H), 1.57 (p, J=7.4 Hz, 3H), 1.48-1.36 (m, 2H), 1.35-1.26 (m, 2H), 1.13 (br, 2H). HRMS (ESI) calcd for C51H64N7O11S+ [M+H]+, 982.4379; found, 982.4381.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS632027) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1204149; 17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecanoic acid; CAS No.: 2378582-20-6). The compound (SIAIS632027) was obtained as yellow solid (12.4 mg, yield 30%). 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.68 (d, J=5.4 Hz, 1H), 8.50-8.45 (m, 1H), 7.86-7.80 (m, 1H), 7.77-7.69 (m, 2H), 7.61-7.57 (m, 2H), 7.33 (dd, J=23.1, 8.7 Hz, 2H), 7.07 (d, J=8.5 Hz, 1H), 7.00-6.95 (m, 1H), 6.86 (dt, J=15.8, 1.9 Hz, 1H), 5.11 (dd, J=12.7, 6.1 Hz, 1H), 4.31 (s, 1H), 4.12 (s, 1H), 3.80 (q, J=6.4 Hz, 2H), 3.73-3.59 (m, 18H), 3.54-3.48 (m, 2H), 3.40-3.23 (m, 12H), 3.08 (s, 1H), 2.93-2.82 (m, 1H), 2.79-2.62 (m, 1H), 2.17-2.08 (m, 1H), 1.74 (br, 1H), 1.64-1.55 (m, 3H), 1.45-1.35 (m, 2H), 1.35-1.25 (m, 2H), 1.15 (br, 2H). HRMS (ESI) calcd for C53H68N7O12S+ [M+H]+, 1026.4641; found, 1026.4646.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS631118) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (SIAIS1213137; 17-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecanoic acid; CAS No.: 2378582-25-1). The compound (SIAIS631118) was obtained as white solid (13.1 mg, yield 32%). 1H NMR (500 MHz, CD3OD) δ 9.03 (d, J=2.1 Hz, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.74 (dt, J=8.2, 1.7 Hz, 1H), 8.04 (dd, J=8.2, 5.6 Hz, 1H), 7.71 (dd, J=7.8, 0.9 Hz, 1H), 7.69-7.59 (m, 2H), 7.54 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.94 (d, J=15.9 Hz, 1H), 5.16 (dd, J=13.4, 5.3 Hz, 1H), 4.49 (d, J=17.3 Hz, 1H), 4.43 (d, J=17.4 Hz, 1H), 4.12 (s, 2H), 3.71-3.63 (m, 7H), 3.62-3.57 (m, 14H), 3.51 (dd, J=6.7, 3.8 Hz, 3H), 3.38 (dd, J=6.6, 3.9 Hz, 3H), 3.35-3.30 (m, 4H), 3.25-3.22 (m, 3H), 2.96-2.87 (m, 1H), 2.82-2.75 (m, 1H), 2.58-2.50 (m, 1H), 2.22-2.17 (m, 1H), 1.73 (br, 2H), 1.62-1.56 (m, 3H), 1.48-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.16 (br, 2H). HRMS (ESI) calcd for C53H70N70O11S+ [M+H]+, 1012.4849; found, 1012.4851.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS633097) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (3-(4-((6-bromohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2413731-77-6). The compound (SIAIS633097) was obtained as white solid (5.7 mg, yield 17%). 1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.80 (d, J=2.2 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H), 8.36 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.53 (dd, J=8.0, 4.9 Hz, 1H), 7.50-7.44 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.31 (d, J=7.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.76 (d, J=15.9 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.13 (t, J=6.3 Hz, 2H), 3.93 (d, J=11.0 Hz, 2H), 3.36-3.23 (m, 5H), 3.22 (q, J=6.6 Hz, 4H), 3.18-3.07 (m, 12H), 2.94-2.80 (m, 1H), 2.65-2.55 (m, 1H), 2.46-2.42 (m, 1H), 2.00 (ddd, J=12.4, 6.4, 3.8 Hz, 1H), 1.79-1.61 (m, 6H), 1.49 (dt, J=14.1, 7.1 Hz, 4H), 1.38 (q, J=7.5 Hz, 2H). HRMS (ESI) calcd for C47H60N7O6+ [M+H]+, 818.4600; found, 818.4607.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS633098) was prepared by using Daporinad derivative 1 (SIAIS630006) and intermediate LM (3-(4-((7-bromoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; CAS No.: 2699962-33-7). The compound (SIAIS633098) was obtained as white solid (6.3 mg, yield 19%). 1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.86 (d, J=2.2 Hz, 1H), 8.64 (dd, J=5.0, 1.5 Hz, 1H), 8.42 (t, J=5.7 Hz, 1H), 8.21 (dt, J=8.1, 1.9 Hz, 1H), 7.63 (dd, J=8.0, 5.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.82 (d, J=15.9 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 3.93 (d, J=12.6 Hz, 2H), 3.27-3.03 (m, 19H), 2.98-2.81 (m, 1H), 2.66-2.57 (m, 1H), 2.45 (dd, J=13.2, 4.5 Hz, 1H), 2.01 (ddd, J=7.1, 5.3, 2.3 Hz, 1H), 1.78-1.70 (m, 8H), 1.50 (dq, J=30.1, 7.3 Hz, 4H), 1.41-1.30 (m, 4H). HRMS (ESI) calcd for C48H62N7O6+ [M+H]+, 832.4756; found, 832.4758.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS633093) was prepared by using Daporinad derivative 7 (SIAIS632044) and intermediate LM (SIAIS292017; 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl methanesulfonate; CAS No.: 2570254-41-8). The compound (SIAIS633093) was obtained as white solid (5.8 mg, yield 18%). 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.88 (d, J=2.1 Hz, 1H), 8.65 (d, J=5.3 Hz, 1H), 8.32-8.25 (m, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.73-7.64 (m, 2H), 7.64-7.57 (m, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.48 (d, J=15.9 Hz, 1H), 6.97 (d, J=9.1 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.51 (d, J=13.0 Hz, 2H), 4.45 (d, J=17.6 Hz, 1H), 4.31 (d, J=17.7 Hz, 1H), 3.79-3.65 (m, 11H), 3.23-3.06 (m, 5H), 2.90 (t, J=13.8 Hz, 4H), 2.61 (d, J=17.3 Hz, 1H), 2.47-2.35 (m, 1H), 2.18-2.11 (m, 1H), 2.09-1.98 (m, 1H), 1.74-1.53 (m, 8H), 1.44 (d, J=9.0 Hz, 5H), 1.40-1.27 (m, 4H), 1.28-1.19 (m, 3H), 1.09-1.03 (m, 2H). HRMS (ESI) calcd for C52H66N9O5+ [M+H]+, 896.5181; found, 896.5186.
Referring to the methods of example 15 and Scheme 16, the compound (SIAIS633094) was prepared by using Daporinad derivative 7 (SIAIS632044) and intermediate LM (SIAIS292020; 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl methanesulfonate; CAS No.: 2570254-42-9). The compound (SIAIS633094) was obtained as white solid (6.1 mg, yield 19%). 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.42 (d, J=8.1 Hz, 1H), 8.34 (t, J=5.7 Hz, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.1, 5.3 Hz, 1H), 7.71 (s, 1H), 7.67-7.62 (m, 2H), 7.51 (dd, J=16.0, 9.0 Hz, 2H), 7.03 (d, J=9.1 Hz, 1H), 6.85 (d, J=15.9 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.51 (d, J=13.2 Hz, 2H), 4.46 (d, J=17.7 Hz, 1H), 4.32 (d, J=17.6 Hz, 1H), 3.85-3.66 (m, 12H), 3.20-3.15 (m, 4H), 3.04-2.84 (m, 4H), 2.72 (d, J=4.9 Hz, 1H), 2.64-2.53 (m, 1H), 2.59-2.50 (m, 4H), 2.49-2.38 (m, 1H), 2.18 (d, J=11.9 Hz, 2H), 2.06-1.95 (m, 1H), 1.81-1.56 (m, 7H), 1.45 (dt, J=15.2, 7.9 Hz, 4H), 1.36-1.17 (m, 5H), 1.07-1.03 (m, 2H). HRMS (ESI) calcd for C53H68N9O5+ [M+H]+, 910.5338; found, 910.5341.
Referring to the methods of example 1 and Scheme 15, the compound (SIAIS633063) was prepared by using Daporinad derivative 5 (SIAIS631135) 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 No.: 2172819-74-6). The compound (SIAIS633063) was obtained as white solid (9.8 mg, yield 25%). 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=1.7 Hz, 2H), 8.76 (d, J=5.4 Hz, 1H), 8.60 (t, J=6.2 Hz, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.38 (t, J=5.7 Hz, 1H), 7.95-7.85 (m, 2H), 7.71-7.60 (m, 1H), 7.58-7.47 (m, 2H), 7.44-7.32 (m, 4H), 6.89 (d, J=15.9 Hz, 1H), 4.61-4.50 (m, 3H), 4.48-4.36 (m, 4H), 4.35 (s, 1H), 4.21 (dd, J=16.0, 5.5 Hz, 1H), 4.04 (s, 2H), 3.94-3.85 (m, 3H), 3.78-3.72 (m, 4H), 3.19 (q, J=6.5 Hz, 2H), 3.03 (q, J=14.1, 13.1 Hz, 4H), 2.94-2.88 (m, 1H), 2.77 (t, J=12.3 Hz, 1H), 2.43 (s, 3H), 2.37-2.30 (m, 2H), 2.29-2.09 (m, 4H), 2.04 (t, J=9.1 Hz, 1H), 1.89 (ddd, J=12.9, 8.8, 4.6 Hz, 1H), 1.80-1.61 (m, 4H), 1.58-1.35 (m, 7H), 1.35-1.29 (m, 2H), 1.27-1.20 (m, 3H), 1.12-1.05 (m, 2H), 0.92 (s, 9H). HRMS (ESI) calcd for C59H81N12O7S+ [M+H]+, 1101.6066; found, 1101.6069.
The tumor cells used herein were cultured in a cell culture medium at 37° C. in an incubator with 5% CO2, where the cell culture medium was supplemented with 10% FBS, as well as penicillin at a final concentration of 100 U/mL and streptomycin at a final concentration of 100 μg/mL. Prior to experimentation, all cells used were identified as correct cells by STR cells, and were negative for mycoplasma through routine testing.
IC50 values of the compounds of the present disclosure (including the compounds in Table 1 and compounds of examples) were measured using the CellTiter-Glo® Luminescent Cell Viability Assay kit from Promega Corporation. Assay details are as follows: Cells were seeded in 100 μL RPMI1640 medium containing serum at a density of 20,000 cells/well. After 24 h, the inoculated cells were treated with the compounds of the present disclosure which were serially diluted. After the cells were treated with the compounds of the present disclosure for 72 h, the CellTiter-Glo® reagent was added to the culture medium for cell viability assessment according to the instructions provided with the kit. DMSO served as the negative control, and FK866 inhibitor was used as the positive control, both treated with the same protocol as the compounds of the present disclosure. The growth inhibition of the compounds of the present disclosure on cells was plotted by Prism Graphpad software, and the IC50 values of the compounds of the present disclosure were calculated therefrom. Results were shown in Table 2.
The results indicate that the compounds of the present invention (including the compounds in Table 1 and compounds of the examples 1-91) can inhibit the proliferation of tumor cells (as shown in Table 2). The IC50 of some example compounds are comparable to, or even superior to, the positive control FK866. For example, the IC50 of SIAIS630010 is 0.3506 nM. This indicates that the compounds of the present invention have a comparable, or even superior, inhibitory effect on tumor cell growth compared to the positive control FK866.
MOLT4 and HL60 tumor cells were seeded separately in 12-well plates containing 1 mL of RPMI1640 medium, with a cell seeding density of 0.5×106 cells/mL. On the second day, the parent inhibitor FK866 and the compounds SIAIS630120 and SIAIS630121 of the present disclosure were individually dissolved in DMSO to obtain stock solutions of the respective compounds at a concentration of 10 μM. Subsequently, 1 μL of the 10 μM compound stock solution was added to 1 mL of cell culture medium to achieve a final concentration of 10 nM. The cells were treated continuously for 4 days, and cell viability was measured once daily during this period. Specifically, cells were sampled once a day, adjusted to a concentration of 1×106/mL using a cell staining buffer, stained with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) (1:250), and then analyzed with a flow cytometer. Initially, the cells were gated based on differences in cell size, followed by DAPI staining to gate for dead cells. Finally, the cytotoxic efficiency was assessed by calculating the DAPI-positive ratio.
The results of the in vitro cytotoxicity experiment were shown in
Tumor cells were seeded at a specific cell density in a 6-well plate containing 2 mL of RPMI1640/DMEM medium. For SW620, HT29, MCF-7, and BEL7404 cells, the seeding density was 1×106 cells per well, respectively; for MOLT4, Jurkat, and HL60 cells, the seeding density was 0.5×106 cells/mL. The disclosed compounds (including those listed in Table 1 and Examples 1-91) were individually dissolved in DMSO to prepare stock solutions at concentrations of 1 μM, 5 μM, 10 μM, and 100 μM. On the second day, cells were treated with different concentrations of the compounds of the present disclosure (including those listed in Table 1 and Examples 1-91) for 24 hours (2 μL of different concentrations of compounds added to 2 mL of cell culture medium, resulting in final concentrations of 1 nM, 5 nM, 10 nM, and 100 nM). After 24 hours of compound treatment, the supernatant was removed, and cells were washed with PBS. The cells were then placed on ice and treated with protein lysis buffer containing protease and phosphatase inhibitors. The lysate was centrifuged at 12,000 RPM for 15 minutes at 4° C., and the supernatant was collected. Equal amounts of protein were mixed with 5×SDS, and after denaturation at 95° C. for 5 minutes, the samples were either frozen at −20° C. or subjected to direct protein electrophoresis. SDS-PAGE was performed using equal amounts of protein, and proteins were transferred to a nitrocellulose membrane at 95 V and 4° C. for 90 minutes. After membrane transfer, the membrane was blocked with TBST containing 5% skim milk powder (purchased from Beijing Cowin Bioscience Co., Ltd.) at room temperature for 1 hour. The membrane was then incubated with the primary antibody overnight at 4° C. After incubation with the primary antibody, the membrane was washed three times with TBST at room temperature for 5 minutes each. Subsequent steps, including the incubation with the secondary antibody (peroxidase-labeled goat anti-rabbit IgG (H+L)) and visualization, were performed according to the instructions provided by Jackson ImmunoResearch Laboratories Inc.
Determining Half-Maximal Degradation Concentration (DC50) value (the drug concentration required for degrading proteins by 50%, abbreviated as DC50) reads method: comparing the grayscale values of the Western blotting bands for the drug treatment with those of the Western blotting band f after treatment with blank DMSO. The DC50 is identified within the range of drug concentrations where the grayscale value matches half of the corresponding Western blotting band's grayscale value after treatment with blank DMSO.
Calculation of the DC50 values can be performed using ImageJ to read the grayscale values of Western blotting bands after drug treatment. A curve fitting the relationship between drug concentration and grayscale values is then generated to estimate the drug concentration corresponding to half of the grayscale value.
The present disclosure employed Western blot analysis to assess the expression levels of NAMPT protein in tumor cells treated with the compounds of the present disclosure (including those listed in Table 1 and Examples 1-91) for 24 hours. The Western blot results are illustrated in
The basic principles, main features and advantages of the present disclosure are shown and described above. Those skilled in the art should understand that the present disclosure is not limited by the foregoing embodiments, and they can make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure. These changes, substitutions and alterations fall within the scope of the present disclosure. The claimed scope of the present disclosure is defined by the appended claims and their equivalents.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111025519.1 | Sep 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/114935 | 8/25/2022 | WO |
