CN116023368A - CRBN immunomodulators - Google Patents
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- CN116023368A CN116023368A CN202211330489.XA CN202211330489A CN116023368A CN 116023368 A CN116023368 A CN 116023368A CN 202211330489 A CN202211330489 A CN 202211330489A CN 116023368 A CN116023368 A CN 116023368A
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Abstract
The invention relates to CRBN immunomodulators shown in formula I, in particular to a small molecule compound for CRBN immunomodulation, a preparation method thereof, a pharmaceutical composition thereof, and application of the compound and the pharmaceutical composition thereof in preparing medicines for treating diseases related to abnormal cell proliferation, such as cancers.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a small molecular compound for CRBN immunoregulation.
Background
The ubiquitin-proteasome system (UPS) has proven to be a very challenging but very promising area of biology for drug discovery and development there are several drugs for the proteasome itself, but considering that the binding area of ubiquitin ligase and deubiquitinase has more than 700 potential drug targets, relatively few drugs in clinical development, fewer approved drugs for these enzymes. It is difficult to develop complex enzyme screening cascades and it is more difficult to find true E3 ligase inhibitors. Only inhibitors of the IAP-53-mdm 2 interaction or Smac mimics have entered the clinical stage. With the effort in this field to find inhibitors of the E3 ligase, another approach has attracted tremendous interest in recent years. Studies in 2001 have shown that E3 ubiquitin ligases can redirect from endogenous substrates, selectively ubiquitinating the protein of interest, resulting in proteasome degradation. Crews and Deshaies open a technology in which the E3 ligase is chosen as a ubiquitinated unnatural protein substrate and the term PROTACs is created. In this method, discrete substrate binding moieties are attached to the E3 ligase recognition element by a linker. Early examples of proteins targeted using this approach include the androgen receptor, estrogen receptor- α, and further work has been successful in targeting BRD4 and in identifying a range of kinases susceptible to this strategy. The requirement for two separate binding moieties has so far created a considerable molecule from the point of view of drug discovery, but this approach has considerable promise.
Currently, thalidomide and its derivatives such as lenalidomide, pomalidomide are clinically used protein degradation agents. These drugs are known to be particularly effective in multiple myeloma. These drugs target the substrate receptor of Cereblon (CRBN), CRL4 type E3 ligase complex. Since 2010 CRBN was found as a direct target of thalidomide, extensive research has been conducted to reveal the mechanism by which CRBN mediates various pharmacological activities of thalidomide and its related compounds, thereby finding more than ten new substrates.
CRBN is a 442 amino acid protein that is evolutionarily conserved from plants to humans, a 1274C/T mutation results in the generation of a premature stop codon at Arg419 CRBN is the substrate receptor for the Cullin cycle E3 ubiquitin ligase 4 (CRL 4) containing DDB1, CUL4 and RBX1, recognizes specific new substrates in the presence of thalidomide or analogues thereof and induces ubiquitination and proteasome degradation thereof.
At present, the development of drugs based on CRBN immunomodulators mainly has two directions: one approach utilizes heterobifunctional ligands capable of binding both E3 ubiquitin ligase and target proteins, also known as proteolytically targeted chimeras (PROTACs), while another class of molecules, known as CELMODs (Cereblon E3 ligase modulating drugs), are low molecular weight small molecules that induce degradation of specific protein targets by binding to Cereblon-CRL 4E 3 ubiquitin ligase and directly attaching to the target proteins through protein-protein interactions. Both of these classes of molecules can act on targets that cannot be formulated, or even linked. Currently, a variety of drugs developed based on CRBN-like immunomodulators have been clinically entered into clinical trials, such as CC-90009 for the treatment of acute leukemia targeted degradation GSPT1, CC-220 for the treatment of relapsed refractory myeloma targeted degradation Ikaros and Aiolos, ARV-110 for the treatment of prostate cancer targeted degradation androgen receptor and ARV-471 for the treatment of breast cancer targeted degradation estrogen.
While ultimately leading to targeted degradation of the protein, the mode of action of CELMoDs or "molecular gums" differs from heterogeneous bifunctional degradants. CELMODs opened the way for protein degradation, have shown their clinical relevance, and have the advantage of low molecular weight and drug-like properties. Molecular encapsulation methods, represented by CELMODs, offer the possibility of recruiting and degrading proteins without ligands, but require specific complementarity between the protein and the ligand. The PROTACs offer unlimited possibilities for compounds that can be linked, but these molecules may require optimization of substrate and ligase compatibility. Each of these methods may provide strategic advantages depending on the specific objective and the tools available.
c-Myc is a transcription factor that is present in the nucleus and regulates cell growth, differentiation, metabolism and death, a common disorder in many human cancers. It is a member of the Myc family, and also contains in mammalian cells the N-Myc and L-Myc proteins, all of which are highly homologous but distributed differently. c-Myc is ubiquitous and highly abundant in proliferating cells, while N-Myc and L-Myc exhibit more restricted expression at different stages of cell and tissue development. MYC proteins are present in Myc/Max/MXD networks. In order to fold and become transcriptionally active, c-Myc must first heterodimerize with MAX, a process controlled by the curling of their bHLHZip domains once dimerized, the c-Myc/Max complex binds to a specific DNA consensus sequence, CANNTG, through its base region, becoming the primary transcriptional regulator, known as the enhancer box (E-box).
The expression of c-Myc in normal cells is tightly controlled but becomes deregulated and overexpressed in most human cancers, making it one of the most important human oncogenes. Overexpression of c-Myc can increase interaction with low affinity E-boxes, triggering tumorigenesis through changes in gene activation, such as those genes that regulate cell proliferation and growth do not occur at normal physiological concentrations.
Lipid nanoparticle-based formulations (DCR-MYC) have been used to deliver siRNA to tumor cells, thereby inhibiting translation and expression of the c-Myc protein. However, the use of antisense oligonucleotides to target c-Myc mRNA continues. Recently, an inhibitor, omomyc, which is a dominant negative protein of c-Myc, elucidated the effect of directly inhibiting c-Myc mediated malignancies. Ommyc has been shown to induce significant tumor regression in a range of cancers, even in those where c-Myc is not driving oncogene, confirming that c-Myc is a potential drug target for cancer. c-Myc deregulation is ubiquitous in cancer, which also makes its inhibition an attractive treatment option for many cancers that have few treatments and poor prognosis. These include lung cancer, pancreatic cancer, esophageal cancer, brain cancer, and the like. For example, c-Myc appears prominent in pancreatic cancer, whereas only 5% of patients survive for more than 5 years.
The PROTAC technology is an emerging technology for artificially chemically inducing target proteins (protein of interest, POI) to be subjected to polyubiquitination, and finally degrading the POI through a proteasome pathway in a targeting way, so that a new strategy is provided for treating diseases. Has great potential in overcoming drug resistance and traditional 'non-patent drug' target points, and is a brand new drug research and development strategy.
The compound disclosed by the invention is a novel anti-tumor CRBN immunomodulator derivative with activity of degrading MYC protein, which has independent intellectual property rights. It can utilize CRBN and induce target protein degradation for safe and effective treatment of various tumors.
Disclosure of Invention
In one aspect, the invention provides a compound of formula (I), or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is CR 8 R 9 Or (c=o),
R 8 and R is 9 Each independently selected from halogen, -CF 3 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl and-NHC 1-6 An alkyl group, a hydroxyl group,
L 1 is-O-CH 2 CH 2 -, wherein C 2 H 2 Optionally by halogen, CF 3 Or C 1-6 An alkyl group is substituted and a substituent is substituted,
L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (O-CH) 2 CH 2 ) 1-8 -、-(CH2) 1-12 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-CR 12 ＝CR 12 -、-CO-CR 12 ＝CR 12 -、-C≡C-、-CO-C≡C-、
-O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 NR 10 -、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-(CO)-NR 10 -CH 2 -、-CH 2 -(CO)-NR 10 -、-CH 2 -(CO)-NR 10 -CH 2 -、-O-(CO)-NR 10 -、-O-CH 2 -(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (5-12 membered heteroarylene) - (CO) -, - (3-12 membered carbocycle) - (CO) -, - (3-12 membered heterocycle) - (CO) -, - (C) 6 H 4 )-(CO)-、-(C 6 H 4 )-(CO)-NR 10 -、-CH 2 -(C 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -、-CH 2 -(C 6 H 4 )-CH 2 -、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) O-, wherein C 6 H 4 Is phenylene, C 2 H 2 、C 6 H 4 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, CF 3 Or C 1-6 Alkyl substitution, L 2 、L 3 、L 4 And L 5 The group selection of (c) does not include the case of chemical failure,
ar is a small molecule ligand capable of binding to a target protein, preferably a small molecule ligand capable of targeted binding to c-Myc or GSPT1, more preferably a c-Myc small molecule ligand,
in particular, the small molecule ligands are 6-10 membered aryl or 5-12 membered heteroaryl groups, which may optionally be substituted with 1-4R 1 Instead of the above-mentioned,
R 1 each independently selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR 11 、-NR 10 R 11 、-(CO)-R 12 、-(CO)-NR 10 R 11 、-NR 11 -(CO)-R 12 、-S(O)R 12 、-S(O) 2 R 12 、-S(O) 2 NR 10 R 11 or-NR 10 S(O) 2 R 12 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be R 2 Instead of the above-mentioned,
R 10 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 11 Each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 2 Instead of the above-mentioned,
R 12 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 2 Instead of the above-mentioned,
R 2 selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR 13 、-NR 13 R 14 、-(CO)-R 15 、-(CO)-NR 13 R 14 、-NH-(CO)-R 15 、-S(O)R 15 、-S(O) 2 R 15 、-S(O) 2 NR 13 R 14 or-NR 14 S(O) 2 R 15 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be R 3 Instead of the above-mentioned,
R 13 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 3 Instead of the above-mentioned,
R 14 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 15 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 3 Instead of the above-mentioned,
R 3 selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, - (CO) -C 1-6 Alkyl, - (CO) -NHC 1-6 Alkyl, -NH- (CO) -C 1-6 Alkyl, -S (O) C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl, -S (O) 2 NHC 1-6 Alkyl, or-NHC 1-6 Alkyl S (O) 2 C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl,-OC 1-6 Alkyl, -NHC 1-6 Alkyl, - (CO) -C 1-6 Alkyl, - (CO) -NHC 1-6 Alkyl, -NH- (CO) -C 1-6 Alkyl, -S (O) C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl, -S (O) 2 NHC 1-6 Alkyl, or-NHC 1-6 Alkyl S (O) 2 C 1-6 An alkyl group is substituted and a substituent is substituted,
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
In some embodiments, L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (CH) 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-CR 12 ＝CR 12 -、-CO-CR 12 ＝CR 12 -、-C≡C-、-CO-C≡C-、
-O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 NR 10 -、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-(CO)-NR 10 -CH2-、-CH 2 -(CO)-NR 10 -、-CH 2 -(CO)-NR 10 -CH 2 -、-O-(CO)-NR 10 -、-O-CH 2 -(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (C) 6 H 4 )-(CO)-NR 10 -、-CH 2 -(C 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -、-CH 2 -(C 6 H 4 )-CH 2 -、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) O-, wherein C 6 H 4 Is phenylene, C 2 H 2 、C 6 H 4 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, CF 3 Or C 1-6 Alkyl substitution, L 2 、L 3 、L 4 And L 5 The group selection of (c) does not include the case of chemical failure,
wherein R is 10 And R is 12 As defined above.
In some embodiments, R 8 And R is 9 Each independently selected from halogen, -CF 3 、-C 1-6 Alkyl and 3-12 membered cycloalkyl;
in some embodiments, X is CH 2 Or (c=o);
in some embodiments, L 1 is-O-CH 2 CH 2 -；
In some embodiments, q is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 3, or 4, more preferably 0;
in some embodiments, L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (CH) 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-CR 12 ＝CR 12 -、-CO-CR 12 ＝CR 12 -、-C≡C-、-CO-C≡C-、
-O-、-S-、-S(O)-、 - S(O) 2 -、-S(O) 2 NR 10 -、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-(CO)-NR 10 -CH 2 -、-CH 2 -(CO)-NR 10 -、-CH 2 -(CO)-NR 10 -CH 2 -、-O-(CO)-NR 10 -、-O-CH 2 -(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (C) 6 H 4 )-(CO)-NR 10 -、-CH 2 -(C 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -、-CH 2 -(C 6 H 4 )-CH 2 -、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) O-, wherein C 6 H 4 Is phenylene, C 2 H 2 、C 6 H 4 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, CF 3 Or C 1-6 Alkyl substitution, wherein R 10 And R is 12 As defined above;
in some embodiments, L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (CH) 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-C≡C-、-CO-C≡C-、-O-、-S-、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-O-(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (C) 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) -O-, wherein R 10 As defined above;
in some embodiments, R 1 Each independently selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR 11 、-NR 10 R 11 、-(CO)-R 12 、-(CO)-NR 10 R 11 、-NR 11 -(CO)-R 12 、-S(O)R 12 、-S(O) 2 R 12 、-S(O) 2 NR 10 R 11 or-NR 10 S(O) 2 R 12 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be R 2 Instead of the above-mentioned,
R 10 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 11 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 2 Instead of the above-mentioned,
R 12 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroarylAryl may optionally be R 2 Instead of the above-mentioned,
R 2 selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OH, -NH 2 、-(CO)-C 1-6 Alkyl, - (CO) -NH 2 、-NH-(CO)-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, -S (O) 2 NH 2 or-NHS (O) 2 R 15 ；
In some embodiments, the invention provides a compound, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing,
the invention provides an intermediate of difunctional small molecule PROTACs,
each substituent group is defined as above.
In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present invention, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing, and optionally a pharmaceutically acceptable adjuvant.
In another aspect, the present application provides a method of treating a disorder associated with abnormal cell proliferation in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof.
In another aspect, the present application provides the use of a compound of the present invention, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease associated with abnormal cell proliferation.
In some embodiments of the present application, the disorder associated with abnormal cell proliferation is acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-hodgkin's lymphoma, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, or multiple myeloma.
The compounds of the invention may exert their primary function by inhibiting/degrading GSPT1 or c-Myc.
Detailed Description
In the following detailed description of the invention, exemplary embodiments are set forth that utilize the principles of the present invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It is to be understood that the scope of the various aspects of the invention is defined by the claims, and methods and structures within the scope of these claims, as well as equivalent methods and structures, are within the scope of the claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter of the invention. The use of the singular also includes the plural unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g.: -CF 2 CF 3 ) Monosubstituted (e.g.: -CH 2 CH 2 F) Or any level between mono-and full-substitution (e.g.: -CH 2 CHF 2 、-CF 2 CH 3 、-CFHCHF 2 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectrometry, and pharmacological methods are employed. Unless specifically defined otherwise, the relevant terms and experimental procedures and techniques herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When writing from left to rightWhere a substituent is described by conventional chemical formulas, the substituent also includes chemically equivalent substituents obtained when writing the formula from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The terms "group", "chemical group" as used herein refer to a particular moiety or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded or attached to a molecule.
Some of the chemical groups named herein may be represented by shorthand notations for the total number of carbon atoms. For example, C 1 -C 6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the shorthand notation does not include carbon atoms on a possible substituent.
The term "halogen", "halo" or "halide" refers to bromine, chlorine, fluorine or iodine.
The terms "aromatic", "aromatic ring", "aromatic ring" as used herein refer to a planar ring or ring portion of multiple rings having a delocalized electron conjugated system of 4n+2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more than 9 atoms. The aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings. The term aromatic compounds includes all carbocycles (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.
The term "bridged ring", as used herein, alone or in combination, refers to a cyclic structure in which any two rings in a compound share two carbon atoms that are not directly attached.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" as used herein alone or as part of another component (e.g., a monoalkylamino group) refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more c=c double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bonds in these groups may be in either cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where no numerical range is specified.
The term "alkynyl", as used herein alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more c≡c triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkynyl "or“C 2-6 Alkynyl "refers to an alkynyl group that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl herein also encompasses cases where no numerical range is specified.
The term "cycloalkyl", "carbocycle", as used herein alone or as part of another component, refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, possibly including fused, spiro or bridged ring systems, containing from 3 to 15 ring-forming carbon atoms, preferably from 3 to 10 ring-forming carbon atoms, more preferably from 3 to 8 ring-forming carbon atoms, which may be saturated or unsaturated, attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", as used herein alone or as part of another ingredient, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of this application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic ring or bicyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuryl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, which has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "arylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent aryl group as defined above.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "heteroarylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent heteroaryl group as defined above.
The term "polymorph" or "polymorphism" as used herein means that the compounds of the present invention have a variety of lattice morphologies. Some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
The present application also includes isotopically-labeled compounds identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Unless otherwise specified, olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by performing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.
"pharmaceutically acceptable salts of acids" refers to those salts that retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, and the like. By "pharmaceutically acceptable salts of bases" is meant those salts which retain the biological effectiveness and properties of the free acid of the compound, are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
The organic bases forming salts include, but are not limited to, primary, secondary, tertiary, cyclic amines and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallization often yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to a complex of one or more molecules of a compound of the invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may only occasionally retain water or a mixture of water with some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "pharmaceutical composition" as used herein refers to a formulation that is mixed with a compound of the present invention and a medium that is generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. Such a medium comprises all pharmaceutically acceptable carriers.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a related disease or condition in a mammal, particularly a human, including
(i) Preventing a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition, from developing the corresponding disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Detailed Description
General synthetic method of compound
Method A:
HATU (1.5 eq) was added to a solution of carboxylic acid (1 eq), amino compound (1.2 eq) and DIEA (3 eq) in DMF at room temperature. The reaction solution was stirred at room temperature for 16h. The solvent was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to obtain the objective amide compound.
Method B:
to the Boc protected amino compound (1 eq) was added HCl dioxane solution (4N, 10 eq) at room temperature. The reaction solution was stirred at room temperature for 16h. The reaction solution was concentrated under reduced pressure to obtain an amino compound hydrochloride.
Method C:
under nitrogen, a DMSO solution of amino compound (1 eq), aryl fluoride (1.2 eq) and DIEA (3 eq) was heated to 140 ℃ and stirred overnight. The reaction solution was cooled to room temperature and slowly poured into water. Filtering to obtain precipitated solid, drying, and purifying by flash silica gel column chromatography to obtain corresponding arylamine compounds.
Method D:
to a solution of benzopyrone derivative (1.0 eq) and potassium carbonate (2.0 eq) in DMF at room temperature was added the halide (1.5 eq). The reaction solution was stirred overnight at 60 ℃. The reaction solution was poured into water, and extracted with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the corresponding target compound.
Method E:
the corresponding hydrazine derivative was added to the ethanol solution of benzopyrone at room temperature. The reaction was heated to 80 ℃ and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to obtain two corresponding pyrazole derivative isomers simultaneously.
Method F:
to the corresponding tert-butyl ester was added 4N HCl dioxane solution (20 eq) at room temperature, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the corresponding carboxylic acid compound which was used in the next reaction without further purification.
Method G:
the corresponding acetal compound was added to a solution of methanol/1N hydrochloric acid water (10:1) at room temperature. The reaction solution was stirred at room temperature for 6h until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding compound aldehyde.
Method H:
to a methanol solution of the amino compound (1.1 eq) and glacial acetic acid (3 eq) at room temperature was added the aldehyde compound (1 eq), and the reaction solution was stirred at room temperature for 2h, followed by addition of sodium cyanoborocyanide (3 eq). The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding organic amine compound.
Method I:
to a solution of the corresponding aryl bromide (1 eq), alkynyl compound (1.5 eq), cuI (0.1 eq) and triethylamine (2 eq) in DMF was added ditolylphosphine palladium dichloride (0.1 eq) under nitrogen. The reaction was heated to 100deg.C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding substituted alkynyl compound.
Method J:
to a dichloromethane solution of the compound alcohol (1 eq) was added Dess-Martin oxidant (1.5 eq) in portions at room temperature. The reaction mixture was quenched by sequentially adding a saturated sodium bicarbonate solution and a saturated sodium thiosulfate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The extracts and the organic phase are combined, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by flash column chromatography to give the corresponding aldehyde compound.
Method K:
glacial acetic acid (10 eq) was added to a mixture of the corresponding nitro compound (1 eq) and reduced iron powder (10 eq) in methanol. The reaction solution was heated to 50 ℃ and stirred overnight, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding organic amine compound.
Method L:
under the protection of nitrogen, aryl halide compound is preparedTo a solution of (1 eq), arylboronic acid (1.5 eq) and anhydrous sodium carbonate (2 eq) in dioxane/water (4:1) was added Pd (dppf) Cl 2 (0.1 eq). The reaction was heated to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to obtain the corresponding target compound.
Method M:
DIAD (2.0 eq) was added dropwise to a solution of the compound alcohol (1 eq), triphenylphosphine (2.0 eq) and the corresponding nucleophilic reactant (1.5 eq) in tetrahydrofuran under ice bath, and the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding target compound.
Method N:
raney nickel (10% by weight) was added to a methanol solution of the corresponding aryl nitrile compound at room temperature. The reaction system was replaced with hydrogen and reacted at room temperature overnight. The nickel catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give the corresponding amino compound.
Method O:
to a dry dioxane solution of aryl halide (1 eq), organic amine (1.2 eq), cesium carbonate (2.0 eq) under nitrogen protection was added RuPhos Pd G3 catalyst (0.1 eq). The reaction was heated to 100deg.C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to obtain the corresponding arylamine compound.
Method P:
lithium aluminum hydride (1.5 eq) was added in portions to the corresponding methyl ester compound (1 eq) in an ice bath, and the reaction mixture was warmed to room temperature and stirred for 2h. The temperature was lowered in the ice bath, and 1% aqueous sodium hydroxide (1.5 eq) was slowly added dropwise to the reaction mixture to quench the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding compound alcohol.
Method Q:
to an ethanol solution of the nitrogen-substituted phthalimide compound (1 eq) was added hydrazine hydrate (5 eq). The reaction solution was heated to 60 ℃ and stirred until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding amino compound.
The method comprises the following steps:
to a solution of the corresponding organic amine or aza-cycle compound (1 eq) and cesium carbonate (3 eq) in DMF was added methanesulfonate (1.5 eq) and the reaction was heated to 80 ℃ and stirred overnight. The reaction solution was poured into water, the obtained aqueous phase was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the corresponding objective compound.
Example 1:4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) methyl) N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 1 was synthesized by using compound 1-1 as a starting material, followed by general synthesis method A, method B, and method C. 1 H NMR(400MHz，DMSO-d 6 )，11.02(s，1H)，9.71(s，1H)，7.81(d，J＝8.0Hz，2H)，7.74(t，J＝6.8Hz，1H)，7.71(dd，J＝7.6Hz，1.6Hz，1H)，7.53(d，J＝8.0Hz，1H)，7.42(d，J＝8.0Hz，2H)，7.06-7.16(m，2H)，6.83-6.96(m，6H)，6.81(dd，J＝8.0Hz，1.6Hz，1H)，4.98(dd，J＝12.4Hz，5.6Hz，1H)，4.51(d，J＝5.2Hz，2H)，3.68(s，3H)，2.78-2.88(m，1H)，2.40-2.58(m，2H)，1.90-1.99(m，1H)。
Example 2:1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) N- (4- ((2- (4-methoxyphenoxy) phenyl) carbamoyl) benzyl) -3,6,9, 12-tetraoxopentadecane-15-amide
The compound of example 2 was synthesized using general synthesis method A starting from compound 2-1. 1 H NMR(400MHz，CDCl 3 )，8.57(s，1H)，8.55(d，J＝8.0Hz，1H)，8.27(s，1H)，7.78(d，J＝7.6Hz，2H)，7.64(t，J＝8.0Hz，1H)，7.44(d，J＝7.2Hz，1H)，7.36(d，J＝8.4Hz，2H)，7.20(d，J＝8.8Hz，1H)，7.08-7.13(m，2H)，6.97-7.02(m，3H)，6.87-6.91(m，2H)，6.77(d，J＝7.6Hz，1H)，4.90(dd，J＝11.6Hz，5.2Hz，1H)，4.47(d，J＝5.6Hz，2H)，4.27(t，J＝4.4Hz，2H)，3.86-3.88(m，2H)，3.80(s，3H)，3.70-3.75(m，4H)，3.56-3.63(m，6H)，3.53(s，4H)，2.65-2.87(m，3H)，2.52(t，J＝5.6Hz，2H)，2.06-2.12(m，1H)。
Example 3:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((2- (4-methoxyphenoxy) phenyl) carbamoyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 3 was synthesized using general synthesis method A starting from compound 3-1. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，9.70(s，1H)，9.50(t，J＝6.0Hz，1H)，8.38(s，1H)，8.35(dd，J＝7.6Hz，1.2Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.82(d，J＝8.0Hz，2H)，7.73(dd，J＝8.0Hz，1.6Hz，1H)，7.42(d，J＝8.0Hz，2H)，7.08-7.16(m，2H)，6.93-6.97(m，2H)，6.88-6.92(m，2H)，6.82(dd，J＝8.0Hz，1.6Hz，1H)，5.17(dd，J＝12.8Hz，5.2Hz，1H)，4.55(d，J＝5.6Hz，2H)，3.69(s，3H)，2.82-2.92(m，1H)，2.49-2.62(m，2H)，2.02-2.10(m，1H)。
Example 4:4- ((2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) acetamide) methyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 4 was synthesized by using compounds 1-3 as starting materials, followed by general synthesis method A, method B, and method C. 1 H NMR(400MHz，DMSO-d 6 )，11.03(s，1H)，9.68(s，1H)，8.64(t，J＝6.0Hz，1H)，7.78(d，J＝7.6Hz，2H)，7.71(dd，J＝7.6Hz，2.0Hz，1H)，7.58(d，J＝8.0Hz，1H)，7.40(t，J＝6.0Hz，1H)，7.31(d，J＝8.4Hz，2H)，7.08-7.17(m，2H)，6.81-6.97(m，7H)，5.02(dd，J＝12.8Hz，6.0Hz，1H)，4.34(d，J＝6.0Hz，2H)，3.92(d，J＝6.4Hz，2H)，3.69(s，3H)，2.79-2.90(m，1H)，2.44-2.56(m，2H)，1.92-2.02(m，1H)。
Example 5:1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (4- ((2- (3-hydroxy-4- (3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetamide) methyl) phenyl) -3,6,9, 12-tetraoxopentadecane-15-amide
Compound 5 of the example was prepared by general synthetic method D, method a, method E, method B, method a, in that order, starting from compound 5-1. 1 H NMR(400MHz，DMSO-d 6 )，13.77-13.87(br，1H)，11.07(s，1H)，9.87(s，1H)，8.62(t，J＝6.0Hz，1H)，7.75-7.79(m，1H)，7.59(d，J＝8.4Hz，1H)，7.46-7.52(m，3H)，7.42(d，J＝6.8Hz，1H)，7.15(d，J＝8.0Hz，2H)，6.97(dd，J＝8.8Hz，2.0Hz，1H)，6.90(d，J＝2.8Hz，1H)，6.70(s，1H)，5.05(dd，J＝12.8Hz，1.6Hz，1H)，4.59(s，2H)，4.28-4.32(m，2H)，4.26(d，J＝6.0Hz，2H)，3.74-3.78(m，2H)，3.58-3.66(m，4H)，3.44-3.50(m，10H)，2.46-2.59(m，5H)，1.94-2.03(m，1H)。
Example 6:2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -N- (4- ((2- (3-hydroxy-4- (3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetamide) methyl) phenyl) acetamide
The compound of example 6 was synthesized using general synthesis method A starting from compound 6-1. 1 H NMR(400MHz，DMSO-d 6 )，13.85(s，1H)，11.03(s，1H)，10.17(s，1H)，8.65(t，J＝6.0Hz，1H)，7.60(d，J＝9.2Hz，1H)，7.57(d，J＝8.4Hz，1H)，7.52(d，J＝8.8Hz，2H)，7.41(t，J＝6.0Hz，1H)，7.19(d，J＝8.4Hz，2H)，6.96-7.00(m，2H)，6.87-6.92(m，2H)，6.70(s，1H)，5.01(dd，J＝12.8Hz，5.6Hz，1H)，4.59(s，2H)，4.27(d，J＝6.0Hz，2H)，4.06(d，J＝7.2Hz，2H)，2.78-2.88(m，1H)，2.42-2.58(m，2H)，1.92-2.01(m，1H)。
Example 7:2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -N- (4- ((2- ((6-hydroxy-5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl) oxy) acetamide) methyl) phenyl) acetamide
The compound 7 was prepared by general synthetic method D, method E, method F, method A, method B, method A in this order starting from compound 7-1. 1 H NMR(400MHz，DMSO-d 6 )，11.03(s，1H)，10.15(s，1H)，9.16(s，1H)，8.31(t，J＝6.4Hz，1H)，8.14(s，2H)，8.00(s，1H)，7.58(d，J＝8.0Hz，1H)，7.51(d，J＝8.0Hz，2H)，7.40(t，J＝5.6Hz，1H)，7.28(d，J＝8.8Hz，1H)，7.12(d，J＝8.0Hz，2H)，6.99(s，1H)，6.90(d，J＝8.8Hz，1H)，6.69-6.71(m，2H)，5.01(dd，J＝12.8Hz，5.6Hz，1H)，4.59(s，2H)，4.22(d，J＝6.0Hz，2H)，4.06(d，J＝6.0Hz，2H)，3.73(s，3H)，2.79-2.90(m，1H)，2.42-2.58(m，2H)，1.92-2.01(m，1H)。
Example 8: n- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) methyl) benzyl) -2- (3-hydroxy-4- (3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetamide
Bromoacetyl bromide (0.62 g) was added to a solution of compound 8-1 (0.5 g) and triethylamine (0.6 mL) in methylene chloride (10 mL) under ice bath. The reaction was stirred at room temperature overnight. Dichloromethane (50 mL) was added to dilute the reaction, which was washed successively with 0.1N aqueous hydrochloric acid (20 ml×3) and saturated sodium bicarbonate (20 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to obtain compound 8-2 (610 mg).
The compound of example 8 was prepared by synthesis of general procedure D, procedure E, procedure G and procedure H, starting from compound 8-2. 1 H NMR(400MHz，DMSO-d 6 )，13.44(s，1H)，10.98(s，1H)，10.49(s，1H)，8.59(t，J＝6.0Hz，1H)，7.57(d，J＝8.8Hz，1H)，7.29(d，J＝8.4Hz，2H)，7.13-7.19(m，3H)，6.95(s，1H)，6.88(d，J＝7.2Hz，1H)，6.56-6.58(m，2H)，6.51(dd，J＝8.8Hz，2.4Hz，1H)，6.27-6.37(br，1H)，5.08(dd，J＝12.8Hz，4.8Hz，1H)，4.50(s，2H)，4.33(s，2H)，4.4.25-4.29(m，3H)，4.16(d，J＝17.6Hz，1H)，2.85-2.94(m，1H)，2.56-2.64(m，1H)，2.24-2.34(m，1H)，1.96-2.06(m，1H)。
Example 9:4- (((5- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) pent-4-yn-1-yl) amino) methyl) N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 9 was synthesized by general synthesis procedure H, procedure I, starting from compounds 1-3. 1 H NMR(400MHz，DMSO-d 6 )，11.11(s，1H)，9.72(s，1H)，7.82-7.87(m，4H)，7.78(d，J＝8.4Hz，1H)，7.71(dd，J＝8.0Hz，1.6Hz，1H)，7.51(d，J＝8.0Hz，2H)，7.08-7.18(m，2H)，6.95(d，J＝8.8Hz，2H)，6.89(d，J＝8.8Hz，2H)，6.82(dd，J＝8.0Hz，1.6Hz，1H)，5.12(dd，J＝12.8Hz，5.6Hz，1H)，3.97(s，2H)，3.69(s，3H)，2.78-2.90(m，3H)，2.44-2.61(m，4H)，1.98-2.06(m，1H)，1.76-1.85(m，2H)。
Example 10: n- (4- (((2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl) amino) methyl) benzyl) -2- (3-hydroxy-4- (3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetamide
The compound of example 10 was prepared by general synthesis method H starting from compound 8-5. 1 H NMR(400MHz，CD 3 OD)，7.50-7.54(m，2H)，7.26(d，J＝7.6Hz，2H)，7.21(d，J＝8.4Hz，2H)，6.92(d，J＝2.4Hz，1H)，6.89(s，1H)，6.79(dd，J＝8.0Hz，2.0Hz，1H)，6.55-6.58(m，2H)，5.01(dd，J＝12.4Hz，5.6Hz，1H)，4.55(s，2H)，4.43(s，2H)，3.77(s，2H)，3.33(t，J＝6.8Hz，2H)，2.62-2.86(m，5H)，2.02-2.10(m，1H)。
Example 11:4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) methyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 11 was prepared by general synthesis method C starting from compounds 1-3. 1 H NMR(400MHz，DMSO-d 6 )，11.08(s，1H)，9.70(s，1H)，7.80(d，J＝8.4Hz，2H)，7.69(dd，J＝7.6Hz，1.6Hz，1H)，7.42-7.48(m，3H)，7.31(t，J＝6.0Hz，1H)，7.06-7.15(m，2H)，6.99(d，J＝6.8Hz，1H)，6.94(d，J＝9.2Hz，2H)，6.86-6.90(m，3H)，6.80(dd，J＝8.0Hz，2.0Hz，1H)，5.05(dd，J＝12.8Hz，5.6Hz，1H)，4.60(d，J＝6.0Hz，2H)，3.68(s，3H)，2.82-2.90(m，1H)，2.45-2.60(m，2H)，1.98-2.06(m，1H).
Example 12: n- (4- ((5- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) pent-4-yn-1-yl) amino) phenyl) -2- (3-hydroxy-4- (3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetamide
Bromoacetyl bromide (0.64 g) was added to a solution of compound 12-1 (0.4 g) and triethylamine (0.6 mL) in methylene chloride (10 mL) under ice bath. The reaction was stirred at room temperature overnight. Dichloromethane (50 mL) was added to dilute the reaction solution, which was washed with 0.1N aqueous hydrochloric acid (20 ml×3) and saturated sodium bicarbonate (20 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to obtain compound 12-2 (660 mg).
The compound of example 12 was synthesized by general synthesis method D, method E, method K, method J, method H, starting from compound 12-2. 1 H NMR(400MHz，DMSO-d 6 )，13.44(s，1H)，11.11(s，1H)，10.51(s，1H)，9.72(s，1H)，7.80-7.87(m，3H)，7.57(d，J＝8.8Hz，1H)，7.31(d，J＝8.4Hz，2H)，6.94(s，1H)，6.52-6.58(m，4H)，5.12(dd，J＝12.8Hz，5.6Hz，1H)，4.58(s，2H)，3.13(t，J＝7.2Hz，2H)，2.81-2.90(m，1H)，2.48-2.61(m，4H)，1.99-2.06(m，1H)，1.76-1.86(m，2H)。
Example 13:1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (4- ((2- ((6-hydroxy-5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl) oxy) acetamide) methyl) phenyl) -3,6,9, 12-tetraoxopentadecane-15-amide
The compound of example 13 was prepared by general synthesis method a starting from compounds 7-6. 1 H NMR(400MHz，CD 3 OD)，8.01(s，2H)，7.87(s，1H)，7.67-7.71(m，1H)，7.46(d，J＝8.4Hz，2H)，7.39(d，J＝2.4Hz，1H)，7.37(s，1H)，7.24(d，J＝8.8Hz，1H)，7.08(d，J＝8.4Hz，2H)，6.69(d，J＝8.4Hz，1H)，6.60(s，1H)，5.04(dd，J＝12.8Hz，5.6Hz，1H)，4.58(s，2H)，4.26-4.32(m，5H)，3.83-3.85(m，2H)，3.75-3.78(m，4H)，3.67-3.69(m，2H)，3.52-3.60(m，10H)，2.76-2.82(m，1H)，2.64-2.73(m，2H)，2.58(t，J＝5.6Hz，2H)，2.03-2.10(m，1H)。
Example 14: n- (4- ((2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
A solution of compound 14-1 (500 mg), compound 14-2 (1.37 g) and anhydrous potassium carbonate (0.8 g) in DMF (5 mL) was heated to 60℃and stirred overnight. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL. Times.3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate: petroleum ether=5:1) to give compound 14-3.
The compound of example 14 was synthesized by the general procedure of synthesis B, followed by method A starting from compound 14-3. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.40(t，J＝5.6Hz，1H)，8.35(s，1H)，8.32(dd，J＝7.6Hz，1.6Hz，1H)，7.96-8.01(m，3H)，7.45-7.50(m，3H)，7.28-7.32(m，3H)，7.23(d，J＝8.0Hz，2H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.62(s，2H)，4.45(d，J＝5.2Hz，2H)，2.80-2.92(m，1H)，2.46-2.62(m，2H)，2.01-2.08(m，1H)。
Example 15:1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (4- (2- ((6-hydroxy-5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl) oxy) acetamide) phenyl) -3,6,9, 12-tetraoxopentadecane-15-amide
The synthesis method of example 15 was the same as that of example 13. 1 H NMR(400MHz，CD 3 OD)，8.08(s，2H)，7.93(s，1H)，7.68-7.72(m，1H)，7.48(d，J＝8.8Hz，2H)，7.35-7.40(m，4H)，7.28(d，J＝8.8Hz，1H)，6.78(d，J＝8.4Hz，1H)，6.60(s，1H)，5.06(dd，J＝12.8Hz，5.6Hz，1H)，4.69(s，2H)，4.29-4.31(m，2H)，3.84-3.87(m，2H)，3.76-3.79(m，5H)，3.68-3.71(m，2H)，3.54-3.61(m，10H)，2.78-2.88(m，1H)，2.62-2.74(m，2H)，2.58(t，J＝6.4Hz，2H)，2.04-2.11(m，1H)。
Example 16:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (2- ((6-hydroxy-5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl) oxy) acetamide) phenyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 16 was prepared by synthesis of general procedure a, procedure K, procedure a, starting from compound 7-4. 1 H NMR(400MHz，CD 3 OD)，8.22(dd，J＝8.0Hz，1.6Hz，1H)，8.17(s，1H)，8.14(s，2H)，7.91(d，J＝7.6Hz，1H)，7.85(s，1H)，7.66(d，J＝8.4Hz，1H)，7.31(d，J＝9.2Hz，1H)，7.18(d，J＝8.8Hz，2H)，6.67(d，J＝8.8Hz，2H)，6.64(s，1H)，5.14(dd，J＝12.8Hz，5.6Hz，1H)，4.83(s，2H)，3.85(s，3H)，2.66-2.90(m，3H)，2.08-2.16(m，1H).
Example 17: n- ((6 '- ((4-chlorobenzyl) oxy) -2' -hydroxy-3 '- (3- (trifluoromethyl) -1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 17 was prepared by synthesis of general procedure L, procedure E, procedure B, procedure a, in sequence, starting from compound 17-1. 1 H NMR(400MHz，DMSO-d 6 )，13.53(s，1H)，11.13(s，1H)，9.52(t，J＝4.8Hz，1H)，8.64-8.76(br，1H)，8.42(s，1H)，8.38(dd，J＝8.0Hz，1.2Hz，1H)，8.03(d，J＝7.6Hz，1H)，7.48-7.55(m，1H)，7.39(dd，J＝7.6Hz，2H)，7.26-7.29(m，3H)，7.19(d，J＝8.0Hz，2H)，6.90(s，1H)，6.75(d，J＝8.4Hz，1H)，5.17(dd，J＝13.2Hz，5.6Hz，1H)，5.04(s，2H)，4.56(d，J＝6.4Hz，2H)，2.82-2.92(m，1H)，2.49-2.62(m，2H)，2.02-2.09(m，1H)。
Example 18:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (2- (naphthalen-1-yloxy) ethoxy) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 18 was prepared by synthesis of general procedure M, procedure N, procedure a, starting from compound 18-1. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，9.38(t，J＝6.0Hz，1H)，8.36(s，1H)，8.34(dd，J＝8.0Hz，1.6Hz，1H)，8.08(d，J＝8.0Hz，1H)，8.01(d，J＝7.6Hz，1H)，7.83(d，J＝7.6Hz，1H)，7.37-7.49(m，4H)，7.28(d，J＝8.8Hz，2H)，6.97-7.01(m，3H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，4.40-4.48(m，6H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.02-2.09(m，1H)。
Example 19:2- (2, 6-Dioxopiperidin-3-yl) -N- (4- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The synthetic route of example 19 was the same as that of example 18. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.37(t，J＝6.0Hz，1H)，8.36(s，1H)，8.33(dd，J＝8.0Hz，1.6Hz，1H)，8.01(d，J＝8.0Hz，1H)，7.39-7.44(m，3H)，7.32-7.36(m，1H)，7.22-7.29(m，5H)，7.14-7.17(m，1H)，7.01(d，J＝9.2Hz，2H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，5.10(s，2H)，4.43(d，J＝5.6Hz，2H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.15(s，3H)，2.02-2.09(m，1H).
Example 20:4- ((((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) methyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 20 was prepared by synthesis of general procedure a, procedure G, procedure a, starting from compound 1-1. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，9.71(s，1H)，7.92(s，1H)，7.79-7.87(m，3H)，7.71(d，J＝7.6Hz，1H)，7.45(d，J＝8.4Hz，2H)，7.06-7.16(m，3H)，6.95(d，J＝9.2Hz，2H)，6.89(d，J＝9.2Hz，2H)，6.81(d，J＝7.2Hz，1H)，5.12(dd，J＝12.8Hz，5.6Hz，1H)，3.88(s，2H)，3.76(s，2H)，3.68(s，3H)，2.81-2.92(m，1H)，2.48-2.61(m，2H)，1.98-2.07(m，1H).
Example 21: (9H-fluoren-9-yl) methyl (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) carbamate
The compound of example 20 was prepared by the general procedure a followed by synthesis starting from compound 21-1. 1 H NMR(400MHz，CDCl 3 )，8.16-8.23(m，3H)，7.87(d，J＝8.0Hz，1H)，7.74(d，J＝7.6Hz，2H)，7.56(d，J＝7.6Hz，2H)，7.38(t，J＝7.6Hz，2H)，7.20-7.30(m，6H)，6.88(t，J＝5.6Hz，1H)，5.21(t，J＝6.0Hz，1H)，4.95(dd，J＝12.4Hz，5.6Hz，1H)，4.60(d，J＝5.6Hz，2H)，4.43(d，J＝6.8Hz，2H)，4.33(d，J＝6.0Hz，2H)，4.19(t，J＝7.6Hz，1H)，2.66-2.90(m，3H)，2.10-2.16(m，1H)。
Example 22: benzyl (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) carbamate
The compound of example 20 was prepared by the sequential synthesis of general procedure a starting from compound 22-1. 1 H NMR(400MHz，CDCl 3 )，8.16-8.22(m，3H)，7.87(d，J＝8.4Hz，1H)，7.20-7.37(m，9H)，6.85-6.92(br，1H)，5.16-5.24(br，1H)，5.10(s，2H)，4.95(dd，J＝12.4Hz，4.8Hz，1H)，4.60(d，J＝5.6Hz，2H)，4.34(d，J＝6.4Hz，2H)，2.66-2.91(m，3H)，2.10-2.16(m，1H)。
Example 23:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((3-hydroxy-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) phenyl) carbamoyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 23 was prepared by synthesis of general procedure L, procedure K, procedure a, procedure B, procedure a, starting from compound 23-1. 1 H NMR(400MHz，CD 3 OD)，8.33(s，1H)，8.31(dd，J＝8.0Hz，1.6Hz，1H)，7.98(d，J＝8.0Hz，1H)，7.92(d，J＝8.0Hz，2H)，7.48(d，J＝8.8Hz，2H)，7.14(d，J＝8.8Hz，1H)，7.70(dd，J＝8.0Hz，2.0Hz，1H)，6.62(d，J＝2.4Hz，1H)，6.43(s，1H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，4.67(s，2H)，3.74(s，3H)，2.83-2.92(m，1H)，2.67-2.78(m，2H)，2.11-2.18(m，1H)。
Example 24: (E) -4- (3- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) allyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
A solution of compound 24-1 (0.4 g), vinyl tri-n-butyltin (0.56 g) and palladium tetraphenylphosphine (0.14 g) in DMF (10 mL) was heated to 80℃under nitrogen and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to obtain compound 24-2 (307 mg).
Compound 1-1 is used as a raw material to synthesize compound 24-4 by a synthetic general method A. Grubb's second generation catalyst (50 mg) was added to a solution of compound 24-4 (200 mg) and compound 24-2 (174 mg) in DMF (2 mL) under nitrogen protection, the reaction was stirred overnight at 40 ℃, the reaction was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane: methanol=50:1 to 10:1) to give example compound 24 (130 mg). 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，9.69(s，1H)，7.98(s，1H)，7.80-7.87(m，4H)，7.72(dd，J＝8.0Hz，2.0Hz，1H)，7.37(d，J＝8.0Hz，2H)，7.07-7.16(m，2H)，6.80-6.89(m，6H)，6.69(d，J＝15.6Hz，1H)，5.11(dd，J＝12.8Hz，4.8Hz，1H)，3.68(s，3H)，3.63(d，J＝6.8Hz，2H)，2.81-2.90(m，1H)，2.44-2.61(m，2H)，1.99-2.06(m，1H)。
Example 25:4- (3- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) propyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
Palladium on carbon catalyst (20 mg) was added to a solution of compound 24 (90 mg) in DMF (2 mL) at room temperature, and stirred under a hydrogen atmosphere overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane: methanol=100:1 to 20:1) to obtain the compound of example 25 (34 mg). 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，9.66(s，1H)，7.75-7.82(m，4H)，7.68-7.72(m，2H)，7.30(d，J＝8.0Hz，2H)，7.06-7.15(m，2H)，6.95(d，J＝8.8Hz，2H)，6.89(d，J＝8.8Hz，2H)，6.80(dd，J＝8.0Hz，1.6Hz，1H)，5.11(dd，J＝12.8Hz，5.6Hz，1H)，3.68(s，3H)，2.76-2.91(m，3H)，2.65(t，J＝7.6Hz，2H)，2.46-2.60(m，2H)，1.90-2.05(m，3H)。
Example 26: n- ((6 '- ((4-chlorobenzyl) oxy) -2' -hydroxy-3 '- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 26 was the same as that of example 17. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，9.51(t，J＝6.0Hz，1H)，8.64(s，1H)，8.41(s，1H)，8.38(d，J＝8.0Hz，1H)，8.03(d，J＝8.0Hz，1H)，7.38(d，J＝8.0Hz，2H)，7.28-7.31(m，4H)，7.21(d，J＝8.8Hz，2H)，7.16(d，J＝8.4Hz，1H)，6.74(d，J＝8.8Hz，1H)，6.67(s，1H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，5.05(s，2H)，4.54(d，J＝5.6Hz，2H)，3.70(s，3H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.01-2.08(m，1H)。
Example 27:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((3-hydroxy-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 27 was prepared by synthesis of general procedure D, procedure E, procedure B, procedure a, starting from compound 5-1. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，10.11(s，1H)，9.45(t，J＝5.2Hz，1H)，8.38(s，1H)，8.34(d，J＝8.0Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.40(d，J＝8.0Hz，2H)，7.35(d，J＝8.0Hz，2H)，7.12(d，J＝8.0Hz，1H)，6.53-6.60(m，3H)，5.17(dd，J＝13.2Hz，5.6Hz，1H)，5.05(s，2H)，4.50(s，2H)，3.68(s，3H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.01-2.09(m，1H).
Example 28:4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) methyl) amino) methyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
The synthesis method of example 28 was identical to that of example 20. 1 H NMR(400MHz，DMSO-d 6 )，10.95(s，1H)，9.68(s，1H)，7.81(d，J＝7.6Hz，2H)，7.72(dd，J＝7.6Hz，1.6Hz，1H)，7.64(d，J＝8.0Hz，1H)，7.55(s，1H)，7.42-7.47(m，3H)，7.07-7.16(m，2H)，6.96(d，J＝8.8Hz，2H)，6.90(d，J＝8.8Hz，2H)，6.81(dd，J＝8.0Hz，1.2Hz，1H)，5.08(dd，J＝13.2Hz，5.2Hz，1H)，4.41(d，J＝17.6Hz，1H)，4.28(d，J＝17.6Hz，1H)，3.77(s，2H)，3.72(s，2H)，3.69(s，3H)，2.84-2.93(m，1H)，2.52-2.60(m，1H)，2.31-2.42(m，1H)，1.94-2.01(m，1H).
Example 29:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((1- (4-methoxyphenyl) -1H-indol-3-yl) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 29 was prepared by synthesis of general procedure O, procedure P, procedure M, procedure Q, procedure a, starting from compound 29-1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.35(t，J＝5.6Hz，1H)，8.34(s，1H)，8.31(d，J＝7.6Hz，1H)，7.99(d，J＝8.0Hz，1H)，7.49(d，J＝7.6Hz，1H)，7.43(，H)J＝8.8Hz，2H)，7.37(d，J＝8.0Hz，2H)，7.30(d，J＝8.0Hz，2H)，7.22(d，J＝8.0Hz，2H)，7.05-7.12(m，3H)，6.98-7.02(m，1H)，5.15(dd，J＝12.8Hz，5.6Hz，1H)，4.44(d，J＝5.6Hz，2H)，4.04(s，2H)，3.79(s，3H)，2.81-2.91(m，1H)，2.47-2.62(m，2H)，2.00-2.09(m，1H).
Example 30:2- (2, 6-Dioxopiperidin-3-yl) -N- (4- ((2- (4-ethoxyphenoxy) phenyl) carbamoyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 30 was the same as that of example 3. 1 H NMR(400MHz，CDCl 3 )，8.52-8.58(m，2H)，8.21-8.26(m，2H)，8.04-8.12(br，1H)，7.90-7.94(m，1H)，7.78-7.84(m，2H)，7.40-7.45(m，2H)，7.10(t，J＝8.0Hz，1H)，6.95-7.03(m，3H)，6.83-6.91(m，3H)，6.77(d，J＝8.4Hz，1H)，4.98(dd，J＝12.0Hz，5.6Hz，1H)，4.71(d，J＝5.6Hz，2H)，4.00(q，J＝6.8Hz，2H)，2.68-2.94(m，3H)，2.13-2.22(m，1H)，1.40(t，J＝6.8Hz，3H)。
Example 31: tert-butyl (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) carbamate
The synthesis method of example 31 was the same as that of example 21. 1 H NMR(400MHz，CDCl 3 )，8.41(s，1H)，8.19-8.21(m，2H)，7.83(d，J＝8.4Hz，1H)，7.27(d，J＝8.0Hz，2H)，7.21(d，J＝8.0Hz，2H)，7.13-7.20(br，1H)，4.91-5.02(m，2H)，4.58(d，J＝5.2Hz，2H)，4.25(d，J＝5.6Hz，2H)，2.68-2.88(m，3H)，2.09-2.16(m，1H)，1.43(s，9H).
Example 32:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((3- (4-methoxyphenyl) -1H-indol-1-yl) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound 32-1 is used as a starting material, and is prepared and implemented by the general synthetic method R, the general synthetic method B and the general synthetic method A in sequenceExample 32 compound. 1 H NMR(400MHz，CDCl 3 )，8.24(s，1H)，8.11-8.16(m，2H)，7.82-7.92(m，2H)，7.48-7.60(m，2H)，7.10-7.29(m，8H)，6.96(d，J＝8.8Hz，2H)，6.72-6.78(m，1H)，5.31(s，2H)，4.93(dd，J＝12.0Hz，5.6Hz，1H)，4.56(d，J＝5.6Hz，2H)，3.82(s，3H)，2.62-2.88(m，3H)，2.06-2.12(m，1H)。
Example 33:2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxo-N- (4- ((1, 3,4, 5-tetrahydro-2H-phenyl-o [ c)]Aza-compounds
-2-yl) methyl) benzyl) isoindoline-5-carboxamide
The compound of example 33 was prepared by synthesis of general procedure R, procedure B, procedure a, starting from compound 33-1. 1 H NMR(400MHz，CDCl 3 )，8.25(dd，J＝8.0Hz，1.6Hz，1H)，8.21(s，1H)，8.07(s，1H)，7.94(d，J＝8.0Hz，1H)，7.43(d，J＝8.0Hz，2H)，7.31(d，J＝8.0Hz，2H)，7.10-7.14(m，2H)，6.95(d，J＝7.6Hz，1H)，6.87(t，J＝7.2Hz，1H)，6.57(t，J＝5.2Hz，1H)，4.98(dd，J＝12.8Hz，5.2Hz，1H)，4.65(d，J＝5.6Hz，2H)，4.31(s，2H)，2.70-2.91(m，7H)，2.13-2.18(m，1H)，1.54-1.65(m，4H).
Example 34:2- (2, 6-dioxopiperidin-3-yl) -5- (((4- ((1- (4-methoxyphenyl) -1H-indol-3-yl) methyl) benzyl) amino) methyl) isoindoline-1, 3-dione
The compound of example 34 was prepared by synthesis of general procedure J followed by procedure H starting from compound 34-1. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，7.87(s，1H)，7.82(d，J＝7.6Hz，1H)，7.78(d，J＝7.6Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.43(d，J＝8.8Hz，2H)，7.36-7.39(m，2H)，7.27(d，J＝7.6Hz，2H)，7.21(d，J＝8.4Hz，2H)，7.06-7.13(m，3H)，7.01(t，J＝7.6Hz，1H)，5.11(dd，J＝12.8Hz，5.6Hz，1H)，4.04(s，2H)，3.81(s，2H)，3.79(s，3H)，3.60(s，2H)，2.82-2.91(m，1H)，2.48-2.60(m，2H)，1.98-2.06(m，1H)。
Example 35:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (((1- (4-methoxyphenyl) -1H-indazol-3-yl) amino) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 35 was prepared by synthesis of general procedure O, procedure B, procedure a, starting from compound 35-1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.39(t，J＝5.6Hz，1H)，8.35(s，1H)，8.32(dd，J＝7.6Hz，1.2Hz，1H)，7.99(d，J＝8.0Hz，1H)，7.84(d，J＝7.6Hz，1H)，7.55(d，J＝8.4Hz，1H)，7.50(d，J＝8.8Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.33(t，J＝8.0Hz，1H)，7.28(d，J＝8.0Hz，2H)，6.98-7.04(m，3H)，6.90(t，J＝6.0Hz，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.49(d，J＝6.4Hz，2H)，4.46(d，J＝5.6Hz，2H)，3.75(s，3H)，2.81-2.91(m，1H)，2.46-2.62(m，2H)，2.00-2.09(m，1H)。
Example 36:2- (2, 6-Dioxopiperidin-3-yl) -N- ((2 ' -hydroxy-3 ' - (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 36 was prepared by synthesis of general procedure L, procedure B, procedure a, starting from compound 36-1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.49(t，J＝5.6Hz，1H)，8.90(s，1H)，8.39(s，1H)，8.36(d，J＝7.6Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.49(d，J＝8.4Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.33(dd，J＝7.6Hz，1.6Hz，1H)，7.20(dd，J＝8.0Hz，1.6Hz，1H)，7.03(t，J＝7.6Hz，1H)，6.75(s，1H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，4.54(d，J＝6.0Hz，2H)，3.73(s，3H)，2.82-2.92(m，1H)，2.48-2.64(m，2H)，2.02-2.10(m，1H)。
Example 37:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (((7-morpholinothiazolo [5,4-d ] pyrimidin-2-yl) amino) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
Cesium carbonate (223 mg) and 37-1 (300 mg) were added to an acetonitrile (10 mL) solution of compound 37-2 (223 mg), and the mixture was stirred at 50℃overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=30:1) to give compound 37-3 (270 mg).
A solution of compound 37-3 (230 mg) and morpholine (0.5 mL) in n-butanol (2 mL) was heated to 140℃with microwaves and reacted for 3h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=20:1) to obtain compound 37-4 (150 mg).
The compound of example 37 was prepared by synthesis of general procedure B, procedure a starting from compound 37-4. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.40(t，J＝5.6Hz，1H)，8.72(t，J＝5.6Hz，1H)，8.35(s，1H)，8.32(d，J＝7.6Hz，1H)，8.10(s，1H)，8.00(d，J＝7.6Hz，1H)，7.29(s，4H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.42-4.49(m，4H)，3.96-4.04(m，4H)，3.56-3.63(m，4H)，2.81-2.92(m，1H)，2.48-2.62(m，2H)，2.01-2.09(m，1H)。
Example 38:6- ((4-chlorobenzyl) oxy) -3- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) carbamate
Triphosgene (35 mg) was added to a solution of compound 38-1 (200 mg) and triethylamine (0.2 mL) in methylene chloride (5 mL) under ice bath, and the reaction solution was warmed to room temperature and stirred overnight. Subsequently, to the reaction solution was added compound 38-2 (95 mg), the reaction solution was stirred at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 38-3 (150 mg).
The compound 38 of the example is prepared by using the compound 38-3 as a raw material through a general synthetic method B and a general synthetic method A. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，9.41(t，J＝5.6Hz，1H)，8.30-8.38(m，3H)，7.94-8.04(m，5H)，7.26-7.33(m，5H)，7.10-7.15(m，3H)，6.84(d，J＝8.0Hz，2H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，5.13(s，2H)，4.44(d，J＝5.6Hz，2H)，3.99(d，J＝6.0Hz，2H)，3.93(s，3H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.02-2.10(m，1H)。
Example 39:5- ((((6 '- ((4-chlorobenzyl) oxy) -2' -hydroxy-3 '- (3- (trifluoromethyl) -1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
The compound 39-1 is used as a starting material, and the general method L, the method E and the method are synthesized in sequenceG. Method H preparation gave the compound of example 39. 1 H NMR(400MHz，CD 3 OD)，7.93(s，1H)，7.87(d，J＝8.0Hz，1H)，7.82(d，J＝8.0Hz，1H)，7.61(d，J＝8.8Hz，1H)，7.48(d，J＝8.0Hz，2H)，7.38(d，J＝8.0Hz，2H)，7.21(d，J＝8.4Hz，2H)，7.17(d，J＝8.4Hz，2H)，6.97(s，1H)，6.78(d，J＝9.2Hz，1H)，5.14(dd，J＝12.8Hz，5.6Hz，1H)，5.01(s，2H)，4.05(s，2H)，3.96(s，2H)，2.82-2.91(m，1H)，2.67-2.78(m，2H)，2.08-2.16(m，1H)。
Example 40:6- ((4-chlorobenzyl) oxy) -3- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -biphenyl ] -2-yl (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) carbamate
The synthesis of example 40 was identical to that of example 38. 1 H NMR(400MHz，CD 3 OD)，8.30(s，1H)，8.28(dd，J＝7.6Hz，1.6Hz，1H)，7.91-7.97(m，4H)，7.49(d，J＝8.4Hz，1H)，7.19-7.28(m，7H)，6.79(d，J＝8.0Hz，2H)，6.60(s，1H)，5.13-5.17(m，3H)，4.54(s，2H)，3.98(s，2H)，3.77(s，3H)，2.80-2.86(m，1H)，2.68-2.77(m，2H)，2.08-2.18(m，1H)。
Example 41:2- (2, 6-Dioxopiperidin-3-yl) -N- (4- ((3- (4-methoxyphenyl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
Compound 41-2 was prepared by synthesis of general procedure H starting from 41-1.
To a solution of compound 41-2 (340 mg) and triethylamine (O.2 mL) in acetonitrile (5 mL) was added triphosgene (82 mg) at room temperature. The reaction was heated to 60 ℃ and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 41-3 (210 mg).
The compound of example 41 was prepared by the general procedure of synthesis B followed by procedure a starting from compound 41-3. 1 H NMR(400MHz，CDCl 3 )，8.42-8.48(br，1H)，8.22(s，1H)，8.20(d，J＝7.6Hz，1H)，7.80(d，J＝7.2Hz，1H)，7.35-7.43(m，3H)，7.22-7.30(m，4H)，6.94-7.02(m，5H)，6.89-6.92(m，1H)，5.04(s，2H)，4.93(dd，J＝12.4Hz，5.6Hz，1H)，4.53(d，J＝6.0Hz，2H)，3.82(s，3H)，2.64-2.88(m，3H)，2.07-2.14(m，1H)。
Example 42:2- (2, 6-dioxopiperidin-3-yl) -5- (((4- ((3-hydroxy-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) methyl) benzyl) amino) methyl) isoindoline-1, 3-dione
The compound of example 42 was prepared by synthesis of general procedure D, procedure E, procedure G, procedure H, starting from compound 42-1. 1 H NMR(400MHz，CD 3 OD)，7.97(s，1H)，7.90(s，2H)，7.46-7.51(m，4H)，7.10(d，J＝8.4Hz，1H)，6.56-6.60(m，2H)，6.46(s，1H)，5.14(dd，J＝12.8Hz，5.6Hz，1H)，5.12(s，2H)，4.24(s，2H)，4.11(s，2H)，3.74(s，3H)，2.82-2.92(m，1H)，2.66-2.78(m，2H)，2.08-2.16(m，1H)。
Example 43:2- (2, 6-dioxopiperidin-3-yl) -N- (4- ((2- ((6-methoxypyridin-3-yl) oxy) phenyl) carbamoyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 43 was the same as that of example 1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.81(s，1H)，9.49(t，J＝6.0Hz，1H)，8.38(s，1H)，8.34(d，J＝8.0Hz，1H)，8.02(d，J＝8.0Hz 1H)，7.91(d，J＝3.2Hz，1H)，7.82(d，J＝8.4Hz，2H)，7.68(dd，J＝8.0Hz，1.6Hz，1H)，7.38-7.43(m，3H)，7.10-7.19(m，2H)，6.87(dd，J＝7.6Hz，1.6Hz，1H)，6.80(d，J＝8.8Hz，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.55(d，J＝5.6Hz，2H)，3.77(s，3H)，2.81-2.92(m，1H)，2.48-2.62(m，2H)，2.02-2.10(m，1H).
Example 44: n- (4- ((2, 5-dioxo-3-phenylpyrrolidin-1-yl) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
To methanol (5 mL solution) of the compound (200 mg) of example 14 was added a palladium on charcoal catalyst (20 mg), stirred under a hydrogen atmosphere overnight, the reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane: methanol=20:1) to obtain the compound (113 mg) of example 44. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.41(t，J＝6.0Hz，1H)，8.36(s，1H)，8.33(dd，J＝8.0Hz，1.2Hz，1H)，8.01(d，J＝7.6Hz，1H)，7.20-7.33(m，9H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.57(s，2H)，4.46(d，J＝6.0Hz，2H)，4.20(dd，J＝9.2Hz，5.2Hz，1H)，3.18-3.25(m，1H)，2.78-2.92(m，2H)，2.48-2.64(m，2H)，2.01-2.09(m，1H)。
Example 45:2- (2, 6-Dioxopiperidin-3-yl) -N- (4- ((methyl ((8- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) methyl) amino) methyl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
Using compound 45-1 as initial raw material, successively making synthesis by general method H and squareMethod R, method L, method B, method A prepare the compound of example 45. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.40(t，J＝6.0Hz，1H)，5.53(d，J＝6.8Hz，1H)，8.36(s，1H)，8.33(dd，J＝8.0Hz，1.2Hz，1H)，8.01(d，J＝8.0Hz，1H)，7.58(s，1H)，7.44(d，J＝6.8Hz，1H)，7.27(d，J＝8.0Hz，2H)，7.23(d，J＝8.0Hz，2H)，7.08(t，J＝6.8Hz，1H)，7.02(s，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.47(d，J＝5.2Hz，2H)，3.89(s，2H)，3.87(s，3H)，3.51(s，2H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，1.98-2.10(m，4H)。
Example 46:2- (2, 6-Dioxopiperidin-3-yl) -N- ((1- ((2- (4-methoxyphenoxy) phenyl) carbamoyl) piperidin-4-yl) methyl) -1, 3-dioxoisoindoline-5-carboxamide
To a solution of compound 46-1 (0.35 g) in methylene chloride (10 mL) at room temperature was added compound 46-2 (370 mg), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 46-3 (312 mg).
The compound of example 46 was prepared by synthesis of general procedure B followed by procedure a starting from 46-3. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，8.86(t，J＝5.6Hz，1H)，8.32(s，1H)，8.29(dd，J＝8.0Hz，1.2Hz，1H)，7.99(d，J＝7.2Hz，1H)，7.81(s，1H)，7.58(dd，J＝7.6Hz，1.6Hz，1H)，6.95-7.03(m，2H)，6.89(s，4H)，6.76(dd，J＝7.2Hz，2.0Hz，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，3.95(d，J＝10.0Hz，2H)，3.69(s，3H)，3.11-3.16(m，2H)，2.80-2.91(m，1H)，2.48-2.72(m，4H)，2.02-2.09(m，1H)，1.67-1.78(m，1H)，1.58-1.66(m，2H)，0.92-1.05(m，2H)。
Example 47: n- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide) methyl) benzyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The compound of example 47 was prepared by synthesis of general procedure a, procedure B, procedure a, starting from compound 47-1. 1 H NMR(400MHz，DMSO-d 6 )，11.11(s，1H)，9.39(t，J＝6.0Hz，1H)，8.97(t，J＝6.0Hz，1H)，8.29-8.35(m，3H)，8.24(s，1H)，7.99(d，J＝7.6Hz，1H)，7.90(d，J＝4.8Hz，1H)，7.24-7.32(m，5H)，7.19(s，1H)，5.15(dd，J＝12.8Hz，5.2Hz，1H)，4.42-4.50(m，4H)，2.81-2.92(m，1H)，2.48-2.62(m，2H)，2.00-2.08(m，1H).
Example 48: n- (4- ((2- (4-cyanophenoxy) phenyl) carbamoyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 48 was the same as that of example 1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.86(s，1H)，9.46(t，J＝6.0Hz，1H)，8.37(s，1H)，8.34(dd，J＝8.0Hz，1.6Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.75(d，J＝8.8Hz，2H)，7.64-7.69(m，3H)，7.37(d，J＝8.4Hz，2H)，7.27-7.30(m，2H)，7.15-7.18(m，1H)，7.00(d，J＝8.0Hz，2H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.52(d，J＝6.0Hz，2H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.02-2.10(m，1H)。
Example 49:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (4-morpholin-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) phenyl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 49 was prepared by synthesis of general procedure L followed by procedure a starting from compound 49-1. 1 H NMR(400MHz，DMSO-d 6 )，12.19(s，1H)，11.15(s，1H)，10.67(s，1H)，8.48(s，1H)，8.42(d，J＝8.4Hz，1H)，8.16(s，1H)，8.07(d，J＝7.6Hz，1H)，7.91(d，J＝8.8Hz，2H)，7.85(d，J＝8.8Hz，2H)，7.14(s，1H)，5.20(dd，J＝12.8Hz，5.2Hz，1H)，3.82-3.89(m，4H)，3.69-3.76(m，4H)，2.84-2.94(m，1H)，2.48-2.64(m，2H)，2.02-2.12(m，1H)。
Example 50:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (4-morpholin-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 50 was the same as that of example 49. 1 H NMR(400MHz，DMSO-d 6 )，12.20(s，1H)，11.13(s，1H)，9.45(t，J＝6.0Hz，1H)，8.39(s，1H)，8.36(d，J＝7.6Hz，1H)，8.15(s，1H)，8.02(d，J＝8.0Hz，1H)，7.86(d，J＝8.0Hz，2H)，7.38(d，J＝8.0Hz，2H)，7.13(s，1H)，5.17(dd，J＝12.8Hz，5.2Hz，1H)，4.52(d，J＝5.6Hz，2H)，3.81-3.88(m，4H)，3.67-3.76(m，4H)，2.82-2.93(m，1H)，2.46-2.63(m，2H)，2.02-2.10(m，1H).
Example 51:4- (((2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl) amino) methyl) -N- (2- (4-methoxyphenoxy) phenyl) benzamide
The compound of example 51 was prepared by synthesis of general procedure H starting from compound 5. 1 H NMR(400MHz，DMSO-d 6 )，11.04(s，1H)，9.80(s，1H)，7.86(d，J＝8.4Hz，2H)，7.69(d，J＝6.4Hz，1H)，7.55-7.60(m，3H)，7.32-7.39(br，1H)，7.08-7.18(m，2H)，7.00(s，1H)，6.95(d，J＝9.2Hz，2H)，6.86-6.92(m，3H)，6.82(d，J＝8.0Hz，1H)，5.01(dd，J＝12.8Hz，5.2Hz，1H)，4.11(s，2H)，3.68(s，3H)，3.43-3.53(m，2H)，2.92-3.02(m，2H)，2.78-2.90(m，1H)，2.42-2.60(m，2H)，1.91-2.01(m，1H)。
Example 52:2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -N- (4- (2- ((6-hydroxy-5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3',5' -bis (trifluoromethyl) - [1,1' -diphenyl ] -2-yl) oxy) acetamido) phenyl) acetamide
The synthesis method of example 52 was the same as that of example 15. 1 H NMR(400MHz，DMSO-d 6 )，11.03(s，1H)，10.11(s，1H)，10.00(s，1H)，9.17(s，1H)，8.15(s，2H)，8.02(s，1H)，7.57(d，J＝8.4Hz，1H)，7.51(d，J＝9.2Hz，2H)，7.46(d，J＝9.2Hz，2H)，7.40(t，J＝6.0Hz，1H)，7.28(d，J＝8.8Hz，1H)，6.98(s，1H)，6.89(dd，J＝8.4Hz，2.0Hz，1H)，6.75(d，J＝9.2Hz，1H)，6.71(s，1H)，5.01(dd，J＝12.8Hz，5.2Hz，1H)，4.73(s，2H)，4.05(d，J＝5.2Hz，2H)，3.73(s，3H)，2.79-2.89(m，1H)，2.41-2.58(m，2H)，1.92-2.00(m，1H).
Example 53: n- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide hydrochloride
The synthesis of example 53 was identical to that of example 14. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.92-10.10(br，1H)，9.49(t，J＝6.0Hz，1H)，8.39(s，1H)，8.35(dd，J＝7.6Hz，1.6Hz，1H)，8.03(d，J＝8.0Hz，1H)，7.37-7.54(m，4H)，7.10-7.30(m，4H)，5.17(dd，J＝12.8Hz，5.6Hz，1H)，4.54(d，J＝5.6Hz，2H)，4.22-4.48(m，3H)，3.52-3.70(m，1H)，3.20-3.34(m，2H)，2.96-3.11(m，2H)，2.82-2.92(m，1H)，2.48-2.64(m，2H)，2.02-2.10(m，1H)。
Example 54: n- (4- ((4- (2- (4- (acrylamidomethyl) benzamido) phenoxy) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The compound of example 54 was prepared by synthesis of general procedure D, procedure K, procedure B, procedure a, starting from compound 54-1. 1 H NMR(400MHz，DMSO-d 6 ) 11.12 (s, 1H), 9.68 (s, 1H), 9.43 (t, j=6.0 hz, 1H), 8.64 (t, j=6.0 hz, 1H), 8.37 (s, 1H), 8.34 (dd, j=8.0 hz,1.6hz, 1H), 8.01 (d, j=7.6 hz, 1H), 7.79 (d, j=8.4 hz, 2H), 7.71 (dd, j=7.6 hz,2.0hz, 1H), 7.37 (d, j=8.0 hz, 2H), 7.30-7.35 (m, 4H), 7.07-7.16 (m, 2H), 6.92-6.98 (m, 4H), 6.82 (dd, j=8.0 hz,1.6 hz), 6.25 (dd, 16.8hz,10 hz), 6.10 hz, 1H), 7.37 (d, j=8.0 hz, 2H), 7.30-7.35 (m, 4H), 7.07-7.16 (m, 2H), 6.92-6.98 (m, 4H), 6.82 (dd, 1.6 hz), 6.6.6H), 6.25 (dd, 2.8hz, 1H), 2.7.7.7.7 (d, 1H), 2.7.7.7 (j=8 hz, 1H), 1.6.6H), 1H (2.7.7.7H), 1H), 1.7.7.7.7 (J, 1H), 1H, 1.7.7.7.7 (J, 1H).
Example 55: n- (4- ((4- (2- (4- ((2-cyanoacetamido) methyl) benzoylamino) phenoxy) methyl) phenyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
Synthesis method and apparatus for example 55The synthesis method of example 54 was the same. 1 H NMR(400MHz，CD 3 OD)，8.30(s，1H)，8.26(dd，J＝8.0Hz，1.6Hz，1H)，8.03-8.08(m，1H)，7.93(d，J＝7.6Hz，1H)，7.74(d，J＝8.0Hz，2H)，7.33-7.39(m，6H)，7.06-7.11(m，2H)，6.89-6.95(m，4H)，6.81-6.85(m，1H)，5.09(dd，J＝12.4Hz，5.6Hz，1H)，5.01(s，2H)，4.58(s，2H)，4.41(s，2H)，3.33(s，2H)，2.68-2.84(m，3H)，2.10-2.16(m，1H)。
Example 56:2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxo-N- (4- ((2- (pyridin-4-yloxy) phenyl) carbamoyl) benzyl) isoindoline-5-carboxamide
The synthesis method of example 56 was the same as that of example 1. 1 H NMR(400MHz，CD 3 OD)，8.32(s，1H)，8.30(dd，J＝8.0Hz，1.6Hz，1H)，7.99(d，J＝8.0Hz，1H)，7.82(d，J＝7.6Hz，2H)，7.78(d，J＝7.6Hz，2H)，7.53-7.63(m，4H)，7.47(d，J＝8.4Hz，2H)，6.43(d，J＝7.6Hz，2H)，5.17(dd，J＝12.8Hz，5.2Hz，1H)，4.65(s，2H)，2.83-2.89(m，1H)，2.71-2.78(m，2H)，2.10-2.19(m，1H)。
Example 57: n- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -4- (2- (furyl-2-yl) -6- (4-nitrophenyl) pyridin-4-yl) benzamide
The compound of example 49 was prepared by synthesis of general procedure a starting from compound 57-1. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，9.37(t，J＝6.0Hz，1H)，8.58(d，J＝8.4Hz，2H)，8.35-8.37(m，3H)，8.15(d，J＝8.4Hz，2H)，8.11(s，1H)，8.08(d，J＝8.4Hz，2H)，7.92(d，J＝1.6Hz，1H)，7.91(d，J＝6.0Hz，1H)，7.85(s，1H)，7.82(d，J＝8.0H b 1H), 7.39 (d, j=3.6 hz, 1H), 6.72 (dd, j=3.2 hz,1.6hz, 1H), 5.12 (dd, j=12.8 hz,5.2hz, 1H), 4.67 (d, j=5.2 hz, 2H), 2.81-2.90 (m, 1H), 2.46-2.65 (m, 2H), 2.01-2.07 (m, 1H).
Example 58:5- (2- (6 '- ((4-chlorobenzyl) oxy) -2' -hydroxy-3 '- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl) - [1,1' -biphenyl ] -4-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
The compound of example 58 was prepared by synthesis of general procedure L, procedure E, procedure M, starting from compound 58-1. 1 H NMR(400MHz，CDCl 3 )，10.40(s，1H)，7.69(d，J＝8.0Hz，1H)，7.42(d，J＝8.4Hz，1H)，7.38(d，J＝7.6Hz，2H)，7.33(d，J＝7.6 1 Hz，2H)，7.24(d，J＝8.4Hz，2H)，7.19(d，J＝2.0Hz，1H)，7.13(d，J＝8.4Hz，2H)，7.07(dd，J＝8.0Hz，2.4Hz，1H)，6.89(s，1H)，6.84(s，1H)，6.58(d，J＝8.8Hz，1H)，5.00(s，2H)，4.93(dd，J＝12.4Hz，5.6Hz，1H)，4.07-4.15(m，2H)，3.96(s，3H)，2.88-2.94(m，3H)，2.64-2.78(m，2H)，2.03-2.10(m，1H)。
Example 59:5- (2- (6 '- ((4-chlorobenzyl) oxy) -2' -hydroxy-3 '- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
The synthesis of example 59 was identical to that of example 58. 1 H NMR(400MHz，CDCl 3 )，8.21(s，1H)，7.76(d，J＝8.0Hz，1H)，7.43(d，J＝8.4Hz，2H)，7.33-7.36(m，3H)，7.14-7.21(m，4H)，7.11(d，J＝8.4Hz，2H)，6.64(d，J＝8.4Hz，1H)，6.51(s，1H)，5.40(s，1H)，5.02(s，2H)，4.93(dd，J＝12.4Hz，5.6Hz，1H)，4.36(t，J＝6.4Hz，2H)，3.81(s，3H)，3.21(t，J＝6.4Hz，2H)，2.66-2.90(m，3H)，2.07-2.16(m，1H)。
Example 60: n- (4- ((2- (9H-carbamoyl-9-yl) acetamido) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 60 was the same as that of example 14. 1 H NMR(400MHz，CDCl 3 )，8.15-8.19(m，2H)，8.09(d，J＝8.0Hz，2H)，7.87(d，J＝8.4Hz，1H)，7.74(s，1H)，7.49(t，J＝7.6Hz，2H)，7.37(d，J＝8.4Hz，2H)，7.29(t，J＝7.6Hz，2H)，7.18(d，J＝8.0Hz，2H)，7.01(d，J＝8.0Hz，2H)，6.67(t，J＝5.6Hz，1H)，6.11(t，J＝5.6Hz，1H)，4.98(s，2H)，4.92(dd，J＝12.8Hz，5.2Hz，1H)，4.54(d，J＝5.2Hz，2H)，4.30-4.40(m，2H)，2.59-2.84(m，3H)，2.08-2.15(m，1H)。
Example 61: n- (4- ((2- (1H-pyrrolo [2,3-b ] pyridin-1-yl) acetamido) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 61 was the same as that of example 14. 1 H NMR(400MHz，CDCl 3 )，8.40(s，1H)，8.26(dd，J＝8.8Hz，1.2Hz，1H)，8.18-8.21(m，2H)，7.91(dd，J＝8.0Hz，1.6Hz，1H)，7.83(d，J＝8.4Hz，1H)，7.24-7.26(m，1H)，7.20(d，J＝8.0Hz，2H)，7.04-7.10(m，4H)，6.84(t，J＝5.6Hz，1H)，6.51(d，J＝7.6Hz，1H)，4.96(s，2H)，4.94(dd，J＝12.4Hz，5.6Hz，1H)，4.55(d，J＝5.2Hz，2H)，4.34(d，J＝6.0Hz，2H)，2.65-2.90(m，3H)，2.10-2.16(m，1H)。
Example 62: n- (4- ((2- (1H-indol-1-yl) acetamido) methyl) benzyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxamide
The synthesis method of example 62 was identical to that of example 14. 1 H NMR(400MHz，CDCl 3 )，8.16-8.20(m，2H)，7.93(s，1H)，7.84(d，J＝8.0Hz，1H)，7.62(d，J＝8.0Hz，1H)，7.23-7.29(m，2H)，7.21(d，J＝7.6Hz，2H)，7.15(t，J＝7.6Hz，1H)，7.06(d，J＝2.8Hz，1H)，7.03(d，J＝8.0Hz，2H)，6.90-6.96(br，1H)，6.57(d，J＝3.6Hz，1H)，5.89(t，J＝6.0Hz，1H)，4.92(dd，J＝12.4Hz，5.6Hz，1H)，4.83(s，2H)，4.55(d，J＝5.6Hz，2H)，4.31-4.33(m，2H)，2.62-2.86(m，3H)，2.07-2.14(m，1H)。
Example 63:2- (2, 6-dioxopiperidin-3-yl) -N- (4- (1- (4-methoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) benzyl) -1, 3-dioxoisoindoline-5-carboxamide
To a solution of compound 42-1 (0.25 g) and glacial acetic acid (0.3 mL) in methanol (10 mL) at room temperature was added compound 63-1 (330 mg). The reaction solution was stirred at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give compound 63-2 (210 mg).
The compound of example 23 was prepared by the following methods, method B and method A, starting from compound 63-2. 1 H NMR(400MHz，CDCl 3 )，8.38(s，1H)，8.22-8.25(m，2H)，7.85(d，J＝8.4Hz，1H)，7.75(d，J＝7.2Hz，1H)，7.66(t，J＝6.0Hz，1H)，7.48(d，J＝8.0Hz，2H)，7.29(td，J＝7.6Hz，1.6Hz，1H)，7.24(td，J＝7.6Hz，1.2Hz，1H)，7.16-7.21(m，5H)，6.97(d，J＝8.8Hz，2H)，4.97(dd，J＝12.4Hz，5.2Hz，1H)，4.62(d，J＝5.6Hz，2H)，3.84(s，3H)，2.68-2.92(m，3H)，2.10-2.17(m，1H)。
Example 64:2- (2, 6-dioxopiperidin-3-yl) -5- (((4- (((1- (4-methoxyphenyl) -1H-indazol-3-yl) amino) methyl) benzyl) amino) methyl) isoindoline-1, 3-dione
The compound of example 64 was prepared by synthesis of general procedure O, procedure G, procedure H, starting from compound 35-1. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，7.78-7.88(m，4H)，7.55(d，J＝8.8Hz，1H)，7.51(d，J＝8.8Hz，2H)，7.26-7.39(m，5H)，7.00-7.04(m，3H)，6.89(t，J＝6.0Hz，1H)，5.11(dd，J＝13.2Hz，5.2Hz，1H)，4.49(d，J＝6.0Hz，2H)，3.82(s，2H)，3.75(s，3H)，3.63(s，2H)，2.81-2.90(m，1H)，2.48-2.64(m，2H)，1.98-2.06(m，1H)。
Example 65: n- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4- (2- (furyl-2-yl) -6- (4-nitrophenyl) pyridin-4-yl) benzamide
The compound of example 49 was prepared by synthesis of general procedure a starting from compound 57-1. 1 H NMR(400MHz，DMSO-d 6 )，10.96(s，1H)，9.31(t，J＝6.0Hz，1H)，8.58(d，J＝8.8Hz，2H)，8.35-8.38(m，3H)，8.15(d，J＝8.8Hz，2H)，8.11(d，J＝1.2Hz，1H)，8.08(d，J＝8.8Hz，2H)，7.92(s，1H)，7.69(d，J＝7.6Hz，1H)，7.55(s，1H)，7.47(d，J＝8.8Hz，1H)，7.39(d，J＝3.2Hz，1H)，6.72(dd，J＝3.2Hz，1.6Hz，1H)，5.08(dd，J＝13.2Hz，5.2Hz，1H)，4.62(d，J＝6.0Hz，2H)，4.43(d，J＝17.6Hz，1H)，4.29(d，J＝17.6Hz，1H)，2.84-2.92(m，1H)，2.52-2.60(m，1H)，2.32-2.41(m，1H)，1.94-2.00(m，1H)。
Example 66:2- (2, 6-Dioxohexahydropyridin-3-yl) -1, 3-dioxo-N- { [4- ({ [2- (pyrido [2,3-b ] indol-9-yl) acetyl ] amino } methyl) phenyl ] methyl } -2, 3-dihydro-1H-isoindole-5-carboxamide
The synthesis method of example 66 was identical to that of example 14. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.40(t，J＝5.6Hz，1H)，8.71(t，J＝6.0Hz，1H)，8.51(d，J＝7.2Hz，1H)，8.41(dd，J＝5.6Hz，2.0Hz，1H)，8.36(s，1H)，8.33(d，J＝8.0Hz，1H)，8.17(d，J＝8.0Hz，1H)，8.01(d，J＝7.6Hz，1H)，7.53(d，J＝7.6Hz，1H)，7.46(t，J＝7.6Hz，1H)，7.20-7.28(m，6H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，5.13(s，2H)，4.46(d，J＝5.6Hz，2H)，4.25(d，J＝5.6Hz，2H)，2.82-2.92(m，1H)，2.46-2.62(m，2H)，2.02-2.09(m，1H)。
Example 67:2- (2, 6-Dioxon-hexahydropyridin-3-yl) -N- [ (4- { [3- (4-methoxyphenyl) -2-thioxo-benzo [ d ] imidazol-1-yl ] methyl } phenyl) methyl ] -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
To a solution of compound 41-2 (300 mg) in tetrahydrofuran (5 mL) were added thiophosgene (80. Mu.L) and triethylamine (0.3 mL), and the reaction solution was heated to reflux and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 3:1) to obtain compound 67-1 (176 mg).
The compound 67 was prepared by the general synthetic method B and method A in this order starting from the compound 67-1. 1 H NMR(400MHz，CDCl 3 )，8.19-8.21(m，2H)，8.17(s，1H)，7.89(d，J＝8.4Hz，1H)，7.38-7.43(m，4H)，7.29(d，J＝8.0Hz，2H)，7.10-7.18(m，3H)，7.05-7.09(m，2H)，6.94-6.96(m，1H)，6.80(t，J＝5.6Hz，1H)，5.61(s，2H)，4.96(dd，J＝12.8Hz，5.6Hz，1H)，4.59(d，J＝5.2Hz，2H)，3.87(s，3H)，2.68-2.90(m，3H)，2.11-2.17(m，1H)。
Example 68:2- (2, 6-Dioxon-3-yl) -N- { [4- ({ [7- (4-methoxyphenyl) -1H-indazol-3-yl ] amino } methyl) phenyl ] methyl } -1, 3-dioxon-2, 3-dihydro-1H-isoindole-5-carboxamide
The compound of example 68 was prepared starting from compound 68-1 by the synthesis of general procedure L, procedure H and procedure a in sequence. 1 H NMR(400MHz，CD 3 OD)，8.27(s，1H)，8.25(d，J＝8.0Hz，1H)，7.93-7.97(m，1H)，7.62(d，J＝8.0Hz，1H)，7.56(d，J＝8.8Hz，2H)，7.42(d，J＝8.0Hz，2H)，7.32(d，J＝8.4Hz，2H)，7.28(d，J＝7.2Hz，1H)，7.01-7.04(m，3H)，5.15(dd，J＝12.8Hz，5.6Hz，1H)，4.56(d，J＝4.4Hz，4H)，3.83(s，3H)，2.66-2.88(m，3H)，2.09-2.16(m，1H)。
Example 69:2- (2, 6-Dioxy-hexahydropyridin-3-yl) -N- { [4- ({ [4- (4-methoxyphenyl) isoquinolin-1-yl ] amino } methyl) phenyl ] methyl } -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
To a solution of compound 69-1 (300 mg) in DMF (5 mL) was added ({ [4- (aminomethyl) phenyl ] methyl } amino) carboxylic acid 2-methylpropan-2-yl ester (380 mg) and cesium carbonate (604 mg). The reaction was heated to 90 ℃ and stirred overnight. The reaction solution was poured into water (20 mL), and extracted with ethyl acetate (30 mL. Times.3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 5:1) to give compound 69-2 (310 mg).
The compound of example 69 was obtained by synthesis using compound 69-2 as starting material, followed by synthesis of general procedure L, procedure B and procedure a. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，9.45(t，J＝5.6Hz，1H)，8.50-8.70(m，1H)，8.35(s，1H)，8.31(dd，J＝7.6Hz，1.6Hz，1H)，8.01(d，J＝7.6Hz，1H)，7.68-7.92(m，3H)，7.52(s，1H)，7.32-7.38(m，6H)，7.06(d，J＝8.8Hz，2H)，5.16(dd，J＝12.8Hz，5.2Hz，1H)，4.81(d，J＝5.2Hz，2H)，4.47(d，J＝5.6Hz，2H)，3.79(s，3H)，2.82-2.91(m，1H)，2.50-2.64(m，2H)，2.01-2.08(m，1H)。
Example 70: n- [ (4- { [3- (2, 3-dichlorophenyl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl ] methyl } phenyl) methyl ] -2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
The synthesis method of example 70 was identical to that of example 14. 1 H NMR(400MHz，CD 3 OD)，8.30(s，1H)，8.27(dd，J＝7.6Hz，1.6Hz，1H)，7.95-7.97(m，1H)，7.63(dd，J＝8.4Hz，1.6Hz，1H)，7.51(dd，J＝7.6Hz，1.6Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.31-7.36(m，4H)，7.03(s，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.72(s，2H)，4.57(s，2H)，2.67-2.88(m，3H)，2.10-2.18(m，1H)。
Example 71:2- (2, 6-Dioxon-3-yl) -N- { [4- ({ [5- (4-methoxyphenyl) -1, 3-thiazapentan-2-yl ] amino } methyl) phenyl ] methyl } -1, 3-dioxon-2, 3-dihydro-1H-isoindole-5-carboxamide
The compound of example 71 was prepared by general synthesis method H, method L, method B and method a in that order starting from compound 71-1. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.27(s，1H)，8.24(d，J＝7.6Hz，1H)，7.90(d，J＝7.6Hz，1H)，7.29-7.33(m，4H)，7.25(d，J＝8.8Hz，2H)，7.12(s，1H)，6.83(d，J＝8.8Hz，2H)，4.98-5.03(m，1H)，4.55(s，2H)，4.42(s，2H)，3.76(s，3H)，2.70-2.84(m，3H)，2.09-2.18(m，1H)。
Example 72:4- {5- [3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxy-3- [ 1-methyl-3- (trifluoromethyl) pyrazol-5-yl ] phenyl } -N- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } benzamide
Compound 72-2 was prepared by general compound synthesis method L starting from compound 72-1.
To a solution of compound 72-2 (509 mg) in methylene chloride (20 mL) were added morpholine (678 mg) and elemental iodine (825 mg), and the reaction solution was stirred at room temperature overnight. Ethyl acetate (60 mL) was added to the reaction solution. The organic phase was washed with saturated sodium thiosulfate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 72-3 (622 mg).
Compound 72-4 was obtained by the general compound synthesis method L using compound 72-3 as a raw material.
To a solution of compound 72-4 (200 mg) in ethanol (10 mL) was added sodium hydroxide (100 mg), and the mixture was heated to reflux and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, water was then added to the residue, the pH of the reaction solution was adjusted to 3 with 1N hydrochloric acid, the mixture was extracted with ethyl acetate (30 mL. Times.3), the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 72-5.
To combine withCompound 72-5 was prepared by general compound synthesis method a starting material to give compound of example 72. 1 H NMR(400MHz，CDCl 3 )，8.07(s，2H)，7.90-7.93(m，4H)，7.77(d，J＝7.6Hz，1H)，7.64-7.67(m，3H)，7.53(d，J＝2.4Hz，1H)，7.48(s，1H)，7.43(d，J＝8.0Hz，1H)，6.74(t，J＝5.6Hz，1H)，6.71(s，1H)，5.75(s，1H)，5.15(dd，J＝13.6Hz，5.6Hz，1H)，4.70-4.81(m，2H)，4.44(d，J＝16.4Hz，1H)，4.30(d，J＝16.4Hz，1H)，3.90(s，3H)，2.78-2.93(m，2H)，2.27-2.37(m，1H)，2.15-2.21(m，1H).
Example 73:4- {5- [3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxy-3- [ 1-methyl-3- (trifluoromethyl) pyrazol-5-yl ] phenyl } -N- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } benzamide
The synthesis of the compound of example 73 was identical to that of example 72. 1 H NMR(400MHz，CDCl 3 )，8.10(s，1H)，8.07(s，2H)，7.91(s，1H)，7.89(d，J＝8.4Hz，2H)，7.82(s，1H)，7.80(d，J＝7.6Hz，1H)，7.72(d，J＝7.6Hz，1H)，7.67(d，J＝2.4Hz，1H)，7.65(d，J＝8.4Hz，2H)，7.53(d，J＝2.4Hz，1H)，6.82(t，J＝6.0Hz，1H)，6.71(s，1H)，5.80(s，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.77(d，J＝5.6Hz，2H)，3.90(s，3H)，2.67-2.90(m，3H)，2.10-2.16(m，1H)。
Example 74: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- { 4-hydroxy-3- [ 1-methyl-3- (trifluoromethyl) pyrazol-5-yl ] -5- (4-nitrophenyl) phenyl } benzamide
EXAMPLE 74 Synthesis of CompoundsThe procedure was the same as for the synthesis of the compound of example 72. 1 H NMR(400MHz，CDCl 3 )，8.36(d，J＝7.6Hz，2H)，7.99(s，1H)，7.90(d，J＝8.4Hz，2H)，7.84-7.86(m，2H)，7.75-7.80(m，3H)，7.65-7.68(m，3H)，7.54(d，J＝2.4Hz，1H)，6.71(t，J＝6.0Hz，1H)，6.70(s，1H)，5.61(s，1H)，4.96(dd，J＝12.4Hz，5.6Hz，1H)，4.81(d，J＝6.4Hz，2H)，3.91(s，3H)，2.69-2.93(m，3H)，2.12-2.18(m，1H)。
Example 75: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [3- (furan-2-yl) -4-hydroxy-5- (4-nitrophenyl) phenyl ] benzamide
The synthesis of the compound of example 75 was identical to that of example 72. 1 H NMR(400MHz，CDCl 3 )，8.32(d，J＝8.4Hz，2H)，7.98(s，1H)，7.83-7.91(m，5H)，7.76-7.81(m，3H)，7.69(d，J＝8.0Hz，2H)，7.58(d，J＝2.0Hz，1H)，7.48(d，J＝2.0Hz，1H)，7.41-7.45(brs，1H)，6.85(d，J＝3.2Hz，1H)，6.72(t，J＝6.4Hz，1H)，6.61(dd，J＝3.2Hz，1.6Hz，1H)，4.97(dd，J＝12.4Hz，5.6Hz，1H)，4.82(d，J＝5.6Hz，2H)，2.70-2.93(m，3H)，2.12-2.18(m，1H)。
Example 76: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- {6- [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] -2- (4-nitrophenyl) pyridin-4-yl } benzamide
Compound 76-1 (2.0 g) and compound 76-2 (1.7 g) were dissolved in methanol (50 mL), and an 8% aqueous potassium hydroxide (10 mL) solution was added. The reaction mixture was stirred at room temperature for 48 hours, resulting in a large amount of yellow solid precipitate. The yellow precipitate was filtered and washed with an appropriate amount of water, and recrystallized from methanol to obtain compound 76-3 (2.6 g).
To a solution of compound 76-3 (2.6 g) and compound 76-4 (2.48 g) in DMF (30 mL) were added glacial acetic acid (20 mL) and ammonium acetate (17.8 g). The reaction solution was heated to 100 ℃ and reacted overnight. The reaction solution was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate solution (30 mL) was added to the residue, followed by extraction with ethyl acetate (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 76-5 (3.1 g).
To a methanol/water solution (20 mL/20 mL) of compound 76-5 (3.1 g) was added lithium hydroxide (1 g), and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was concentrated, water (20 mL) was added to the residue, and the pH thereof was adjusted to 3 with 1N hydrochloric acid, and extracted with ethyl acetate (30 ml×3). The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to give compound 76-6 (2.1 g).
The compound of example 76 was prepared by general synthesis method a starting from compound 76-6. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，9.38(t，J＝5.6Hz，1H)，8.58(d，J＝8.8Hz，2H)，8.54(s，1H)，8.36-8.39(m，3H)，8.24(d，J＝8.0Hz，2H)，8.10(d，J＝8.4Hz，2H)，7.90(d，J＝8.0Hz，1H)，7.86(s，1H)，7.83(d，J＝8.0Hz，1H)，7.70(s，1H)，5.12(dd，J＝12.8Hz，5.2Hz，1H)，4.68(d，J＝6.0Hz，2H)，4.38(s，3H)，2.42-2.61(m，3H)，2.01-2.06(m，1H)。
Example 77: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [6- (2-methylpyrazol-3-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
Method for the Synthesis of Compound of example 77The synthesis was identical to that of the compound of example 76. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，9.38(t，J＝6.4Hz，1H)，8.57(d，J＝8.8Hz，2H)，8.45(s，1H)，8.37(d，J＝9.2Hz，2H)，8.18-8.21(m，3H)，8.09(d，J＝8.4Hz，2H)，7.90(d，J＝7.6Hz，1H)，7.85(s，1H)，7.82(d，J＝8.4Hz，1H)，7.54(d，J＝2.0Hz，1H)，7.12(d，J＝2.0Hz，1H)，5.12(dd，J＝12.8Hz，5.2Hz，1H)，4.68(d，J＝6.0Hz，2H)，4.28(s，3H)，2.40-2.61(m，3H)，2.00-2.06(m，1H)。
Example 78:2- (2, 6-dioxo-hexahydropyridin-3-yl) -N- ({ 4- [ ({ 2-hydroxy-3- [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] phenyl } amino) methyl ] phenyl } methyl) -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
The compound 78 was synthesized by general synthetic method H, method L, method B and method A in this order starting from compound 78-1. 1 H NMR(400MHz，CD 3 OD)，8.30(d，J＝1.6Hz，1H)，8.28(dd，J＝7.6Hz，1.6Hz，1H)，7.95-7.97(m，1H)，7.31-7.36(m，4H)，7.65(d，J＝7.6Hz，1H)，6.57-6.61(m，1H)，6.44-6.52(m，2H)，5.47(s，3H)，5.16(dd，J＝12.8Hz，5.2Hz，1H)，4.57(s，2H)，4.32(s，2H)，2.66-2.92(m，3H)，2.10-2.18(m，1H)。
Example 79: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyrimidin-4-yl ] benzamide
To an isopropanol solution (20 mL) of compound 79-2 (1.06 g) was added sodium metal (270 mg), and the reaction solution was then heated to reflux and reacted for 2h. To the reaction solution was added compound 79-1 (3.0 g) and the reaction was refluxed overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1). Compound 79-3 (1.5 g) is obtained.
To a methanol/water solution (10 mL/10 mL) of compound 79-3 (1.2 g) was added lithium hydroxide (0.2 g), and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was concentrated, water (20 mL) was added to the residue, and the pH thereof was adjusted to 3 with 1N hydrochloric acid, and extracted with ethyl acetate (20 ml×3). The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to give compound 79-4 (2.1 g).
The compound of example 79 was synthesized by general synthesis method A starting from 79-4. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.53(d，J＝9.2Hz，2H)，8.39-8.43(m，4H)，8.30(s，1H)，8.07(d，J＝8.8Hz，2H)，7.90(s，1H)，7.82-7.87(m，2H)，7.75(s，1H)，7.54(d，J＝2.8Hz，1H)，6.66(dd，J＝3.2Hz，1.6Hz，1H)，5.05-5.09(m，1H)，4.75(d，J＝5.6Hz，2H)，2.71-2.84(m，3H)，2.08-2.16(m，1H)。
Example 80: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -3-oxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 80 was identical to that of example 57. 1 H NMR(400MHz，DMSO-d 6 )，10.96(s，1H)，9.30(t，J＝6.0Hz，1H)，8.58(d，J＝8.8Hz，2H)，8.35-8.38(m，3H)，8.15(d，J＝8.8Hz，2H)，8.11(d，J＝1.2Hz，1H)，8.08(d，J＝8.4Hz，2H)，7.93(s，1H)，7.68(s，1H)，7.61(dd，J＝8.0Hz，1.2Hz，1H)，7.56(d，J＝8.0Hz，1H)，7.40(d，J＝3.2Hz，1H)，6.72(dd，J＝3.2Hz，1.6Hz，1H)，5.09(dd，J＝13.2Hz，5.2Hz，1H)，4.61(d，J＝6.0Hz，2H)，4.42(d，J＝17.6Hz，1H)，4.29(d，J＝17.6Hz，1H)，2.83-2.93(m，1H)，2.35-2.43(m，1H)，2.54-2.61(m，1H)，1.93-2.01(m，1H)。
Example 81: n- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 81 was the same as that of the compound of example 57. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，10.96(s，1H)，8.60(d，J＝8.4Hz，2H)，8.44(d，J＝1.6Hz，1H)，8.37-8.39(m，3H)，8.18-8.25(m，5H)，8.15(d，J＝1.2Hz，1H)，7.92-7.95(m，1H)，7.41(d，J＝3.2Hz，1H)，6.74(dd，J＝3.2Hz，1.6Hz，1H)，5.13(dd，J＝12.8Hz，5.6Hz，1H)，2.83-2.93(m，1H)，2.48-2.63(m，3H)，2.01-2.10(m，1H)。
Example 82:2- (2, 6-Dioxy-hexahydropyridin-3-yl) -N- {4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] -2- [ (trifluoromethyl) oxy ] phenyl } -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
The synthesis of the compound of example 82 was identical to that of example 76. 1 H NMR(400MHz，DMSO-d 6 )，11.16(s，1H)，10.82(s，1H)，8.60(d，J＝8.8Hz，2H)，8.47(s，1H)，8.36-8.43(m，4H)，8.20(s，1H)，8.10-8.16(m，3H)，7.91-7.94(m，2H)，7.41(d，J＝3.6Hz，1H)，6.73(dd，J＝3.2Hz，1.6Hz，1H)，5.21(dd，J＝12.8Hz，4.8Hz，1H)，2.84-2.94(m，1H)，2.50-2.66(m，2H)，2.04-2.12(m，1H)。
Example 83:2- (2, 6-Dioxon-hexahydropyridin-3-yl) -N- {4- [2- (furan-2-yl) -6- (example 83:2- (2, 6-Dioxon-idin-3-yl) -N- { [4- ({ 4- [ 1-methyl-3- (trifluoromethyl) pyrazol-5-yl ] benzo [ d ] imidazol-1-yl } methyl) phenyl ] methyl } -1, 3-dioxon-2, 3-dihydro-1H-isoindole-5-carboxamide
Using 83-1 as raw material, and getting compound 83-3 through general synthetic method C and method K.
A solution of compound 83-3 (500 mg) in triethyl orthoformate (12 mL) and glacial acetic acid (2 mL) was heated to 60℃and stirred for 3 hours. The reaction solution was poured into ethyl acetate (50 mL), and washed with water (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate=5:1 to 2:1) to obtain compound 83-4 (420 mg).
The compound 83 was prepared from compound 83-4 by the general synthetic method L, method B and method a in that order. 1 H NMR(400MHz，CDCl 3 )，8.25(s，1H)，8.20(d，J＝7.6Hz，1H)，8.16(s，1H)，8.01(s，1H)，7.89(d，J＝7.6Hz，1H)，7.39(d，J＝7.6Hz，1H)，7.30-7.34(m，3H)，7.25-7.27(m，1H)，7.19(d，J＝8.0Hz，2H)，6.88(t，J＝5.6Hz，1H)，6.73(s，1H)，5.39(s，2H)，4.96(dd，J＝12.4Hz，5.2Hz，1H)，4.62(d，J＝5.2Hz，2H)，3.92(s，3H)，2.67-2.90(m，3H)，2.10-2.16(m，1H)。
Example 84: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyrimidin-4-yl ] benzamide
The synthesis of the compound of example 84 was identical to that of example 79. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，9.41(t，J＝5.6Hz，1H)，8.81(d，J＝8.8Hz，2H)，8.53(d，J＝8.4Hz，2H)，8.41(d，J＝8.8Hz，2H)，8.37(s，1H)，8.11(d，J＝8.4Hz，2H)，8.07(d，J＝2.0Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.87(s，1H)，7.84(d，J＝8.0Hz，1H)，7.72(d，J＝3.6Hz，1H)，6.82(dd，J＝3.6Hz，1.6Hz，1H)，5.13(dd，J＝12.8Hz，5.6Hz，1H)，4.68(d，J＝6.0Hz，2H)，2.82-2.91(m，1H)，2.47-2.62(m，2H)，1.99-2.08(m，1H)。
Example 85: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] -2- [ (trifluoromethyl) oxy ] benzenesulfonamide
To a concentrated hydrochloric acid (10 mL) solution of compound 85-1 (400 mg) was slowly added dropwise a water (2 mL) solution of sodium nitrite (100 mg) under ice bath. Subsequently, cuprous chloride (40 mg) was added to the reaction solution, and a saturated sulfur dioxide acetic acid solution (10 mL) was added dropwise at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was poured into an ice-water mixture, filtered and dried to obtain a crude product (314 mg) of compound 85-2.
To a solution of crude pyridine (5 mL) of the above compound 85-2 (314 mg) was added compound 85-3 (220 mg), and the reaction solution was heated to 90℃under microwaves and reacted for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to obtain the compound of example 85 (103 mg). 1 H NMR(400MHz，DMSO-d 6 )，11.06(s，1H)，8.79(t，J＝5.6Hz，1H)，8.56(d，J＝8.8Hz，2H)，8.38(d，J＝8.4Hz，2H)，8.28(s，1H)，8.09(d，J＝8.0Hz，1H)，8.01-8.05(m，2H)，7.94-7.98(m，2H)，7.80(d，J＝7.2Hz，1H)，7.71-7.75(m，2H)，7.40(d，J＝3.6Hz，1H)，6.74(dd，J＝3.6Hz，1.6Hz，1H)，5.02(dd，J＝12.8Hz，5.2Hz，1H)，4.38(d，J＝5.6Hz，2H)，2.71-2.82(m，1H)，2.30-2.54(m，2H)，1.78-1.86(m，1H)。
Example 86:2- (2, 6-Dioxypyridin-3-yl) -5- (4- { [4- ({ 4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] phenyl } carbonyl) piperazin-1-yl ] methyl } hexahydropyridin-1-yl) isoindole-1, 3-dione
The compound of example 86 was prepared starting from compound 86-1 by the general synthetic method C, method B and method A in that order. 1 H NMR(400MHz，DMSO-d 6 )，11.05(s，1H)，8.58(d，J＝8.4Hz，2H)，8.36(d，J＝8.8Hz，2H)，8.34(s，1H)，8.07-8.09(m，3H)，7.92(d，J＝1.6Hz，1H)，7.62(d，J＝8.4Hz，1H)，7.56(d，J＝8.4Hz，2H)，7.39(d，J＝3.6Hz，1H)，7.28(d，J＝2.0Hz，1H)，7.20(dd，J＝8.8Hz，2.0Hz，1H)，6.72(dd，J＝3.2Hz，1.6Hz，1H)，5.04(dd，J＝12.8Hz，5.2Hz，1H)，3.98-4.06(m，2H)，3.58-3.70(m，2H)，3.32-3.43(m，2H)，2.81-2.98(m，3H)，2.29-2.59(m，6H)，2.17(d，J＝6.4Hz，2H)，1.92-2.02(m，1H)，1.74-1.88(m，3H)，1.07-1.19(m，2H)。
Example 87:2- (2, 6-Dioxy-hexahydropyridin-3-yl) -N- {4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] phenyl } -1, 3-dioxo-2, 3-dihydro-1H-isoindole-5-carboxamide
The synthesis of the compound of example 87 was identical to that of example 76. 1 H NMR(400MHz，DMSO-d 6 )，11.15(s，1H)，10.80(s，1H)，8.58(d，J＝8.8Hz，2H)，8.52(s，1H)，8.45(d，J＝8.0Hz，1H)，8.36(d，J＝8.4Hz，2H)，8.32(s，1H)，8.06-8.11(m，4H)，8.01(d，J＝8.8Hz，2H)，7.92(d，J＝1.6Hz，1H)，7.37(d，J＝3.6Hz，1H)，6.72(dd，J＝3.6Hz，1.6Hz，1H)，5.21(dd，J＝12.8Hz，5.2Hz，1H)，2.84-2.94(m，1H)，2.50-2.65(m，2H)，2.05-2.13(m，1H)。
Example 88: n- ({ 4- [ ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) methyl ] phenyl } methyl) -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The compound of example 88 was prepared by the general synthetic procedure A, method B, method A, starting from compound 57-1. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.43(t，J＝6.0Hz，1H)，9.18(t，J＝6.8Hz，1H)，8.58(d，J＝8.4Hz，2H)，8.32-8.38(m，5H)，8.13(d，J＝8.4Hz，2H)，8.11(s，1H)，8.06(d，J＝8.4Hz，2H)，8.01(d，J＝7.6Hz，1H)，7.93(s，1H)，7.30(s，4H)7.40(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，4.48(d，J＝5.6Hz，4H)，2.8(m，1H)，2.36-2.62(m，2H)，2.02-2.08(m，1H)。
Example 89:4- [2, 6-bis (furan-2-yl) pyridin-4-yl ] -N- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -2- [ (trifluoromethyl) oxy ] benzamide
The synthesis of the compound of example 89 was identical to the synthesis of the compound of example 76. 1 H NMR(400MHz，CDCl 3 )，8.19(d，J＝8.0Hz，1H)，7.96(s，1H)，7.87-7.89(m，2H)，7.77-7.82(m，2H)，7.73(s，2H)，7.64-7.66(m，1H)，7.57(d，J＝1.6Hz，2H)，7.22(d，J＝3.6Hz，2H)，7.11(t，J＝5.6Hz，1H)，6.57(dd，J＝3.6Hz，1.6Hz，2H)，4.98(dd，J＝12.4Hz，5.6Hz，1H)，4.84(d，J＝6.4Hz，2H)，2.70-2.93(m，3H)，2.13-2.18(m，1H)。
Example 90:4- [6- (4-aminophenyl) -2- (furan-2-yl) pyridin-4-yl ] -N- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -2- [ (trifluoromethyl) oxy ] benzamide
The synthesis of the compound of example 90 was identical to that of example 76. 1 H NMR(400MHz，CDCl 3 )，8.14(d，J＝8.4Hz，1H)，8.06(s，1H)，7.96(d，J＝8.4Hz，2H)，7.86-7.88(m，2H)，7.75-7.80(m，2H)，7.69(d，J＝1.2Hz，1H)，7.60-7.63(m，2H)，7.56(s，1H)，7.23(d，J＝3.2Hz，1H)，7.14(t，J＝6.0Hz，1H)，6.78(d，J＝8.8Hz，2H)，6.57(dd，J＝3.2Hz，1.6Hz，1H)，4.98(dd，J＝12.4Hz，5.6Hz，1H)，4.82(d，J＝6.0Hz，2H)，3.82-4.05(brs，2H)，2.68-2.94(m，3H)，2.12-2.18(m，1H)。
Example 91:4- [ ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -3-oxo-2, 3-dihydro-1H-pyrrolo [4,3-c ] pyridin-6-yl ] carbonyl } amino) methyl ] -N-phenylbenzamide methoxybenzene
In 3atm carbon monoxide, compound 91-1 (8 g), pd (dppf) Cl 2 (1g) And triethylamine (5 mL) in methanol (30 mL) were heated to 100 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 3:1) to obtain compound 91-2 (5.1 g).
A solution of compound 91-2 (1.83 g), NBS (1.5 g) and BPO (0.2 g) in carbon tetrachloride (50 mL) was heated to reflux under stirring overnight under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 3:1) to give compound 91-3 (1.78 g).
A solution of compound 91-3 (1.2 g), 91-4 (684 mg) and triethylamine (1 mL) in DMF (10 mL) was heated to 100deg.C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 10:1) to obtain compound 91-5 (572 mg).
To a solution of compound 91-5 (180 mg) in water (2 mL) under ice bath was added dropwise 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred under ice bath cooling for 30 minutes. The pH of the reaction system was then adjusted to 3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure, and the crude residue 91-6 was used in the next reaction without purification.
The compound of example 91 was prepared by general synthesis method a starting from 91-6 crude. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.99(s，1H)，8.30(s，1H)，8.24(d，J＝7.6Hz，1H)，7.78(d，J＝8.0Hz，2H)，7.44(d，J＝8.4Hz，2H)，7.00-7.09(m，2H)，6.95(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，2H)，6.78(d，J＝8.0Hz，1H)，5.12(dd，J＝13.2Hz，5.2Hz，1H)，4.68(s，2H)，4.52-4.63(m，2H)，3.75(s，3H)，2.81-2.85(m，2H)，2.36-2.48(m，1H)，2.15-2.21(m，1H)。
Example 92: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] -2- [ (trifluoromethyl) oxy ] benzamide
The synthesis of the compound of example 92 was identical to that of example 76. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.29(s，4H)，7.78-7.87(m，7H)，7.68(s，1H)，7.60(s，1H)，7.22(d，J＝3.6Hz，1H)，6.57(dd，J＝3.2Hz，1.6Hz，1H)，5.00-5.05(m，1H)，4.71(s，2H)，2.69-2.81(m，3H)，2.10-2.15(m，1H)。
Example 93: n- {4- [ ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) methyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 93 was identical to that of the compound of example 88. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，9.36(s，1H)，8.52(t，J＝5.6Hz，1H)，8.20-8.29(m，6H)，8.00(d，J＝8.0Hz，2H)，7.88(s，1H)，7.84(d，J＝8.0Hz，2H)，7.79(s，1H)，7.77(d，J＝8.0Hz，2H)，7.54-7.58(m，3H)，7.27(d，J＝8.0Hz，2H)，7.20(d，J＝3.6Hz，1H)，6.54(dd，J＝3.6Hz，1.6Hz，1H)，4.91-4.95(m，1H)，4.52(d，J＝5.6Hz，2H)，2.68-2.82(m，3H)，2.06-2.11(m，1H)。
Example 94: n- (2- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } ethyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The compound of example 94 was prepared by general synthesis method a starting from compound 57-1. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.33-8.39(m，4H)，8.01(d，J＝1.6Hz，1H)，7.99(d，J＝1.6Hz，1H)，7.95(d，J＝8.4Hz，2H)，7.88(d，J＝8.0Hz，2H)，7.65(d，J＝1.6Hz，1H)，7.54(d，J＝8.0Hz，1H)，7.27(d，J＝2.8Hz，1H)，7.05(d，J＝2.0Hz，1H)，6.88(dd，J＝8.4Hz，2.4Hz，1H)，6.60(dd，J＝3.2Hz，1.6Hz，1H)，4.93-4.98(m，1H)，3.66(t，J＝6.4Hz，2H)，3.51(t，J＝6.4Hz，2H)，2.67-2.78(m，3H)，2.04-2.08(m，1H)。
Example 95:4- (2- {4- [4- ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] piperazin-1-yl } methyl) hexahydropyridin-1-yl ] phenyl } -6- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
To a solution of compound 95-1 (200 mg), 95-2 (164 mg) and anhydrous cesium carbonate (600 mg) in dioxane (5 mL) under nitrogen protection was added RuPhos Pd G3 catalyst (100 mg). The reaction solution was heated to 100 ℃ and stirred overnight, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 30:1) to give compound 95-3 (180 mg).
To a methanol/water (2 mL/2 mL) solution of compound 95-3 (180 mg) was added LiOH (50 mg), and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product of the residual compound 95-4 was used in the next reaction without purification.
To a solution of crude compound 95-4 in DMF (5 mL) was added ammonium chloride (200 mg), DIEA (0.2 mL) and HATU (150 mg) in this order, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to obtain compound 95-5 (125 mg).
To a solution of compound 95-5 (125 mg) in methanol (5 mL) was added palladium on charcoal catalyst (20 mg), and the reaction mixture was stirred overnight at room temperature in hydrogen, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 95-6, which was used in the next reaction without further purification.
The compound of example 95 was prepared by general synthesis method C starting from compound 95-6. 1 H NMR(400MHz，DMSO-d 6 )，11.06(s，1H)，8.13(d，J＝8.8Hz，2H)，8.10(s，1H)，7.99-8.05(m，5H)，7.87(s，1H)，7.85(s，1H)，7.66(d，J＝8.4Hz，1H)，7.46(s，1H)，7.32(s，1H)，7.28(d，J＝3.2Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.03(d，J＝8.8Hz，2H)，6.68(dd，J＝3.2Hz，1.6Hz，1H)，5.05(dd，J＝12.8Hz，5.2Hz，1H)，3.80-3.88(m，2H)，3.38-3.47(m，4H)，2.72-2.90(m，3H)，2.42-2.60(m，6H)，2.21(d，J＝6.8Hz，2H)，1.93-2.04(m，1H)，1.70-1.86(m，3H)，1.14-1.29(m，2H)。
Example 96:4- (2- {4- [4- ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -6-fluoro-1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] piperazin-1-yl } methyl) hexahydropyridin-1-yl ] phenyl } -6- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The synthesis of the compound of example 96 was the same as that of example 95. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.13(d，J＝9.2Hz，2H)，8.10(s，1H)，8.00-8.04(m，5H)，7.87(s，1H)，7.85(s，1H)，7.71(d，J＝11.6Hz，1H)，7.42-7.47(m，2H)，7.28(d，J＝3.6Hz，1H)，7.03(d，J＝8.4Hz，2H)，6.68(dd，J＝3.2Hz，1.6Hz，1H)，5.08(dd，J＝12.8Hz，5.6Hz，1H)，3.80-3.88(m，2H)，3.20-3.28(m，4H)，2.72-2.91(m，3H)，2.43-2.60(m，6H)，2.22(d，J＝6.4Hz，2H)，1.96-2.03(m，1H)，1.70-1.86(m，3H)，1.16-1.29(m，2H)。
Example 97:4- [2- (4- {4- [ (4- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } piperazin-1-yl) methyl ] hexahydropyridin-1-yl } phenyl) -6- (furan-2-yl) pyridin-4-yl ] benzene-1-carboxamide
The compound of example 97 was prepared by general synthesis method a starting from compound 95-6. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，8.13(d，J＝8.8Hz，2H)，8.10(s，1H)，8.00-8.04(m，5H)，7.97(d，J＝7.2Hz，1H)，7.83-7.89(m，4H)，7.46(s，1H)，7.27(d，J＝3.6Hz，1H)，7.02(d，J＝9.2Hz，2H)，6.68(dd，J＝3.2Hz，1.6Hz，1H)，5.16(dd，J＝12.8Hz，5.2Hz，1H)，3.79-3.86(m，2H)，3.60-3.69(m，2H)，3.25-3.31(m，2H)，2.82-2.92(m，1H)，2.70-2.79(m，2H)，2.28-2.62(m，6H)，2.19(d，J＝7.6Hz，2H)，2.01-2.08(m，1H)，1.67-1.84(m，3H)，1.16-1.27(m，2H)。
Example 98: n- (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 98 was identical to that of example 94. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.27-8.33(m，4H)，7.91-7.93(m，3H)，7.86(d，J＝1.6Hz，1H)，7.79(d，J＝8.4Hz，2H)，7.75(t，J＝6.0Hz，1H)，7.57(d，J＝1.6Hz，1H)，7.52(d，J＝8.8Hz，1H)，7.23(d，J＝3.2Hz，1H)，6.91(d，J＝2.0Hz，1H)，6.71(dd，J＝8.8Hz，2.4Hz，1H)，6.57(dd，J＝3.6Hz，1.6Hz，1H)，4.84-4.88(m，1H)，3.41(q，J＝6.4Hz，2H)，3.16(t，J＝7.2Hz，2H)，2.66-2.79(m，3H)，2.02-2.07(m，1H)，1.60-1.67(m，4H)，1.37-1.50(m，4H).
Example 99: n- (4- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 99 was identical to that of example 94. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.33-8.39(m，4H)，8.10(d，J＝1.6Hz，1H)，7.99(d，J＝1.6Hz，1H)，7.95(d，J＝8.4Hz，2H)，7.88(d，J＝8.4Hz，2H)，7.64(d，J＝2.0Hz，1H)，7.54(d，J＝8.0Hz，1H)，7.27(d，J＝2.8Hz，1H)，7.05(d，J＝2.0Hz，1H)，6.88(dd，J＝8.4Hz，2.4Hz，1H)，6.60(dd，J＝3.2Hz，1.6Hz，1H)，4.95(d，J＝11.6Hz，4.8Hz，1H)，3.66(t，J＝6.4Hz，2H)，3.51(t，J＝6.4Hz，2H)，2.64-2.78(m，3H)，2.04-2.08(m，1H)，1.20-1.32(m，4H)。
Example 100: n- (4- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } butyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 100 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.36(d，J＝8.8Hz，2H)，8.32(d，J＝8.8Hz，2H)，7.90-7.95(m，4H)，7.85(d，J＝1.2Hz，1H)，7.80(d，J＝8.4Hz，2H)，7.59-7.60(m，1H)，7.46-7.51(m，1H)，7.27(d，J＝3.6Hz，1H)，7.09(d，J＝7.2Hz，1H)，6.90(d，J＝8.0Hz，1H)，6.60(dd，J＝3.2Hz，1.6Hz，1H)，6.26(t，J＝5.6Hz，2H)，4.91(dd，J＝12.8Hz，5.2Hz，1H)，3.52-3.60(m，2H)，3.34-3.40(m，2H)，2.68-2.91(m，3H)，2.10-2.15(m，1H)，1.76-1.83(m，4H).
Example 101: n- (2- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } ethyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 101 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.69(s，1H)，8.28(d，J＝8.8Hz，2H)，8.24(d，J＝8.8Hz，2H)，7.86-7.90(m，3H)，7.78(s，1H)，7.72(d，J＝8.8Hz，2H)，7.55(s，1H)，7.35-7.39(m，1H)，7.25-7.39(m，1H)，7.22(d，J＝3.2Hz，1H)，6.94-6.97(m，2H)，6.56(dd，J＝3.2Hz，1.6Hz，1H)，6.45(t，J＝5.6Hz，1H)，4.89(dd，J＝11.6Hz，5.2Hz，1H)，3.62-3.72(m，2H)，3.50-3.60(m，2H)，2.65-2.84(m，3H)，2.04-2.10(m，1H)。
Example 102: n- (8- { [2- (2, 6-Dioxon-3-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 102 was identical to that of example 94. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.31-8.36(m，4H)，7.94-7.98(m，4H)，7.85(d，J＝8.4Hz，2H)，7.61(s，1H)，7.51(d，J＝8.8Hz，1H)，7.25(d，J＝3.6Hz，1H)，6.92(d，J＝2.0Hz，1H)，6.74(dd，J＝8.8Hz，2.0Hz，1H)，6.59(dd，J＝3.6Hz，2.0Hz，1H)，4.88-4.93(m，1H)，3.39(t，J＝7.2Hz，2H)，3.16(t，J＝7.2Hz，2H)，2.67-2.77(m，3H)，2.02-2.09(m，1H)，1.53-1.68(m，6H)，1.22-1.44(m，6H)。
Example 103:2- (2, 6-Dioxypyridin-3-yl) -5- [ (4- { [1- ({ 4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] phenyl } carbonyl) hexahydropyridin-4-yl ] methyl } piperazin-1-yl) carbonyl ] isoindole-1, 3-dione
The compound of example 103 was prepared starting from compound 57-1 by the general synthetic method A, method B, method A in this order. 1H NMR (400 MHz, DMSO-d 6), 11.12 (s, 1H), 8.58 (d, J=8.8 Hz, 2H), 8.36 (d, J=8.8 Hz, 2H), 8.34 (s, 1H), 8.05-8.08 (m, 3H), 7.97 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.39 (d, J=3.6 Hz, 1H), 6.71-6.73 (m, 1H), 5.16 (dd, J=12.8 Hz,5.2Hz, 1H), 4.41-4.52 (m, 1H), 3.52-3.70 (m, 3H), 3.21-3.31 (m, 2H), 2.98 (m, 2H), 2.12.52-3.12.6 Hz, 2H), 7.38 (d, 2.12.12H), 2.32 (m, 2H), 2.32 (2H), 2.38-2.12.32 (m, 2H), 2.38 (2.32H).
Example 104: n- [2- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) ethyl ] -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The compound of example 104 was prepared from compound 57-1 as starting material by general synthetic method A, method B, method A in this order. 1H NMR (400 MHz, DMSO-d 6), 11.13 (s, 1H), 9.13 (s, 1H), 8.78 (s, 1H), 8.58 (d, J=8.8 Hz, 2H), 8.30-8.37 (m, 5H), 8.10-8.13 (m, 3H), 8.00-8.03 (m, 3H), 7.92 (s, 1H), 7.39 (d, J=3.6 Hz, 1H), 6.72 (dd, J=3.2 Hz,1.6Hz, 1H), 5.17 (dd, J=12.8 Hz,5.2Hz, 1H), 3.45-3.55 (m, 4H), 2.82-2.92 (m, 1H), 2.49-2.63 (m, 2H), 2.02-2.10 (m, 1H).
Example 105: n- {10- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -10-oxo-9-aza-3, 6-dioxadec-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 105 was identical to that of example 104. 1 H NMR(400MHz，CDCl 3 )，8.93(s，1H)，8.24-8.32(m，4H)，8.12-8.17(m，2H)，7.87(d，J＝8.4Hz，2H)，7.85(s，1H)，7.80(s，1H)，7.76(d，J＝7.6Hz，1H)，7.71(d，J＝8.4Hz，2H)，7.56(s，1H)，7.34(t，J＝4.8Hz，1H)，7.23(d，J＝3.2Hz，1H)，7.00(t，J＝4.8Hz，1H)，6.57(dd，J＝3.2Hz，1.6Hz，1H)，4.93-4.97(m，1H)，3.60-3.76(m，12H)，2.66-2.87(m，3H)，2.08-2.14(m，1H)。
Example 106: n- {4- [ ({ 5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] pent-4-ynyl } amino) carbonyl ] phenyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The compound 106 was prepared by using the compound 106-1 as a raw material and sequentially passing through a general synthesis method A, a general synthesis method B and a general synthesis method A. 1H NMR (400 MHz, DMSO-d 6), 11.11 (s, 1H), 10.55 (s, 1H), 8.60 (d, J=8.0 Hz, 2H), 8.34-8.51 (m, 4H), 8.11-8.25 (m, 5H), 7.78-7.96 (m, 8H), 7.41 (s, 1H), 6.74 (s, 1H), 5.09-5.17 (m, 1H), 3.36-3.47 (m, 2H), 2.78-2.92 (m, 1H), 2.38-2.64 (m, 4H), 1.98-2.06 (m, 1H), 1.78-1.90 (m, 2H).
Example 107: n- {4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] but-3-ynyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 107 was identical to that of example 94. 1H NMR (400 MHz, DMSO-d 6), 11.11 (s, 1H), 8.94 (t, J=5.6 Hz, 1H), 8.58 (d, J=8.8 Hz, 2H), 8.35-8.38 (m, 3H), 8.14 (d, J=8.8 Hz, 2H), 8.11 (s, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.92 (d, J=1.6 Hz, 1H), 7.83-7.89 (m, 3H), 7.39 (d, J=3.6 Hz, 1H), 6.72 (dd, J=3.2 Hz,1.6Hz, 1H), 5.12 (dd, J=12.8 Hz,5.2Hz, 1H), 3.56 (q, J=6.0 Hz, 2H), 2.67-2.90 (m, 3H), 2.34-2.61 (m, 2.1H), 1.99 m-2.1H.
Example 108: n- {4- [ ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] but-3-ynyl } amino) carbonyl ] phenyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 108 was identical to that of example 106. 1H NMR (400 MHz, DMSO-d 6), 11.11 (s, 1H), 10.58 (s, 1H), 8.66-8.73 (m, 1H), 8.60 (d, J=8.4 Hz, 2H), 8.36-8.40 (m, 3H), 8.21 (d, J=8.4 Hz, 2H), 8.13-8.18 (m, 3H), 7.83-7.94 (m, 8H), 7.42 (s, 1H), 6.73 (s, 1H), 5.10-5.16 (m, 1H), 3.48-3.56 (m, 2H), 2.80-2.92 (m, 1H), 2.75 (t, J=6.0 Hz, 2H), 2.46-2.61 (m, 2H), 2.00-2.08 (m, 1H).
Example 109: n- {5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] pent-4-ynyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 109 was identical to that of example 94. 1H NMR (400 MHz, DMSO-d 6), 11.10 (s, 1H), 8.71 (t, J=5.6 Hz, 1H), 8.58 (d, J=8.8 Hz, 2H), 8.33-8.38 (m, 3H), 8.08-8.13 (m, 3H), 8.03 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80-7.83 (m, 2H), 7.39 (d, J=3.2 Hz, 1H), 6.72-6.73 (m, 1H), 5.10 (dd, J=12.8 Hz,5.2Hz, 1H), 3.46 (q, J=6.0 Hz, 2H), 2.80-2.90 (m, 1H), 2.38-2.60 (m, 4H), 1.94-2.94 (m, 1.83, 1H), 1.83 (m-2H).
Example 110: n- (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } hexyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 110 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.26-8.34(m，5H)，7.89-7.93(m，3H)，7.81(d，J＝1.2Hz，1H)，7.76(d，J＝8.0Hz，2H)，7.57(s，1H)，7.43-7.47(m，1H)，7.24(d，J＝3.6Hz，1H)，7.04(d，J＝7.2Hz，1H)，6.84(d，J＝8.4Hz，1H)，6.58(dd，J＝3.6Hz，1.6Hz，1H)，6.40(t，J＝5.6Hz，1H)，6.21(t，J＝5.6Hz，1H)，4.87-4.91(m，1H)，3.48(q，J＝6.8Hz，2H)，3.25(q，J＝6.8Hz，2H)，2.65-2.88(m，3H)，2.06-2.14(m，1H)，1.62-1.72(m，4H)，1.40-1.53(m，4H)。
Example 111: n- (10- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } decyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 111 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.33(d，J＝8.8Hz，2H)，8.28(d，J＝8.8Hz，2H)，8.23(s，1H)，7.90-7.92(m，3H)，7.82(d，J＝1.2Hz，1H)，7.78(d，J＝8.0Hz，2H)，7.57-7.58(m，1H)，7.43-7.48(m，1H)，7.24-7.26(m，1H)，7.05(d，J＝7.2Hz，1H)，6.85(d，J＝8.8Hz，1H)，6.58(dd，J＝3.6Hz，1.6Hz，1H)，6.31(t，J＝6.0Hz，1H)，6.20(t，J＝5.6Hz，1H)，4.87-4.91(m，1H)，3.47(q，J＝6.4Hz，2H)，3.23(q，J＝6.8Hz，2H)，2.66-2.88(m，3H)，2.08-2.13(m，1H)，1.60-1.68(m，4H)，1.27-1.43(m，12H)。
Example 112: n- (8- { [2- (2, 6-Dioxon-3-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } octyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 112 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.36(d，J＝8.8Hz，2H)，8.31(d，J＝8.8Hz，2H)，8.05(s，1H)，7.91-7.94(m，3H)，7.85(d，J＝1.2Hz，1H)，7.80(d，J＝8.4Hz，2H)，7.59(d，J＝1.6Hz，1H)，7.46-7.50(m，1H)，7.27(d，J＝3.6Hz，1H)，7.07(d，J＝6.8Hz，1H)，6.87(d，J＝8.4Hz，1H)，6.60(dd，J＝3.6Hz，1.6Hz，1H)，6.20-6.25(m，2H)，4.90(dd，J＝12.0Hz，5.6Hz，1H)，3.49(q，J＝6.8Hz，2H)，3.26(q，J＝6.8Hz，2H)，2.66-2.90(m，3H)，2.09-2.15(m，1H)，1.60-1.70(m，4H)，1.34-1.46(m，8H)。
Example 113: n- (10- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } decyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 113 was identical to that of example 94. 1 H NMR(400MHz，CDCl 3 )，8.36(d，J＝8.8Hz，2H)，8.31(d，J＝8.8Hz，2H)，7.90-7.95(m，4H)，7.85(d，J＝1.2Hz，1H)，7.81(d，J＝8.0Hz，2H)，7.58-7.61(m，2H)，7.27(d，J＝3.6Hz，1H)，6.95(d，J＝2.0Hz，1H)，6.72(dd，J＝8.4Hz，2.0Hz，1H)，6.60(dd，J＝3.2Hz，2.0Hz，1H)，6.17-6.22(m，1H)，4.91(dd，J＝12.0Hz，5.2Hz，1H)，4.48-4.57(m，1H)，3.49(q，J＝6.8Hz，2H)，3.18-3.24(m，2H)，2.66-2.90(m，3H)，2.08-2.14(m，1H)，1.61-1.69(m，4H)，1.22-1.45(m，12H)。
Example 114: n- (4- { [ (4- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } butyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 114 was identical to that of example 106. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.33-8.38(m，4H)，8.11(d，J＝8.4Hz，2H)，7.99-8.01(m，2H)，7.93(d，J＝8.0Hz，2H)，7.80-7.83(m，4H)，7.63-7.64(m，1H)，7.46-7.50(m，1H)，7.27(d，J＝3.2Hz，1H)，7.02(d，J＝7.2Hz，1H)，6.96(d，J＝8.4Hz，1H)，6.59-6.61(m，1H)，4.95(dd，J＝12.0Hz，5.6Hz，1H)，3.40-3.47(m，2H)，3.32-3.38(m，2H)，2.65-2.80(m，3H)，2.06-2.12(m，1H)，1.71-1.78(m，4H)。
Example 115: n- {5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] pent-4-ynyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 115 was identical to that of example 94. 1H NMR (400 mhz, dmso-d 6), 10.99 (s, 1H), 8.69 (t, j=5.6 hz, 1H), 8.58 (d, j=8.4 hz, 2H), 8.37 (d, j=9.2 hz, 2H), 8.33 (s, 1H), 8.06-8.11 (m, 3H), 8.01 (d, j=8.0 hz, 2H), 7.93 (d, j=1.6 hz, 1H), 7.67 (d, j=7.6 hz, 1H), 7.60 (d, j=8.0 hz, 1H), 7.49 (t, j=7.6 hz, 1H), 7.40 (d, j=3.6 hz, 1H), 6.73 (dd, j=3.2 hz,1.6hz, 1H), 5.14 (ddj=13.2 hz, 5.1 hz), 4.48 (d, j=1.6 hz, 1H), 7.60 (d, j=8.0 hz, 1H), 7.49 (t, j=7.6 hz, 1H), 7.40 (d, j=3.6 hz, 1H), 6.3.6 hz, 1H), 1.14 (d, 1.1H), 4.33 (d, 1.6hz, 1H), 1.4.4 (1H), 1.8.6 hz, 1H).
Example 116: n- [3- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -3-oxon-ropy-l ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The compound 116 was prepared from compound 116-1 by the general synthetic method A, method B, method A in this order. 1 H NMR(400MHz，CDCl 3 )，8.67(s，1H)，8.25-8.34(m，4H)，7.88(s，1H)，7.75-7.82(m，4H)，7.71(d，J＝8.4Hz，2H)，7.65(d，J＝7.2Hz，1H)，7.55-7.59(m，2H)，7.22-7.29(m，2H)，6.90(t，J＝6.0Hz，1H)，6.57-6.60(m，1H)，4.94(dd，J＝12.0Hz，5.2Hz，1H)，4.47-4.58(m，2H)，3.68-3.75(m，2H)，2.60-2.88(m，5H)，2.05-2.12(m，1H)。
Example 117: n- {4- [ ({ 5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] pent-4-ynyl } amino) carbonyl ] phenyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 117 was identical to that of example 106. 1H NMR (400 mhz, dmso-d 6), 10.99 (s, 1H), 10.56 (s, 1H), 8.60 (d, j=8.8 hz, 2H), 8.46 (t, j=5.6 hz, 1H), 8.36-8.39 (m, 3H), 8.21 (d, j=8.8 hz, 2H), 8.13-8.18 (m, 3H), 7.93 (s, 1H), 7.84-7.89 (m, 4H), 7.69 (d, j=7.2 hz, 1H), 7.61 (d, j=7.2 hz, 1H), 7.50 (t, j=7.6 hz, 1H), 7.41 (d, j=3.6 hz, 1H), 6.74 (dd, j=3.6 hz, 2.8 hz, 1H), 5.14 (dd, j=13.2 hz, 5.89, 4 hz), 7.84-7.89 (m, 4H), 7.84-7.61 (d, j=7.2 hz, 1H), 7.50 (t, j=7.6 hz, 1H), 7.41 (d, j=3.6 hz, 1H), 6.4 (t, 1H), 6.74 (d, j=3.6 hz, 1H), 1.4 (d, 1H).
Example 118: n- {4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] but-3-ynyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 118 was identical to that of example 94. 1H NMR (400 mhz, dmso-d 6), 11.00 (s, 1H), 8.88 (t, j=5.6hz, 1H), 8.58 (d, j=8.8 hz, 2H), 8.35-8.38 (m, 3H), 8.10-8.13 (m, 3H), 8.03 (d, j=8.8 hz, 2H), 7.92 (s, 1H), 7.68 (d, j=7.2 hz, 1H), 7.62 (d, j=7.6 hz, 1H), 7.50 (t, j=7.6 hz, 1H), 7.39 (d, j=3.6 hz, 1H), 6.72 (dd, j=3.2 hz,1.6hz, 1H), 5.08 (dd, j=13.2 hz,5.2hz, 1H), 4.38 (d, j=17.6 hz, 1H), 4.25 (d, j=7.2 hz, 1H), 7.50 (t, j=7.6 hz, 1H), 7.39 (d, j=3.6 hz, 1H), 7.72 (t, j=3.6 hz, 1H), 6.72 (d, 1H), 1.72 (d, 1H), 1.8.8 hz, 1H).
Example 119: n- {4- [ ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] but-3-ynyl } amino) carbonyl ] phenyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 119 was identical to that of example 106. 1H NMR (400 mhz, dmso-d 6), 10.96 (s, 1H), 10.56 (s, 1H), 8.66 (t, j=5.2 hz, 1H), 8.60 (d, j=8.8 hz, 2H), 8.36-8.40 (m, 3H), 8.21 (d, j=8.8 hz, 2H), 8.13-8.18 (m, 3H), 7.94 (d, j=1.6 hz, 1H), 7.86-7.91 (m, 4H), 7.68 (d, j=7.2 hz, 1H), 7.62 (d, j=7.6 hz, 1H), 7.50 (t, j=7.6 hz, 1H), 7.41 (d, j=3.6 hz, 1H), 6.74 (dd, j=3.2 hz,1.6hz, 1H), 5.06 (dd, j=13.5 hz, 4 hz), 7.86-7.91 (m, 4H), 7.68 (d, j=7.2 hz, 1H), 7.50 (d, j=7.2 hz, 1H), 7.41 (d, j=3.6 hz, 1H), 1.4H), 7.50 (d, 1.6H), 1.6-6 (2 hz, 1H), 1.8.6-2H), 1.6-2 (2H), 1.6-2H (d, 1H), 1.8.6-2 hz (1.6H).
Example 120: n- {5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] pentyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 120 was identical to that of example 94. 1H NMR (400 MHz, DMSO-d 6), 11.09 (s, 1H), 8.55-8.61 (m, 3H), 8.32-8.39 (m, 3H), 8.08-8.13 (m, 3H), 7.99 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.76-7.82 (m, 2H), 7.69 (d, J=6.8 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 6.72 (dd, J=3.2 Hz,1.6Hz, 1H), 5.10 (dd, J=13.2 Hz,5.2Hz, 1H), 3.24-3.30 (m, 2H), 2.75-2.89 (m, 3H), 2.50-2.59 (m, 2H), 1.98-2.04 (m, 1H), 1.52-1.72 (m, 4.2H), 1.29-1.39 (m, 1H).
Example 121: n- {4- [ ({ 5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] pentyl } amino) carbonyl ] phenyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 121 was carried out in the same manner as the synthesis of the compound of example 106. 1H NMR (400 MHz, DMSO-d 6), 11.10 (s, 1H), 10.55 (s, 1H), 8.59 (d, J=8.4 Hz, 2H), 8.32-8.46 (m, 4H), 8.12-8.24 (m, 5H), 7.93 (s, 1H), 7.76-7.89 (m, 6H), 7.69 (d, J=7.6 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 6.70-6.78 (m, 1H), 5.08-5.16 (m, 1H), 3.19-3.28 (m, 2H), 2.74-2.92 (m, 3H), 2.50-2.61 (m, 2H), 1.98-2.08 (m, 1H), 1.50-1.70 (m, 4H), 1.27-1.38 (m, 2H).
Example 122: n- {5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] pentyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 122 was the same as that of example 94. 1H NMR (400 MHz, DMSO-d) 6 )，10.97(s，1H)，8.55-8.62(m，3H)，8.34-8.40(m，3H)，8.08-8.13(m，3H)，7.99(d，J＝8.4Hz，2H)，7.93(s，1H)，7.54(dd，J＝6.4Hz，2.0Hz，1H)，7.42-7.45(m，2H)，7.40(d，J＝3.6Hz，1H)，6.73(dd，J＝3.6Hz，1.6Hz，1H)，5.11(dd，J＝13.2Hz，4.8Hz，1H)，4.46(d，J＝17.2Hz，1H)，4.30(d，J＝17.2Hz，1H)，3.26-3.32(m，2H)，2.83-2.95(m，1H)，2.36-2.66(m，4H)，1.94-2.03(m，1H)，1.55-1.68(m，4H)，1.33-1.42(m，2H).
Example 123: n- (4- { [ (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } hexyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 123 was identical to that of example 106. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.31-8.36(m，4H)，8.10(d，J＝8.4Hz，2H)，7.98(d，J＝1.6Hz，1H)，7.93(d，J＝1.2Hz，1H)，7.89(d，J＝8.4Hz，2H)，7.76-7.81(m，4H)，7.60(s，1H)，7.45-7.47(m，1H)，7.25(d，J＝3.6Hz，1H)，7.02(d，J＝7.2Hz，1H)，6.89(d，J＝8.8Hz，1H)，6.59(dd，J＝3.6Hz，1.6Hz，1H)，4.88-4.92(m，1H)，3.37(t，J＝7.2Hz，2H)，3.26(t，J＝7.2Hz，2H)，2.66-2.81(m，3H)，2.06-2.10(m，1H)，1.58-1.72(m，4H)，1.36-1.50(m，4H).
Example 124: n- (4- { [ (4- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 124 was the same as that of example 106. 1H NMR (400 MHz, CD) 3 OD+CDCl 3 )，8.31-8.35(m，4H)，8.09(d，J＝8.4Hz，2H)，8.04(t，J＝5.2Hz，1H)，7.98(s，1H)，7.94(s，1H)，7.89(d，J＝8.0Hz，2H)，7.76-7.81(m，4H)，7.61(s，1H)，7.50(d，J＝8.8Hz，1H)，7.25(d，J＝3.6Hz，1H)，6.93(d，J＝2.0Hz，1H)，6.74(dd，J＝8.8Hz，2.0Hz，1H)，6.59(dd J＝3.6Hz，1.6HZ，1H)，4.88-4.92(m，1H)，3.38-3.46(m，2H)，3.20-3.26(m，2H)，2.66-2.80(m，3H)，2.04-2.10(m，1H)，1.67-1.76(m，4H)。
Example 125: n- (4- { [ (8- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } octyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 125 was the same as that of example 106. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.30-8.36(m，4H)，8.09(d，J＝8.4Hz，2H)，7.98(s，1H)，7.94(s，1H)，7.85-7.91(m，3H)，7.76-7.82(m，4H)，7.61(s，1H)，7.45-7.49(m，1H)，7.25(d，J＝3.6Hz，1H)，7.01(d，J＝7.2Hz，1H)，6.89(d，J＝8.8Hz，1H)，6.59(dd，J＝3.6Hz，1.6Hz，1H)，6.23(t，J＝5.2Hz，1H)，4.89-4.93(m，1H)，3.36(q，J＝6.8Hz，2H)，3.22-3.27(m，2H)，2.66-2.80(m，3H)，2.05-2.12(m，1H)，1.55-1.70(m，4H)，1.30-1.44(m，8H)。
Example 126: n- (4- { [ (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 126 was identical to that of example 106. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.30-8.36(m，4H)，8.10(d，J＝8.4Hz，2H)，8.02(t，J＝5.6Hz，1H)，7.99(d，J＝1.2Hz，1H)，7.96(d，J＝1.2Hz，1H)，7.90(d，J＝8.8Hz，2H)，7.78-7.81(m，4H)，7.62(s，1H)，7.51(d，J＝8.4Hz，1H)，7.26(d，J＝3.6HZ，1H)，6.91(d，J＝2.0Hz，1H)，6.73(dd，J＝8.4Hz，2.0Hz，1H)，6.58-6.60(m，1H)，4.88-4.93(m，1H)，3.35-3.41(m，2H)，3.17(t，J＝7.2Hz，2H)，2.67-2.80(m，3H)，2.04-2.10(m，1H)，1.59-1.70(m，4H)，1.38-1.50(m，4H)。
Example 127: n- (4- { [ (8- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) amino ] carbonyl } phenyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 127 was the same as that of the compound of example 106。 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.29-8.34(m，4H)，8.08(d，J＝8.0Hz，2H)，7.96(d，J＝1.6Hz，1H)，7.91(d，J＝1.6Hz，1H)，7.87(d，J＝8.8Hz，2H)，7.74-7.79(m，5H)，7.59(d，J＝2.0Hz，1H)，7.51(d，J＝8.0Hz，1H)，7.25(d，J＝3.6Hz，1H)，6.90(d，J＝2.0Hz，1H)，6.71(dd，J＝8.4Hz，2.0Hz，1H)，6.58(dd，J＝3.6Hz，2.0Hz，1H)，4.86-4.91(m，1H)，3.31-3.39(m，2H)，3.14(t，J＝7.2Hz，2H)，2.65-2.79(m，3H)，2.04-2.08(m，1H)，1.53-1.65(m，4H)，1.29-1.43(m，8H)。
Example 128: n- {4- [ ({ 5- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] pentyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 128 was the same as that of example 106. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.57(s，1H)，8.60(d，J＝9.2Hz，2H)，8.36-8.40(m，4H)，8.21(d，J＝8.8Hz，2H)，8.14-8.15(m，3H)，7.94(s，1H)，7.88(d，J＝8.4Hz，2H)，7.83(d，J＝8.8Hz，2H)，7.54(dd，J＝6.4Hz，2.0Hz，1H)，7.40-7.45(m，3H)，6.73-6.74(m，1H)，5.11(dd，J＝13.2Hz，5.2Hz，1H)，4.45(dd，J＝17.6Hz，1H)，4.30(d，J＝17.6Hz，1H)，3.20-3.28(m，2H)，2.86-2.94(m，1H)，2.54-2.65(m，3H)，2.36-2.46(m，1H)，1.96-2.02(m，1H)，1.51-1.66(m，4H)，1.31-1.41(m，2H)。
Example 129: n- {4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] butyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 129 was the same as that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，10.99(s，1H)，8.63(t，J＝5.2Hz，1H)，8.58(d，J＝8.0Hz，2H)，8.35-8.38(m，3H)，8.08-8.13(m，3H)，8.00(d，J＝8.0Hz，2H)，7.93(s，1H)，7.55(d，J＝6.8Hz，1H)，7.42-7.48(m，2H)，7.40(d，J＝3.2Hz，1H)，6.71-6.74(m，1H)，5.11(dd，J＝13.2Hz，4.8Hz，1H)，4.45(d，J＝17.2Hz，1H)，4.29(d，J＝17.2Hz，1H)，3.31-3.38(m，2H)，2.85-2.94(m，1H)，2.67-2.71(m，2H)，2.52-2.59(m，1H)，2.32-2.39(m，1H)，1.93-2.01(m，1H)，1.55-1.70(m，4H)。
Example 130: n- {4- [ ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] butyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 130 was identical to that of example 106. 1 H NMR(400MHz，DMSO-d 6 )，10.97(s，1H)，10.56(s，1H)，8.60(d，J＝9.2Hz，2H)，8.37-8.39(m，4H)，8.21(d，J＝8.8Hz，2H)，8.14-8.16(m，3H)，7.94(s，1H)，7.88(d，J＝8.8Hz，2H)，7.84(d，J＝8.8Hz，2H)，7.53-7.56(m，1H)，7.43-7.48(m，2H)，7.41(d，J＝3.2Hz，1H)，6.72-6.75(m，1H)，5.10(dd，J＝13.2Hz，5.2Hz，1H)，4.44(d，J＝16.8Hz，1H)，4.29(d，J＝16.8Hz，1H)，3.28-3.36(m，2H)，2.85-2.94(m，1H)，2.66-2.69(m，2H)，2.50-2.61(m，1H)，2.32-2.41(m，1H)，1.92-2.00(m，1H)，1.52-1.69(m，4H)。
Example 131: n- {4- [ ({ 4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] butyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 131 was identical to that of example 106. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，10.56(s，1H)，8.61(d，J＝8.4Hz，2H)，8.37-8.39(m，4H)，8.21(d，J＝8.0Hz，2H)，8.12-8.17(m，3H)，7.93(s，1H)，7.79-7.89(m，6H)，7.71(d，J＝8.0Hz，1H)，7.41(d，J＝3.2Hz，1H)，6.72-6.75(m，1H)，5.11(dd，J＝12.8Hz，4.8Hz，1H)，3.24-3.30(m，2H)，2.79-2.81(m，3H)，2.48-2.62(m，2H)，1.99-2.06(m，1H)，1.61-1.71(m，2H)，1.48-1.58(m，2H)。
Example 132: n- {4- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] butyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 132 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，8.62(t，J＝5.6Hz，1H)，8.58(d，J＝8.8Hz，2H)，8.34-8.38(m，3H)，8.08-8.13(m，3H)，8.00(d，J＝8.0Hz，2H)，7.92(s，1H)，7.82(d，J＝7.6Hz，1H)，7.79(s，1H)，7.72(d，J＝8.0Hz，1H)，7.39(d，J＝3.2Hz，1H)，6.72(dd，J＝3.6Hz，1.6Hz，1H)，5.11(dd，J＝12.8Hz，5.2Hz，1H)，3.28-3.36(m，2H)，2.80-2.91(m，3H)，2.45-2.61(m，2H)，1.98-2.06(m，1H)，1.62-1.72(m，2H)，1.50-1.60(m，2H)。
Example 133:4- (6- {4- [ (8- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } -3, 6-dioxaoct-1-yl) oxy ] phenyl } -2- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
Boron tribromide (0.2 mL) was added dropwise to a solution of compound 133-1 (500 mg) in methylene chloride (15 mL) under ice bath, and the reaction mixture was warmed to room temperature and stirred for 20 hours. Methanol (1 mL) was added dropwise to the reaction mixture to quench the reaction. The reaction solution was then concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to obtain compound 133-2 (310 mg).
The compound of example 133 was prepared by general synthesis method M starting from compound 133-2. 1 H NMR(400MHz，DMSO-d 6 )，11.08(s，1H)，8.22(d，J＝8.8Hz，2H)，8.01-8.12(m，6H)，7.91(s，1H)，7.98(s，1H)，7.52-7.56(m，1H)，7.47(s，1H)，7.31(d，J＝2.8Hz，1H)，7.12(d，J＝8.4Hz，1H)，7.04(d，J＝8.4Hz，2H)，6.99(d，J＝6.8Hz，1H)，6.68-6.70(m，1H)，6.59(t，J＝6.0Hz，1H)，5.02(dd，J＝12.8Hz，5.2Hz，1H)，4.12-4.16(m，2H)，3.74-3.78(m，2H)，3.56-3.64(m，6H)，3.45(q，J＝5.6Hz，2H)，2.79-2.88(m，1H)，2.38-2.57(m，2H)，1.94-2.01(m，1H)。
Example 134: n- [9- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -9-oxosubunit nonyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 134 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.35(d，J＝8.8Hz，2H)，8.31(d，J＝8.8Hz，2H)，8.23(s，1H)，7.92(s，1H)，7.87(d，J＝8.4Hz，2H)，7.84(s，1H)，7.72-7.80(m，4H)，7.63(d，J＝8.0Hz，1H)，7.59(s，1H)，7.26(d，J＝3.2Hz，1H)，6.58-6.61(m，1H)，6.48(t，J＝5.6Hz，1H)，6.39(t，J＝5.6Hz，1H)，4.92-4.97(m，1H)，4.55(d，J＝6.4Hz，2H)，3.41-3.46(m，2H)，2.66-2.94(m，3H)，2.28(t，J＝7.6Hz，2H)，2.08-2.15(m，1H)，1.54-1.67(m，6H)，1.29-1.41(m，6H)。
Example 135: n- [10- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -10-oxodec ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 135 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.37(s，1H)，8.33(d，J＝9.2Hz，2H)，8.29(d，J＝9.2Hz，2H)，7.91(d，J＝1.2Hz，1H)，7.88(d，J＝8.0Hz，2H)，7.83(d，J＝1.6Hz，1H)，7.71-7.79(m，4H)，7.62(d，J＝7.6Hz，1H)，7.58(d，J＝1.2Hz，1H)，7.25-7.26(m，1H)，6.59(dd，J＝3.2Hz，1.6Hz，1H)，6.40-6.45(m，2H)，4.92-4.96(m，1H)，4.54(d，J＝6.0Hz，2H)，3.44(q，J＝6.8Hz，2H)，2.66-2.90(m，3H)，2.26(t，J＝7.6Hz，2H)，2.08-2.14(m，1H)，1.54-1.73(m，6H)，1.20-1.46(m，8H)。
Example 136: n- [2- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) ethyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 136 was identical to that of example 104. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.28-8.34(m，5H)，8.25(dd，J＝8.0Hz，1.2Hz，1H)，7.97(d，J＝8.4Hz，2H)，7.91-7.95(m，3H)，7.84(d，J＝8.4Hz，2H)，7.60-7.61(m，1H)，7.23(d，J＝2.8Hz，1H)，6.57-6.58(m，1H)，5.03-5.07(m，1H)，3.67(s，4H)，2.69-2.81(m，3H)，2.10-2.16(m，1H)。
Example 137: n- [4- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) butyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 137 was identical to that of example 104. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.26-8.32(m，5H)，8.24(dd，J＝7.6Hz，1.2Hz，1H)，7.96(d，J＝8.0Hz，2H)，7.92(d，J＝1.6Hz，1H)，7.90(d，J＝7.6Hz，1H)，7.85(d，J＝1.2Hz，1H)，7.79(d，J＝8.4Hz，2H)，7.56-7.58(m，1H)，7.22(d，J＝3.6Hz，1H)，6.56(dd，J＝3.6Hz，2.0Hz，1H)，4.96-5.00(m，1H)，3.42-3.48(m，4H)，2.71-2.83(m，3H)，2.09-2.14(m，1H)，1.66-1.73(m，4H)。
Example 138: n- [6- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) hexyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 138 was identical to that of example 104. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.59(t，J＝5.6Hz，1H)，8.24-8.30(m，6H)，8.21(dd，J＝8.0Hz，2.0Hz，1H)，7.93(d，J＝8.0Hz，2H)，7.86-7.89(m，3H)，7.79(d，J＝8.8Hz，2H)，7.58-7.59(m，1H)，7.20(d，J＝3.2Hz，1H)，6.56(dd，J＝3.6Hz，2.0Hz，1H)，5.01-5.05(m，1H)，3.36-3.44(m，4H)，2.68-2.80(m，3H)，2.08-2.14(m，1H)，1.59-1.71(m，4H)，1.40-1.50(m，4H)。
Example 139: n- [8- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) octyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 139 was the same as that of example 104. 1 H NMR(400MHz，CD 3 OD+CDCl 3 )，8.36(t，J＝5.6Hz，1H)，8.24-8.30(m，4H)，8.23(s，1H)，8.20(d，J＝7.6Hz，1H)，7.90-7.95(m，3H)，7.89(d，J＝1.2Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.84(d，J＝1.2Hz，1H)，7.78(d，J＝8.0Hz，2H)，7.57(s，1H)，7.21(d，J＝3.6Hz，1H)，6.56(dd，J＝3.6Hz，1.6Hz，1H)，4.96-5.01(m，1H)，3.34-3.41(m，4H)，2.68-2.83(m，3H)，2.06-2.16(m，1H)，1.56-1.66(m，4H)，1.31-1.42(m，8H)。
Example 140: n- [10- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) decyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 140 was identical to that of example 104. 1 H NMR(400MHz，CDCl 3 )，8.62-8.69(brs，1H)，8.24-8.30(m，4H)，8.16(dd，J＝7.6Hz，1.2Hz，1H)，8.13(s，1H)，7.85-7.87(m，3H)，7.81(d，J＝7.6Hz，1H)，7.78(d，J＝1.2Hz，1H)，7.72(d，J＝8.4Hz，2H)，7.56(d，J＝1.2Hz，1H)，7.22(d，J＝3.2Hz，1H)，6.99-7.09(brs，1H)，6.52-6.59(m，2H)，4.94-4.99(m，1H)，3.38-3.48(m，4H)，2.66-2.90(m，3H)，2.08-2.15(m，1H)，1.56-1.67(m，4H)，1.21-1.42(m，12H).
Example 141: n- {13- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -13-oxo-12-aza-3, 6, 9-trioxotridelan-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 141 was identical to that of example 104. 1 H NMR(400MHz，CDCl 3 )，8.40(s，1H)，8.30-8.36(m，4H)，8.20-8.23(m，2H)，7.88-7.91(m，3H)，7.83-7.85(m，2H)，7.75(d，J＝8.4Hz，2H)，7.58-7.60(m，1H)，7.30-7.34(brs，1H)，7.27(d，J＝3.2Hz，1H)，6.94(t，J＝5.2Hz，1H)，6.59(dd，J＝3.2Hz，1.6Hz，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.60-3.74(m，16H)，2.67-2.90(m，3H)，2.12-2.18(m，1H)。
Example 142: n- {7- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -7-oxo-6-aza-3-oxahept-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 142 was identical to that of example 104. 1 H NMR(400MHz，CDCl 3 )，8.48(s，1H)，8.27-8.33(m，5H)，8.17(dd，J＝8.0Hz，1.2Hz，1H)，7.85-7.88(m，3H)，7.81(d，J＝1.2Hz，1H)，7.79(d，J＝8.0Hz，1H)，7.72(d，J＝8.0Hz，2H)，7.58-7.59(m，1H)，7.35-7.38(m，1H)，7.26(d，J＝3.6Hz，1H)，6.90(t，J＝5.2Hz，1H)，6.59(dd，J＝3.6Hz，1.6Hz，1H)，4.89-4.93(m，1H)，3.64-3.80(m，8H)，2.62-2.86(m，3H)，2.04-2.19(m，1H)。
Example 143: n- {10- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -8-oxo-9-aza-3, 6-dioxadec-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 143 was carried out in the same manner as that of the compound of example 116. 1 H NMR(400MHz，CDCl 3 )，8.29-8.35(m，5H)，7.90(d，J＝1.2Hz，1H)，7.87(d，J＝8.8Hz，2H)，7.83(d，J＝1.2Hz，1H)，7.73-7.77(m，3H)，7.71(d，J＝8.0Hz，1H)，7.58-7.60(m，2H)，7.51(t，J＝6.4Hz，1H)，7.26(d，J＝3.2Hz，1H)，6.74-6.79(m，1H)，6.59(dd，J＝3.6Hz，1.6Hz，1H)，4.89-4.93(m，1H)，4.57(d，J＝6.4Hz，2H)，4.10(s，2H)，3.62-3.76(m，8H)，2.64-2.88(m，3H)，2.06-2.12(m，1H)。
Example 144:4- {2- [4- ({ 2- [ (2- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] oxy } ethyl) oxy ] ethyl } oxy) phenyl ] -6- (furan-2-yl) pyridin-4-yl } benzene-1-carboxamide
The synthesis of the compound of example 144 was identical to the synthesis of the compound of example 133. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.23(d，J＝8.8Hz，2H)，8.08-8.12(m，2H)，8.01-8.06(m，4H)，7.91(d，J＝1.2Hz，1H)，7.87-7.88(m，1H)，7.80(d，J＝8.0Hz，1H)，7.47(s，1H)，7.45(d，J＝2.0Hz，1H)，7.35(dd，J＝8.4Hz，2.0Hz，1H)，7.31(d，J＝3.2Hz，1H)，7.06(d，J＝8.4Hz，2H)，6.69(dd，J＝3.2Hz，1.6Hz，1H)，5.08(dd，J＝13.2Hz，5.2Hz，1H)，4.33-4.35(m，2H)，4.18-4.21(m，2H)，3.84-3.88(m，4H)，2.80-2.89(m，1H)，2.41-2.58(m，2H)，1.94-2.03(m，1H)。
Example 145:4- (6- {4- [ (8- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] oxy } -3, 6-dioxaoct-1-yl) oxy ] phenyl } -2- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The synthesis of the compound of example 145 was identical to the synthesis of the compound of example 133. 1 H NMR(400MHz，DMSO-d 6 )，11.08(s，1H)，8.23(d，J＝8.4Hz，2H)，8.08-8.12(m，2H)，8.01-8.06(m，4H)，7.91(s，1H)，7.87-7.88(m，1H)，7.78(d，J＝8.4Hz，1H)，7.47(s，1H)，7.43(d，J＝2.4Hz，1H)，7.33(dd，J＝8.0Hz，2.4Hz，1H)，7.30(d，J＝3.2Hz，1H)，7.06(d，J＝9.2Hz，2H)，6.68-6.69(m，1H)，5.08(dd，J＝13.6Hz，5.2Hz，1H)，4.28-4.29(m，2H)，4.15-4.17(m，2H)，3.75-3.79(m，4H)，3.62(s，4H)，2.80-2.89(m，1H)，2.42-2.58(m，2H)，1.96-2.02(m，1H)。
Example 146:4- (2- {4- [ (11- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] oxy } -3,6, 9-trioxaundec-1-yl) oxy ] phenyl } -6- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The synthesis of the compound of example 146 was identical to that of example 133. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.23(d，J＝8.8Hz，2H)，8.11(s，1H)，8.09(s，1H)，8.01-8.06(m，4H)，7.90(s，1H)，7.88(s，1H)，7.77(d，J＝8.0Hz，1H)，7.47(s，1H)，7.41(d，J＝2.0Hz，1H)，7.30-7.33(m，2H)，7.06(d，J＝9.2Hz，2H)，6.67-6.69(m，1H)，5.07(dd，J＝12.8Hz，5.2Hz，1H)，4.25-4.28(m，2H)，4.13-4.16(m，2H)，3.74-3.77(m，4H)，3.52-3.61(m，8H)，2.80-2.89(m，1H)，2.40-2.59(m，2H)，1.93-2.03(m，1H).
Example 147: n- (10- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -10-oxon-dec-yl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 147 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.54(s，1H)，8.28-8.35(m，4H)，8.22(s，1H)，8.07(d，J＝1.6Hz，1H)，8.01(s，1H)，7.82-7.96(m，4H)，7.83(d，J＝1.6Hz，1H)，7.79(d，J＝8.4Hz，2H)，7.73(d，J＝8.0Hz，1H)，7.25-7.26(m，1H)，6.59-6.60(m，1H)，6.41(t，J＝5.6Hz，1H)，4.93(dd，J＝12.4Hz，5.2Hz，1H)，3.49(q，J＝6.8Hz，2H)，2.66-2.90(m，3H)，2.38(t，J＝7.6Hz，2H)，2.08-2.14(m，1H)，1.56-1.78(m，8H)，1.30-1.45(m，6H)。
Example 148: n- {7- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -5-oxo-6-aza-3-oxahept-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 148 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 +CD 3 OD)，8.54(t，J＝6.4Hz，1H)，8.42(t，J＝6.4Hz，1H)，8.34(s，4H)，7.92-7.97(m，4H)，7.83(d，J＝8.4Hz，2H)，7.72-7.76(m，2H)，7.66(d，J＝7.6Hz，1H)，7.61(d，J＝1.2Hz，1H)，7.26(d，J＝2.8Hz，1H)，6.58-6.60(m，1H)，4.91-4.95(m，1H)，4.55(s，2H)，4.07(s，2H)，3.70-3.74(m，2H)，3.64-3.69(m，2H)，2.64-2.78(m，3H)，2.00-2.05(m，1H)。
Example 149: n- (8- { [2- (2, 6-Dioxon-3-ylpyridin-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -8-oxo-3, 6-dioxaoct-1-yl) -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 149 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，9.13(s，1H)，8.49(s，1H)，8.28-8.34(m，4H)，8.04(d，J＝2.0Hz，1H)，7.90(dd，J＝8.4Hz，1.6Hz，1H)，7.88(d，J＝1.6Hz，1H)，7.86(d，J＝8.4Hz，2H)，7.82(d，J＝1.6Hz，1H)，7.71-7.78(m，2H)，7.61(d，J＝8.0Hz，1H)，7.58(s，1H)，7.25-7.16(m，1H)，6.93(t，J＝5.6Hz，1H)，6.58-6.60(m，1H)，4.89(dd，J＝12.0Hz，5.6Hz，1H)，4.14(s，2H)，3.70-3.85(m，8H)，2.63-2.88(m，3H)，2.03-2.09(m，1H)。
Example 150: n- {2- [ (2- { [2- (2, 6-Dioxon-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -2-oxoethyleneethyl) oxy ] ethyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 150 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，9.32(s，1H)，8.28-8.35(m，5H)，8.17(dd，J＝8.4Hz，1.6Hz，1H)，8.06(s，1H)，7.96(d，J＝8.4Hz，2H)，7.92(s，1H)，7.78-7.83(m，4H)，7.58-7.59(m，1H)，7.26(d，J＝3.2Hz，1H)，6.70-6.75(brs，1H)，6.59-6.60(m，1H)，4.93(dd，J＝12.4Hz，5.2Hz，1H)，4.17(s，2H)，3.84(s，4H)，2.67-2.90(m，3H)，2.08-2.14(m，1H)。
Example 151: n- (11- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -11-oxo-3, 6, 9-trioxaundec-1-yl) -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 151 was carried out in the same manner as in example 116. 1 H NMR(400MHz，CDCl 3 )，9.29(s，1H)，8.33-8.38(m，4H)，8.18(dd，J＝8.0Hz，1.2Hz，1H)，8.01(d，J＝1.6Hz，1H)，7.96(s，1H)，7.93(s，1H)，7.86-7.89(m，3H)，7.74-7.77(m，3H)，7.60(s，1H)，7.28(d，J＝3.6Hz，1H)，6.87-6.92(brs，1H)，6.60-6.61(m，1H)，4.91(dd，J＝12.0Hz，4.8Hz，1H)，4.14(s，2H)，3.63-3.80(m，12H)，2.64-2.90(m，3H)，2.08-2.14(m，1H)。
Example 152: n- (4- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) -5- (furan-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The compound of example 152 was prepared by general synthesis method a starting from compound 152-1. 1 H NMR(400MHz，CDCl 3 )，8.03(s，1H)，7.68(d，J＝1.6Hz，1H)，7.67(s，1H)，7.58(d，J＝8.0Hz，1H)，7.35(d，J＝3.6Hz，1H)，7.32(s，1H)，7.28(t，J＝6.0Hz，1H)，6.95(d，J＝2.0Hz，1H)，6.74(dd，J＝8.4Hz，2.0Hz，1H)，6.66(dd，J＝3.6Hz，2.0Hz，1H)，4.89-4.96(m，2H)，3.57(q，J＝6.4Hz，2H)，3.26-3.33(m，2H)，2.66-2.91(m，3H)，2.08-2.14(m，1H)，1.74-1.85(m，4H)。
Example 153: n- (8- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) -5- (furan-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 153 was identical to the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.09(s，1H)，7.67(d，J＝1.6Hz，1H)，7.65(s，1H)，7.57(d，J＝8.4Hz，1H)，7.33(d，J＝4.0Hz，1H)，7.30(s，1H)，7.18(t，J＝6.0Hz，1H)，6.92(d，J＝2.0Hz，1H)，6.71(dd，J＝8.0Hz，2.0Hz，1H)，6.64-6.65(m，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.60(t，J＝5.2Hz，1H)，3.48(q，J＝7.2Hz，2H)，3.15-3.21(m，2H)，2.65-2.90(m，3H)，2.08-2.18(m，1H)，1.59-1.70(m，4H)，1.31-1.45(m，8H)。
Example 154: n- (10- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } decyl) -5- (furan-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 154 was identical to that of example 152. 1 H NMR(400MHz，CDCl 3 )，7.94(s，1H)，7.67(d，J＝1.6Hz，1H)，7.65(s，1H)，7.59(d，J＝8.8Hz，1H)，7.34(d，J＝7.6Hz，1H)，7.30(s，1H)，7.17(t，J＝5.6Hz，1H)，6.94(d，J＝2.0Hz，1H)，6.72(dd，J＝8.0Hz，2.0Hz，1H)，6.64-6.66(m，1H)，4.91(dd，J＝12.0Hz，5.2Hz，1H)，4.52(t，J＝5.6Hz，1H)，3.48(q，J＝7.2Hz，2H)，3.17-3.22(m，2H)，2.68-2.91(m，3H)，2.08-2.14(m，1H)，1.60-1.74(m，4H)，1.28-1.44(m，12H)。
Example 155: n- (2- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } ethyl) -5- (furan-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 155 was carried out in the same manner as the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.00(s，1H)，7.67-7.68(m，2H)，7.59(d，J＝8.4Hz，1H)，7.54(t，J＝6.0Hz，1H)，7.35(d，J＝4.0Hz，1H)，7.32(s，1H)，6.98(d，J＝2.4Hz，1H)，6.80(dd，J＝8.0Hz，2.0Hz，1H)，6.66(dd，J＝3.6Hz，2.0Hz，1H)，5.62(t，J＝4.8Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，3.82(q，J＝6.0Hz，2H)，3.50(q，J＝5.2Hz，2H)，2.66-2.90(m，3H)，2.08-2.14(m，1H)。
Example 156: n- {4- [ ({ 3- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] prop-2-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 156 was identical to that of example 106. 1 H NMR(400MHz，DMSO-d 6 )，11.00(s，1H)，10.60(s，1H)，8.99(t，J＝5.6Hz，1H)，8.60(d，J＝9.2Hz，2H)，8.37-8.39(m，3H)，8.21(d，J＝8.4Hz，2H)，8.14-8.17(m，3H)，7.88-7.94(m，5H)，7.73(d，J＝7.6Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.53(t，J＝7.6Hz，1H)，7.41(d，J＝3.2Hz，1H)，6.73-6.74(m，1H)，5.11-5.15(m，1H)，4.45(d，J＝17.6Hz，1H)，4.37(d，J＝5.6Hz，2H)，4.31(d，J＝17.6Hz，1H)，2.84-2.94(m，1H)，2.29-2.66(m，2H)，1.92-2.02(m，1H)。
Example 157:4- (6- {4- [ (11- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } -3,6, 9-trioxaundec-1-yl) oxy ] phenyl } -2- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The synthesis of the compound of example 157 was identical to the synthesis of the compound of example 133. 1 H NMR(400MHz，DMSO-d 6 )，11.08(s，1H)，8.23(d，J＝8.8Hz，2H)，8.08-8.13(m，2H)，8.01-8.06(m，4H)，7.91(s，1H)，7.88(s，1H)，7.51-7.55(m，1H)，7.47(s，1H)，7.30(d，J＝2.8Hz，1H)，7.10(d，J＝8.8Hz，1H)，7.06(d，J＝9.2Hz，2H)，6.99(d，J＝6.8Hz，1H)，6.68-6.70(m，1H)，6.57(t，J＝6.0Hz，1H)，5.02(dd，J＝13.2Hz，5.2Hz，1H)，4.13-4.15(m，2H)，4.73-4.75(m，2H)，3.49-3.61(m，10H)，3.41-3.45(m，2H)，2.80-2.89(m，1H)，2.39-2.58(m，2H)，1.92-2.00(m，1H)。
Example 158: n- {4- [ ({ 6- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] hex-5-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 158 was identical to the synthesis of the compound of example 106. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.57(s，1H)，8.60(d，J＝8.4Hz，2H)，8.43(t，J＝5.2Hz，1H)，8.36-8.40(m，3H)，8.21(d，J＝8.8Hz，2H)，8.14-8.16(m，3H)，7.94(s，1H)，7.88(d，J＝8.8Hz，2H)，7.84(d，J＝8.8Hz，2H)，7.68(d，J＝7.6Hz，1H)，7.62(d，J＝7.2Hz，1H)，7.50(t，J＝7.6Hz，1H)，7.41(d，J＝3.2Hz，1H)，6.73-6.74(m，1H)，5.11(dd，J＝12.8Hz，5.2Hz，1H)，4.44(d，J＝17.6Hz，1H)，4.30(d，J＝17.6Hz，1H)，3.26-3.34(m，2H)，2.83-2.93(m，1H)，2.38-2.58(m，4H)，1.94-2.01(m，1H)，1.57-1.73(m，4H)。
Example 159: n- (9- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -9-oxon-onyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 159 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.73(s，1H)，8.24-8.37(m，5H)，8.15(s，1H)，8.10(s，1H)，7.90-8.02(m，3H)，7.74-7.87(m，4H)，7.59(s，1H)，7.25-7.28(m，1H)，6.59(s，1H)，6.37(t，J＝5.6Hz，1H)，4.93(dd，J＝12.4Hz，5.2Hz，1H)，3.53(q，J＝6.0Hz，2H)，2.66-2.90(m，3H)，2.41(t，J＝7.6Hz，2H)，2.08-2.15(m，1H)，1.53-1.83(m，8H)，1.34-1.45(m，4H)。
Example 160: n- (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) -5- (furan-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 160 was identical to that of example 152. 1 H NMR(400MHz，CDCl 3 )，7.98(s，1H)，7.67(d，J＝2.0Hz，1H)，7.66(s，1H)，7.58(d，J＝8.0Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.31(s，1H)，7.20(t，J＝6.0Hz，1H)，6.94(d，J＝2.0Hz，1H)，6.73(dd，J＝8.4Hz，2.4Hz，1H)，6.65(dd，J＝3.6Hz，1.6Hz，1H)，4.91(dd，12.8Hz，5.2Hz，1H)，1.68(t，J＝5.6Hz，1H)，3.52(q，J＝7.2Hz，2H)，3.21(q，J＝6.8Hz，2H)，2.67-2.90(m，3H)，2.08-2.14(m，1H)，1.64-1.73(m，4H)，1.41-1.54(m，4H)。
Example 161: n- {3- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] propyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 161 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.63(t，J＝5.6Hz，1H)，8.58(d，J＝8.4Hz，2H)，8.34-8.38(m，3H)，8.09-8.12(m，3H)，7.99(d，J＝8.0Hz，2H)，7.92(s，1H)，7.81-7.83(m，2H)，7.74(d，J＝8.0Hz，1H)，7.39(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.11(dd，J＝12.8Hz，4.8Hz，1H)，3.33(t，J＝7.6Hz，2H)，2.81-2.91(m，3H)，2.50-2.60(m，2H)，1.89-2.04(m，3H)。
Example 162: n- (5- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -5-oxopentyl) -4- [6- (furan-2-yl) -4- (4-nitrophenyl) pyridin-2-yl ] benzamide
The synthesis of the compound of example 162 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.81(s，1H)，8.30-8.36(m，4H)，8.22(s，1H)，8.16(s，1H)，7.95-7.99(m，4H)，7.84-7.86(m，3H)，7.74(d，J＝8.4Hz，1H)，7.59(s，1H)，7.27(d，J＝3.6Hz，1H)，6.66(t，J＝6.0Hz，1H)，6.60-6.61(m，1H)，4.94(dd，J＝12.4Hz，5.2Hz，1H)，3.62(q，J＝6.4Hz，2H)，2.65-2.90(m，3H)，2.57(t，J＝7.2Hz，2H)，2.09-2.14(m，1H)，1.71-1.90(m，4H)。
Example 163: n- (6- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -6-oxon-exyl) -4- [6- (furan-2-yl) -4- (4-nitrophenyl) pyridin-2-yl ] benzamide
The synthesis of the compound of example 163 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.31-8.37(m，4H)，8.15-8.20(m，2H)，8.03(s，1H)，7.92-7.97(m，3H)，7.80-7.90(m，4H)，7.74(d，J＝8.0Hz，1H)，7.60(d，J＝1.2Hz，1H)，7.27(d，J＝3.6Hz，1H)，6.60-6.61(m，1H)，6.49-6.54(m，1H)，4.88(dd，J＝12.4Hz，5.2Hz，1H)，3.56(q，J＝6.8Hz，2H)，2.61-2.88(m，3H)，2.48(t，J＝7.2Hz，2H)，2.02-2.08(m，1H)，1.82-1.90(m，2H)，1.69-1.78(m，2H)，1.48-1.58(m，2H)。
Example 164: n- (7- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -7-oxoheptyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 164 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.49(s，1H)，8.30-8.37(m，4H)，8.15(s，1H)，8.02(dd，J＝8.8Hz，2.0Hz，1H)，7.92-7.98(m，4H)，7.82-7.86(m，3H)，7.79(d，J＝8.4Hz，1H)，7.59(s，1H)，7.28(d，J＝3.6Hz，1H)，6.60-6.61(m，1H)，6.29-6.34(m，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.51-3.56(m，2H)，2.68-2.71(m，3H)，2.43(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.76-1.84(m，2H)，1.65-1.72(m，2H)，1.43-1.52(m，4H)。
Example 165:7- (chlorodifluoromethyl) -N- (2- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } ethyl) -5- (furan-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 165 was the same as that of example 152. 1 H NMR(400MHz，CDCl 3 )，8.03(s，1H)，7.68(d，J＝1.6Hz，1H)，7.63(s，1H)，7.59(d，J＝7.6Hz，1H)，7.56(t，J＝6.8Hz，1H)，7.35(d，J＝3.2Hz，1H)，7.33(s，1H)，6.98(d，J＝2.4Hz，1H)，6.80(dd，J＝8.0Hz，2.0Hz，1H)，6.65-6.66(m，1H)，5.56-5.70(brs，1H)，4.89-4.93(m，1H)，3.81-3.85(m，2H)，3.50(t，J＝5.2Hz，2H)，2.66-2.89(m，3H)，2.08-2.13(m，1H)。
Example 166:7- (chlorodifluoromethyl) -N- (4- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) -5- (furan-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 166 was carried out in the same manner as the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，7.96(s，1H)，7.68(d，J＝1.2Hz，1H)，7.62(s，1H)，7.59(d，J＝8.4Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.33(s，1H)，7.29(t，J＝6.0Hz，1H)，6.96(d，J＝2.0Hz，1H)，6.76(dd，J＝8.0Hz，2.0Hz，1H)，6.65(dd，J＝3.6Hz，2.0Hz，1H)，4.88-4.95(m，2H)，3.59(q，J＝6.8Hz，2H)，3.28-3.34(m，2H)，2.68-2.90(m，3H)，2.08-2.14(m，1H)，1.76-1.84(m，4H)。
Example 167:7- (chlorodifluoromethyl) -N- (6- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) -5- (furan-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 167 was carried out in the same manner as the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，7.91(s，1H)，7.67(d，J＝2.0Hz，1H)，7.61(s，1H)，7.59(d，J＝8.4Hz，1H)，7.34(d，J＝3.6Hz，1H)，7.32(s，1H)，7.22(t，J＝6.4Hz，1H)，6.95(d，J＝2.0Hz，1H)，6.74(dd，J＝8.4Hz，2.0Hz，1H)，6.65(dd，J＝3.6Hz，2.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.64(t，J＝5.2Hz，1H)，3.52(q，J＝6.8Hz，2H)，3.20-3.25(m，2H)，2.70-2.91(m，3H)，2.08-2.14(m，1H)，1.65-1.74(m，4H)，1.43-1.52(m，4H).
Example 168:7- (chlorodifluoromethyl) -N- (8- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) -5- (furan-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 168 was the same as that of example 152. 1 H NMR(400MHz，CDCl 3 )，8.24(s，1H)，7.66(d，J＝1.6Hz，1H)，7.60(s，1H)，7.55(d，J＝8.8Hz，1H)，7.32(d，J＝3.6Hz，1H)，7.30(s，1H)，7.21(t，J＝6.0Hz，1H)，6.91(d，J＝2.0Hz，1H)，6.69(dd，J＝8.4Hz，2.0Hz，1H)，6.63(dd，J＝3.6Hz，2.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.54-4.82(brs，1H)，3.48(q，J＝6.8Hz，2H)，3.16(t，J＝7.2Hz，2H)，2.65-2.89(m，3H)，2.07-2.12(m，1H)，1.57-1.71(m，4H)，1.29-1.45(m，8H)。
Example 169:7- (chlorodifluoromethyl) -N- (10- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } decyl) -5- (furan-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 169 was carried out in the same manner as in the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.05(s，1H)，7.66(d，J＝1.6Hz，1H)，7.60(s，1H)，7.58(d，J＝8.4Hz，1H)，7.32(d，J＝3.6Hz，1H)，7.31(s，1H)，7.20(t，J＝6.0Hz，1H)，6.93(d，J＝2.0Hz，1H)，6.71(dd，J＝8.0Hz，2.0Hz，1H)，6.64(dd，J＝3.2Hz，1.6Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.56-4.61(brs，1H)，3.46-3.51(m，2H)，3.16-3.21(m，2H)，2.68-2.89(m，3H)，2.08-2.13(m，1H)，1.59-1.70(m，4H)，1.26-1.42(m，12H).
Example 170: n- (2- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } ethyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 170 was identical to that of example 152. 1 H NMR(400MHz，CDCl 3 )，8.21(s，1H)，7.74(d，J＝3.6Hz，1H)，7.61(d，J＝4.4Hz，1H)，7.53-7.59(m，3H)，7.27(s，1H)，7.16-7.19(m，1H)，6.96(s，1H)，6.77(d，J＝8.8Hz，1H)，6.64(t，J＝4.4Hz，1H)，4.91(dd，J＝12.0Hz，5.2Hz，1H)，3.77-3.82(m，2H)，3.45-3.51(m，2H)，2.65-2.88(m，3H)，2.07-2.13(m，1H)。
Example 171: n- (4- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 171 was identical to that of example 152. 1 H NMR(400MHz，DMSO-d 6 )，11.03(s，1H)，8.45(t，J＝6.4Hz，1H)，8.31(d，J＝4.0Hz，1H)，8.24(s，1H)，7.90(d，J＝5.2Hz，1H)，7.52(d，J＝8.4Hz，1H)，7.25-7.28(m，1H)，7.17(s，1H)，7.12(t，J＝5.2Hz，1H)，7.92(d，J＝2.0Hz，1H)，6.82(dd，J＝8.4Hz，2.0Hz，1H)，4.99(dd，J＝12.4Hz，5.2HZ，1H)，3.31-3.37(m，2H)，3.16-3.22(m，2H)，2.78-2.88(m，1H)，2.42-2.58(m，2H)，1.92-1.98(m，1H)，1.56-1.68(m，4H)。
Example 172: n- (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 172 was the same as that of example 152. 1 H NMR(400MHz，DMSO-d 6 )，11.03(s，1H)，8.41(t，J＝6.0Hz，1H)，8.31(d，J＝3.6Hz，1H)，8.24(s，1H)，7.90(d，J＝5.2Hz，1H)，7.52(dd，J＝8.8Hz，1H)，7.25-7.28(m，1H)，7.16(s，1H)，7.08(t，J＝5.2Hz，1H)，6.91(d，J＝2.0Hz，1H)，6.81(dd，J＝8.4Hz，2.0Hz，1H)，4.99(dd，J＝12.8Hz，5.2Hz，1H)，3.26-3.33(m，2H)，3.10-3.15(m，2H)，2.80-2.89(m，1H)，2.42-2.58(m，2H)，1.92-2.00(m，1H)，1.51-1.61(m，4H)，1.30-1.44(m，4H)。
Example 173: n- (8- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 173 was the same as that of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.06(s，1H)，7.75(d，J＝3.6Hz，1H)，7.60(d，J＝5.2Hz，1H)，7.57(d，J＝8.0Hz，1H)，7.55(s，1H)，7.28(s，1H)，7.15-7.19(m，2H)，6.92(d，J＝2.0Hz，1H)，6.71(dd，J＝8.4Hz，2.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.59(t，J＝5.2Hz，1H)，3.46-3.51(m，2H)，3.16-3.21(m，2H)，2.68-2.89(m，3H)，2.08-2.13(m，1H)，1.60-1.70(m，4H)，1.32-1.45(m，8H)。
Example 174: n- (10- { [2- (2, 6-Dioxosoxypyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } decyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 174 was the same as that of example 152. 1 H NMR(400MHz，CDCl 3 )，7.97(s，1H)，7.76(d，J＝4.0Hz，1H)，7.58-7.61(m，2H)，7.55(s，1H)，7.29(s，1H)，7.14-7.20(m，2H)，6.94(d，J＝2.0Hz，1H)，6.71(dd，J＝8.4Hz，2.4Hz，1H)，4.91(dd，J＝12.0Hz，5.2Hz，1H)，4.54(t，J＝4.8Hz，1H)，3.46-3.51(m，2H)，3.17-3.22(m，2H)，2.66-2.90(m，3H)，2.08-2.13(m，1H)，1.60-1.70(m，4H)，1.26-1.44(m，12H)。
Example 175:7- (chlorodifluoromethyl) -N- (2- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } ethyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
Synthesis of Compound of example 175 same procedure as that of Compound of example 152The synthesis method is the same. 1 H NMR(400MHz，DMSO-d 6 )，11.07(s，1H)，8.59(t，J＝5.6Hz，1H)，8.34(d，J＝3.2Hz，1H)，8.20(s，1H)，7.93(d，J＝5.2Hz，1H)，7.58(d，J＝8.8Hz，1H)，7.35(t，J＝5.6Hz，1H)，7.28-7.31(m，1H)，7.24(s，1H)，7.07(d，J＝1.6Hz，1H)，6.95(dd，J＝8.4Hz，2.0Hz，1H)，5.04(dd，J＝12.8Hz，5.6Hz，1H)，3.50-3.53(m，2H)，3.40-3.44(m，2H)，2.83-2.92(m，1H)，2.42-2.60(m，2H)，1.96-2.02(m，1H)。
Example 176:7- (chlorodifluoromethyl) -N- (4- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } butyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 176 was the same as that of example 152. 1 H NMR(400MHz，CDCl 3 )，7.90(s，1H)，7.77(d，J＝3.6Hz，1H)，7.59-7.62(m，2H)，7.52(s，1H)，7.31(s，1H)，7.26-7.29(m，1H)，7.18-7.20(m，1H)，6.96(d，J＝2.0Hz，1H)，6.76(dd，J＝8.4Hz，2.0Hz，1H)，4.86-4.93(m，2H)，3.56-3.61(m，2H)，3.29-3.35(m，2H)，2.66-2.90(m，3H)，2.09-2.12(m，1H)，1.77-1.84(m，4H)。
Example 177:7- (chlorodifluoromethyl) -N- (6- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } hexyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 177 was the same as that of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.20(s，1H)，7.75(d，J＝3.6Hz，1H)，7.59(d，J＝5.2Hz，1H)，7.55(d，J＝8.8Hz，1H)，7.51(s，1H)，7.29(s，1H)，7.22(t，J＝6.0Hz，1H)，7.16-7.19(m，1H)，6.91(s，1H)，6.71(d，J＝8.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.65-4.86(brs，1H)，3.49-3.54(m，2H)，3.19(t，J＝6.8Hz，2H)，2.65-2.88(m，3H)，2.07-2.12(m，1H)，1.59-1.76(m，4H)，1.40-1.54(m，4H)。
Example 178:7- (chlorodifluoromethyl) -N- (8- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } octyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 178 was the same as that of example 152. 1 H NMR(400MHz，CDCl 3 )，8.18(s，1H)，7.75(d，J＝4.0Hz，1H)，7.59(d，J＝5.2Hz，1H)，7.56(d，J＝8.4Hz，1H)，7.50(s，1H)，7.29(s，1H)，7.16-7.21(m，2H)，6.91(d，J＝1.6Hz，1H)，6.70(dd，J＝8.4Hz，2.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.52-4.76(brs，1H)，3.46-3.51(m，2H)，3.17(t，J＝7.2Hz，2H)，2.66-2.88(m，3H)，2.07-2.12(m，1H)，1.58-1.70(m，4H)，1.30-1.45(m，8H)。
Example 179:7- (chlorodifluoromethyl) -N- (10- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } decyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 179 was carried out in the same manner as the synthesis of the compound of example 152. 1 H NMR(400MHz，CDCl 3 )，8.14(s，1H)，7.75(d，J＝4.0Hz，1H)，7.59(d，J＝5.2Hz，1H)，7.56(d，J＝8.4Hz，1H)，7.50(s，1H)，7.31(s，1H)，7.16-7.20(m，2H)，6.92(d，J＝2.0Hz，1H)，6.70(dd，J＝8.4Hz，2.0Hz，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，4.51-4.75(brs，1H)，3.46-3.51(m，2H)，3.18(t，J＝7.2Hz，2H)，2.65-2.88(m，3H)，2.07-2.12(m，1H)，1.58-1.69(m，4H)，1.23-1.44(m，12H)。
Example 180: n- [8- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -8-oxon-ctyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 180 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.38(s，1H)，8.29-8.35(m，4H)，7.83-7.90(m，4H)，7.71-7.76(m，4H)，7.58-7.61(m，2H)，7.24-7.26(m，1H)，6.59(s，1H)，6.51-6.56(m，1H)，6.44-6.50(m，1H)，4.90-4.94(m，1H)，4.48-4.60(m，2H)，3.42-3.50(m，2H)，2.66-2.88(m，3H)，2.28(t，J＝7.2Hz，2H)，2.07-2.13(m，1H)，1.56-1.73(m，6H)，1.34-1.44(m，4H)。
Example 181: n- (8- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -8-oxon-ctyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 181 was carried out in the same manner as the synthesis of the compound of example 116. 1 H NMR(400MHz，CDCl 3 )，8.48(s，1H)，8.29-8.36(m，4H)，8.13(s，1H)，8.07(s，1H)，7.89-7.96(m，4H)，7.78-7.83(m，3H)，7.73(d，J＝8.4Hz，1H)，7.59(s，1H)，7.26(d，J＝3.2Hz，1H)，6.59-6.60(m，1H)，6.35(t，J＝5.2Hz，1H)，4.92(dd，J＝12.4Hz，5.2Hz，1H)，3.50-3.55(m，2H)，2.64-2.90(m，3H)，2.41(t，J＝7.6Hz，2H)，2.08-2.13(m，1H)，1.62-1.80(m，4H)，1.37-1.47(m，6H)。
Example 182: n- {13- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] -11-oxo-12-aza-3, 6, 9-trioxotridelan-1-yl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 182 was identical to that of example 116. 1 H NMR(400MHz，CDCl 2 )，8.31-8.36(m，4H)，8.11(s，1H)，7.92-7.95(m，3H)，7.86(d，J＝1.2Hz，1H)，7.76-7.80(m，4H)，7.63-7.69(m，2H)，7.59(s，1H)，7.27(d，J＝3.6Hz，1H)，6.96-7.01(brs，1H)，6.59-6.61(m，1H)，4.93(dd，J＝12.4Hz，5.2Hz，1H)，4.59(d，J＝7.2Hz，2H)，4.10(s，2H)，3.58-3.72(m，12H)，2.66-2.90(m，3H)，2.10-2.15(m，1H)。
Example 183:4- {6- [4- ({ 2- [ (2- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl ] amino } ethyl) oxy ] ethyl } oxy) phenyl ] -2- (furan-2-yl) pyridin-4-yl } benzene-1-carboxamide
The synthesis of the compound of example 183 was carried out in the same manner as the synthesis of the compound of example 133. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.21(d，J＝8.8Hz，2H)，8.08-8.13(m，2H)，8.01-8.07(m，4H)，7.91(d，J＝1.2Hz，1H)，7.88(d，J＝1.2Hz，1H)，7.54-7.58(m，1H)，7.46(s，1H)，7.31(d，J＝3.6Hz，1H)，7.14(d，J＝8.4Hz，1H)，7.06(d，J＝9.2Hz，2H)，7.01(d，J＝7.2Hz，1H)，6.69(dd，J＝3.6Hz，2.0Hz，1H)，6.64(t，J＝6.0Hz，1H)，5.02(dd，J＝12.8Hz，5.2Hz，1H)，4.17-4.19(m，2H)，3.79-3.83(m，2H)，3.70(t，J＝5.2Hz，2H)，3.49(q，J＝5.6Hz，2H)，2.80-2.88(m，1H)，2.42-2.58(m，2H)，1.94-2.03(m，1H)。
Example 184: n- {4- [ ({ 7- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] hept-6-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 184 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.56(s，1H)，8.59(d，J＝8.8Hz，2H)，8.36-8.42(m，4H)，8.21(d，J＝8.8Hz，2H)，8.14-8.16(m，3H)，7.94(s，1H)，7.82-7.88(m，4H)，7.67(d，J＝8.0Hz，1H)，7.58(d，J＝7.2Hz，1H)，7.48(t，J＝7.6Hz，1H)，7.41(d，J＝3.6Hz，1H)，6.73-6.74(m，1H)，5.12(dd，J＝13.6Hz，5.2Hz，1H)，4.43(d，J＝17.6Hz，1H)，4.29(d，J＝17.6Hz，1H)，3.23-3.28(m，2H)，2.83-2.93(m，1H)，2.40-2.60(m，4H)，1.94-2.02(m，1H)，1.42-1.64(m，6H)。
Example 185: n- {7- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] heptyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 185 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.56-8.60(m，3H)，8.34-8.38(m，3H)，8.08-8.12(m，3H)，8.00(d，J＝8.4Hz，2H)，7.92(s，1H)，7.80(d，J＝8.0Hz，1H)，7.74(s，1H)，7.68(d，J＝8.0Hz，1H)，7.39(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.10(dd，J＝12.8Hz，5.2Hz，1H)，3.24-3.30(m，2H)，2.80-2.90(m，1H)，2.76(t，J＝7.6Hz，2H)，2.36-2.60(m，2H)，1.98-2.04(m，1H)，1.48-1.65(m，4H)，1.23-1.36(m，6H)。
Example 186: n- {4- [ ({ 8- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] oct-7-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 186 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.56(s，1H)，8.59(d，J＝8.4Hz，2H)，8.34-8.39(m，4H)，8.21(d，J＝8.4Hz，2H)，8.14-8.16(m，3H)，7.94(s，1H)，7.83-7.89(m，4H)，7.68(d，J＝8.0Hz，1H)，7.61(d，J＝7.6Hz，1H)，7.49(t，J＝7.6Hz，1H)，7.41(d，J＝3.6Hz，1H)，6.73-6.74(m，1H)，5.12(dd，J＝13.6Hz，4.8Hz，1H)，4.43(d，J＝17.6Hz，1H)，4.29(d，J＝17.6Hz，1H)，3.21-3.28(m，2H)，2.83-2.93(m，1H)，2.38-2.59(m，4H)，1.94-2.02(m，1H)，1.31-1.62(m，8H)。
Example 187: n- {8- [2- (2, 6-Dioxon-3-ylpyridin-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] octyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 187 was carried out in the same manner as in the synthesis of the compound of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，8.57-8.60(m，3H)，8.34-8.38(m，3H)，8.09-8.12(m，3H)，8.01(d，J＝8.4Hz，2H)，7.92(s，1H)，7.80(d，J＝8.0Hz，1H)，7.74(s，1H)，7.68(d，J＝7.6Hz，1H)，7.39(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.10(dd，J＝12.4Hz，5.2Hz，1H)，3.23-3.29(m，2H)，2.81-2.90(m，1H)，2.75(t，J＝7.6Hz，2H)，2.41-2.60(m，2H)，1.98-2.04(m，1H)，1.48-1.64(m，4H)，1.23-1.33(m，8H)。
Example 188: n- {4- [ ({ 9- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] non-8-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 188 was the same as that of example 106. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.56(s，1H)，8.60(d，J＝8.8Hz，2H)，8.33-8.39(m，4H)，8.21(d，J＝8.8Hz，2H)，8.14-8.16(m，3H)，7.94(d，J＝1.6Hz，1H)，7.83-7.89(m，4H)，7.68(d，J＝7.6Hz，1H)，7.61(d，J＝7.2Hz，1H)，7.49(t，J＝7.6Hz，1H)，7.41(d，J＝3.2Hz，1H)，6.73-6.74(m，1H)，5.12(dd，J＝13.2Hz，5.2Hz，1H)，4.43(d，J＝17.6Hz，1H)，4.28(d，J＝17.6Hz，1H)，3.20-3.26(m，2H)，2.82-2.93(m，1H)，2.37-2.61(m，4H)，1.94-2.02(m，1H)，1.29-1.60(m，10H).
Example 189: n- {9- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] nonyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 189 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.10(s，1H)，8.57-8.61(m，3H)，8.34-8.38(m，3H)，8.09-8.12(m，3H)，8.01(d，J＝8.0Hz，2H)，7.92(s，1H)，7.79(d，J＝8.0Hz，1H)，7.73(s，1H)，7.67(d，J＝8.0Hz，1H)，7.39(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.10(dd，J＝12.8Hz，5.6Hz，1H)，3.23-3.28(m，2H)，2.80-2.90(m，1H)，2.73(t，J＝7.6Hz，2H)，2.43-2.59(m，2H)，1.97-2.04(m，1H)，1.47-1.63(m，4H)，1.16-1.34(m，10H)。
Example 190: n- {6- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] hexyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 190 was identical to that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.56-8.59(m，3H)，8.34-8.37(m，3H)，8.09-8.12(m，3H)，8.00(d，J＝8.4Hz，2H)，7.92(s，1H)，7.80(d，J＝7.6Hz，1H)，7.75(s，1H)，7.69(d，J＝7.6Hz，1H)，7.39(d，J＝3.2Hz，1H)，6.72-6.73(m，1H)，5.11(dd，J＝12.8Hz，5.2Hz，1H)，3.23-3.29(m，2H)，2.81-2.90(m，1H)，2.77(t，J＝7.2Hz，2H)，2.48-2.60(m，2H)，1.99-2.06(m，1H)，1.48-1.68(m，4H)，1.28-1.39(m，4H)。
Example 191: n- {4- [ ({ 10- [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1-oxo-2, 3-dihydro-1H-isoindol-4-yl ] dec-9-ynyl } amino) carbonyl ] phenyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 191 was carried out in the same manner as the synthesis of the compound of example 106. 1 H NMR(400MHz，DMSO-d 6 )，10.98(s，1H)，10.56(s，1H)，8.60(d，J＝9.2Hz，2H)，8.32-8.39(m，4H)，8.21(d，J＝8.8Hz，2H)，8.14-8.16(m，3H)，7.93(s，1H)，7.83-7.89(m，4H)，7.68(d，J＝7.6Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.49(t，J＝7.6Hz，1H)，7.41(d，J＝3.2Hz，1H)，6.73-6.74(m，1H)，5.12(dd，J＝13.2Hz，5.2Hz，1H)，4.42(d，J＝18.0Hz，1H)，4.28(d，J＝18.0Hz，1H)，3.20-3.25(m，2H)，2.84-2.94(m，1H)，2.38-2.60(m，4H)，1.93-2.01(m，1H)，1.37-1.60(m，6H)，1.26-1.34(m，6H)。
Example 192: n- {10- [2- (2, 6-Dioxon-3-ylpyridin-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] decyl } -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 192 was the same as that of example 94. 1 H NMR(400MHz，DMSO-d 6 )，11.09(s，1H)，8.56-8.60(m，3H)，8.34-8.38(m，3H)，8.09-8.12(m，3H)，8.01(d，J＝8.4Hz，2H)，7.92(s，1H)，7.79(d，J＝8.0Hz，1H)，7.73(s，1H)，7.67(d，J＝8.0Hz，1H)，7.39(d，J＝3.6Hz，1H)，6.72-6.73(m，1H)，5.10(dd，J＝12.8Hz，5.2Hz，1H)，3.23-3.33(m，2H)，2.81-2.90(m，1H)，2.74(t，J＝7.2Hz，2H)，2.32-2.60(m，2H)，1.94-2.04(m，1H)，1.48-1.63(m，4H)，1.18-1.32(m，12H)。
Example 193: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- {4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] phenyl } benzamide
To a solution of compound 193-1 (2.0 g) and compound 76-4 (2.34 g) in DMF (30 mL) was added glacial acetic acid (20 mL) and ammonium acetate (17.0 g). The reaction was heated to 100deg.C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, saturated sodium bicarbonate solution (30 mL) was added to the residue, and extracted with ethyl acetate (30 ml×3), the extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether: ethyl acetate=2:1), to obtain compound 193-2 (1.65 g).
The compound 193 was prepared by the general synthetic procedure L followed by procedure A starting from compound 193-2. 1 H NMR(400MHz，DMSO-d 6 )，11.11(s，1H)，9.31(t，J＝6.0Hz，1H)，8.59(d，J＝8.8Hz，2H)，8.36-8.38(m，3H)，8.15(d，J＝8.0Hz，2H)，8.12(s，1H)，8.03(d，J＝8.0Hz，2H)，7.89-7.95(m，6H)，7.85(s，1H)，7.82(d，J＝8.0Hz，1H)，7.40(d，J＝3.6Hz，1H)，6.73(dd，J＝3.2Hz，1.6Hz，1H)，5.12(dd，J＝12.8Hz，5.2Hz，1H)，4.66(d，J＝5.6Hz，2H)，2.81-2.91(m，1H)，2.50-2.61(m，2H)，2.00-2.06(m，1H)。
Example 194: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -1- {4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] phenyl } hexahydropyridine-4-carboxamide
The compound 193 was prepared by the general synthetic procedure O followed by procedure a starting from compound 193-2. 1 H NMR(400MHz，DMSO-d 6 )，11.11(s，1H)，8.54-8.59(m，3H)，8.35(d，J＝8.8Hz，2H)，8.23(s，1H)，7.98(s，1H)，7.85-7.90(m，4H)，7.75(s，1H)，7.72(d，J＝8.0Hz，1H)，7.34(d，J＝3.2Hz，1H)，7.08(d，J＝8.8Hz，2H)，6.70(dd，J＝3.2Hz，1.6Hz，1H)，5.12(dd，J＝12.8Hz，5.2Hz，1H)，4.43(d，J＝5.6Hz，2H)，3.88-3.95(m，2H)，2.79-2.91(m，3H)，2.40-2.61(m，3H)，2.00-2.07(m，1H)，1.78-1.85(m，2H)，1.62-1.72(m，2H)。
Example 195: n- [ (3Z) -5- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) -2-methylpent-3-enyl ] -4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 195 was the same as that of the compound of example 88. 1 H NMR(400MHz，DMSO-d 6 )，11.14(s，1H)，10.58(s，1H)，9.20(t，J＝6.0Hz，1H)，8.59(d，J＝8.4Hz，2H)，8.47(s，1H)，8.36-8.42(m，4H)，8.05-8.16(m，6H)，7.93(s，1H)，7.75(d，J＝8.8Hz，2H)，7.40(d，J＝3.6Hz，1H)，7.35(d，J＝8.4Hz，2H)，6.72-6.73(m，1H)，5.19(dd，J＝13.2Hz，5.2Hz，1H)，4.50(d，J＝5.6Hz，2H)，2.84-2.93(m，1H)，2.49-2.64(m，2H)，2.04-2.10(m，1H)。
Example 196:4- {6- [4- ({ [2- (2, 6-Dioxon-3-ylpyridin-3-yl) -1, 3-dioxon-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) phenyl ] -2- (furan-2-yl) pyridin-4-yl } benzene-1-carboxamide
The compound 196-1 was prepared by the general synthetic method K and method A in this order, starting from the compound 196-1. 1 H NMR(400MHz，DMSO-d 6 )，11.15(s，1H)，10.78(s，1H)，8.52(s，1H)，8.46(d，J＝8.4Hz，1H)，8.35(d，J＝8.4Hz，2H)，8.19(s，1H)，7.97-8.12(m，9H)，7.90(s，1H)，7.47(s，1H)，7.36(d，J＝3.6Hz，1H)，6.70-6.72(m，1H)，5.21(dd，J＝12.8Hz，5.2Hz，1H)，2.84-2.94(m，1H)，2.37-2.60(m，2H)，2.06-2.11(m，1H).
Example 197:4- (6- {4- [ ({ 4- [ ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] carbonyl } amino) methyl ] phenyl } methyl) amino ] phenyl } -2- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The compound 196-2 was used as a starting material to prepare a compound of example 197 by general synthetic method H, method B, method a in this order. 1 H NMR(400MHz，DMSO-d 6 )，11.12(s，1H)，9.41(t，J＝6.0Hz，1H)，8.37(s，1H)，8.33(d，J＝8.4Hz，1H)，8.08(s，1H)，7.98-8.02(m，7H)，7.93(s，1H)，7.85(s，1H)，7.78(s，1H)，7.44(s，1H)，7.34(d，J＝8.0Hz，2H)，7.29(d，J＝8.4Hz，2H)，7.24(d，J＝3.6Hz，1H)，6.65-6.70(m，4H)，5.16(dd，J＝12.8Hz，5.2Hz，1H)，4.47(d，J＝5.6Hz，2H)，4.32(d，J＝5.2Hz，2H)，2.82-2.92(m，1H)，2.50-2.62(m，2H)，2.02-2.07(m，1H).
Example 198:2- (2, 6-Dioxypyridin-3-yl) -5- (4- { [1- ({ 4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] phenyl } carbonyl) hexahydropyridin-4-yl ] methyl } piperazin-1-yl) isoindole-1, 3-dione
The synthesis of the compound of example 198 was the same as that of example 86. 1 H NMR(400MHz，DMSO-d 6 )，11.06(s，1H)，8.58(d，J＝8.8Hz，2H)，8.36(d，J＝8.8Hz，2H)，8.34(s，1H)，8.06-8.08(m，3H)，7.92(s，1H)，7.65(d，J＝8.4Hz，1H)，7.54(d，J＝8.0Hz，2H)，7.39(d，J＝3.6Hz，1H)，7.31(s，1H)，7.23(d，J＝8.4Hz，1H)，6.72-6.73(m，1H)，5.04(dd，J＝12.8Hz，5.2Hz，1H)，4.42-4.54(m，1H)，3.54-3.66(m，1H)，3.36-3.46(m，4H)，3.03-3.15(m，1H)，2.74-2.90(m，2H)，2.42-2.59(m，6H)，213-2.26(m，2H)，1.95-2.02(m，1H)，1.77-1.92(m，2H)，1.62-1.73(m，1H)，1.06-1.26(m，2H)。
Example 199: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzenesulfonamide
The synthesis of the compound of example 199 was the same as that of example 85. 1 H NMR(400MHz，DMSO-d 6 )，11.07(s，1H)，8.54-8.59(m，3H)，8.38(d，J＝9.2Hz，2H)，8.32(d，J＝1.2Hz，1H)，8.17(d，J＝8.4Hz，2H)，8.07(d，J＝1.2Hz，1H)，7.94(s，1H)，7.90(d，J＝8.4Hz，2H)，7.81(d，J＝7.6Hz，1H)，7.72-7.75(m，2H)，7.40(d，J＝3.6Hz，1H)，6.74(dd，J＝3.6Hz，1.6Hz，1H)，5.04(dd，J＝12.8Hz，5.2Hz，1H)，4.28(d，J＝6.0Hz，2H)，2.72-2.82(m，1H)，2.34-2.51(m，2H)，1.81-1.88(m，1H)。
Example 200:2- (2, 6-Dioxypyridin-3-yl) -5- [ (4- { [4- ({ 4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] phenyl } carbonyl) piperazin-1-yl ] methyl } hexahydropyridin-1-yl) carbonyl ] isoindole-1, 3-dione
The synthesis of the compound of example 200 was identical to that of example 88. 1 H NMR(400MHz，DMSO-d 6 )，11.13(s，1H)，8.58(d，J＝8.8Hz，2H)，8.36(d，J＝8.8Hz，2H)，8.34(s，1H)，8.07-8.09(m，3H)，7.96(d，J＝7.6Hz，1H)，7.92(s，1H)，7.85(s，1H)，7.82(d，J＝8.8Hz，1H)，7.55(d，J＝8.4Hz，2H)，7.39(d，J＝3.2Hz，1H)，6.72(dd，J＝3.2Hz，1.6Hz，1H)，5.16(dd，J＝12.8Hz，5.2Hz，1H)，4.41-4.50(m，1H)，3.54-3.69(m，2H)，3.26-3.47(m，3H)，3.00-3.09(m，1H)，2.74-2.92(m，2H)，2.28-2.63(m，6H)，2.14-2.23(m，2H)，2.02-2.07(m，1H)，1.76-1.86(m，2H)，1.57-1.66(m，1H)，1.06-1.18(m，2H)。
Example 201: n- [4- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -4-oxon-butyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 201 was the same as that of example 116. 1H NMR (400 MHz, CDCl 3), 8.30-8.36 (m, 4H), 8.17 (s, 1H), 7.93-7.96 (m, 3H), 7.85 (s, 1H), 7.79-7.81 (m, 3H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.59 (s, 1H), 7.27 (d, J=3.2 Hz, 1H), 7.12 (t, J=5.6 Hz, 1H), 6.97 (t, J=5.6 Hz, 1H), 6.59-6.60 (m, 1H), 4.93 (dd, J=12.0 Hz,5.2Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.57 (q, J=6.0 Hz, 2H), 2.65-2.89 (m, 3.6 Hz, 1H), 6.97 (m, 1H), 2.43-2.46 (m, 2H).
Example 202: n- [5- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -5-oxon-entyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 202 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.29-8.34(m，5H)，7.91(d，J＝1.2Hz，1H)，7.88(d，J＝8.0Hz，2H)，7.83(d，J＝1.2Hz，1H)，7.72-7.77(m，4H)，7.63(d，J＝8.0Hz，1H)，7.58(s，1H)，7.25-7.26(m，1H)，6.83(t，J＝5.6Hz，1H)，6.64(t，J＝5.6Hz，1H)，6.58-6.60(m，1H)，4.92(dd，J＝12.4Hz，5.2Hz，1H)，4.56(d，J＝6.0Hz，2H)，3.50(q，J＝6.0Hz，2H)，2.64-2.91(m，3H)，2.39(t，J＝7.2Hz，2H)，2.06-2.12(m，1H)，1.76-1.83(m，2H)，1.66-1.73(m，2H)。
Example 203: n- [6- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -6-oxon-exyl ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 203 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.31-8.37(m，4H)，7.97(s，1H)，7.90-7.93(m，3H)，7.85(s，1H)，7.73-7.79(m，4H)，7.63(d，J＝8.4Hz，1H)，7.60(s，1H)，7.27(d，J＝3.2Hz，1H)，6.60-6.61(m，1H)，6.51(t，J＝5.6Hz，1H)，6.24(t，J＝5.6Hz，1H)，4.94(dd，J＝12.0Hz，5.6Hz，1H)，4.57(d，J＝6.4Hz，2H)，3.49-3.54(m，2H)，2.68-2.91(m，3H)，2.34(t，J＝6.8Hz，2H)，2.10-2.14(m，1H)，1.66-1.82(m，6H)。
Example 204: n- [7- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -7-oxohepty-l ] -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 204 was identical to that of example 116. 1 H NMR(400MHz，CDCl 3 )，8.30-8.37(m，4H)，8.02(s，1H)，7.93(d，J＝1.2Hz，1H)，7.90(d，J＝8.8Hz，2H)，7.85(d，J＝1.2Hz，1H)，7.77-7.80(m，4H)，7.66(d，J＝7.6Hz，1H)，7.60(s，1H)，7.27(d，J＝3.6Hz，1H)，6.60-6.61(m，1H)，6.40(t，J＝6.0Hz，1H)，6.31(t，J＝6.0Hz，1H)，4.94(dd，J＝12.4Hz，5.6Hz，1H)，4.58(d，J＝5.2Hz，2H)，3.46(q，J＝6.4Hz，2H)，2.66-2.90(m，3H)，2.29(t，J＝7.2Hz，2H)，2.09-2.15(m，1H)，1.61-1.76(m，4H)，1.38-1.46(m，4H)。
Example 205: n- (3- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -3-oxoidenepropyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 205 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，9.22(s，1H)，8.86(s，1H)，8.42(s，1H)，8.35(d，J＝8.8Hz，2H)，8.29(d，J＝8.8Hz，2H)，8.14(s，1H)，7.88-7.95(m，4H)，7.80-7.83(m，3H)，7.76(d，J＝8.8Hz，1H)，7.58(s，1H)，7.08-7.11(m，1H)，6.59(s，1H)，4.98(dd，J＝12.8Hz，5.6Hz，1H)，3.88(q，J＝6.0Hz，2H)，2.70-2.95(m，5H)，2.10-2.16(m，1H)。
Example 206: n- (4- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -4-oxon-butyl) -4- [6- (furan-2-yl) -2- (4-nitrophenyl) pyridin-4-yl ] benzamide
The synthesis of the compound of example 206 was the same as that of example 116. 1 H NMR(400MHz，CDCl 3 )，9.83(s，1H)，8.36(d，J＝8.8Hz，2H)，8.32(d，J＝8.8Hz，2H)，8.19(s，2H)，8.01(d，J＝8.0Hz，1H)，7.93-7.96(m，3H)，7.84(s，1H)，7.81(d，J＝8.0Hz，2H)，7.76(d，J＝8.0Hz，1H)，7.60(s，1H)，7.28(d，J＝3.2Hz，1H)，6.72(t，J＝6.0Hz，1H)，6.60-6.62(m，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，3.64-3.71(m，2H)，2.63-2.90(m，3H)，2.50-2.53(m，2H)，1.98-2.13(m，3H)。
Example 207:4- (2- {4- [ (2- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] oxy } ethyl) oxy ] phenyl } -6- (furan-2-yl) pyridin-4-yl) benzene-1-carboxamide
The synthesis of the compound of example 207 was identical to the synthesis of the compound of example 133. 1 H NMR(400MHz，CD 3 OD)，8.49(s，1H)，8.27(s，1H)，8.17(d，J＝8.0Hz，2H)，8.11(d，J＝8.0Hz，2H)，8.02(s，1H)，7.97(d，J＝8.4Hz，2H)，7.82(d，J＝3.6Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.25(d，J＝8.8Hz，2H)，7.20(d，J＝2.0Hz，1H)，7.14(dd，J＝8.0Hz，2.0Hz，1H)，6.85-6.86(m，1H)，5.13(dd，J＝12.8Hz，5.6Hz，1H)，4.17-4.29(m，4H)，2.85-2.95(m，2H)，2.64-2.75(m，1H)，2.06-2.14(m，1H)。
Example 208: n- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } -2- (furan-2-yl) -6- (4-nitrophenyl) pyridine-4-carboxamide
Step 1: a solution of compound 208-1 (2 mL), compound 208-2 (4.56 g), and concentrated hydrochloric acid (3.4 mL) in glacial acetic acid (68 mL) was heated to 120℃and reacted overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to obtain compound 208-3 (1.68 g).
Step 2: a solution of compound 208-3 (166 mg), compound 208-4 (322 mg), ammonium acetate (1.55 g) in glacial acetic acid/acetic anhydride (4 mL/0.4 mL) was heated to 100deg.C and reacted overnight. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash column chromatography (dichloromethane: methanol=100:1 to 20:1) to obtain compound 208-5 (250 mg).
Step 3: to a solution of compound 208-5 (50 mg), compound 208-6 (40 mg), HOBt (29 mg), triethylamine (0.1 mL) in DMF (1.5 mL) was addedEDCI (41 mg) was introduced. The reaction was allowed to react overnight at 80℃until completion. The reaction was diluted with water (15 mL) and extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (dichloromethanol: methanol=10:1) to give the compound of example 208 (27 mg). 1 H NMR(400MHz，CD 3 OD)，9.49(t，J＝6.0Hz，1H)，8.33(s，4H)，8.15-8.17(m，2H)，7.88(s，1H)，7.80-7.85(m，2H)，7.61(s，1H)，7.25(d，J＝3.2Hz，1H)，6.58(dd，J＝3.6Hz，1.6Hz，1H)，4.99-5.03(m，1H)，4.74(d，J＝5.6Hz，2H)，2.70-2.80(m，3H)，2.08-2.14(m，1H)。
Example 209: n- [8- ({ [2- (2, 6-Dioxon-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -8-oxon-yloxy ] -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The compound of example 209 was prepared from compound 152-1 as starting material, followed by general synthetic method a, method F, method a. 1 H NMR(400MHz，CDCl 3 )，8.16(s，1H)，7.74-7.80(m，3H)，7.65(d，J＝7.6Hz，1H)，7.61(d，J＝4.8Hz，1H)，7.56(s，1H)，7.23(s，1H)，7.18-7.21(m，2H)，6.33(t，J＝6.0Hz，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.57(d，J＝5.6Hz，2H)，3.48(q，J＝7.2Hz，2H)，2.68-2.91(m，3H)，2.27(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.60-1.72(m，4H)，1.32-1.44(m，6H)。
Example 210:7- (chlorodifluoromethyl) -N- [8- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -8-oxon-yloxy ] -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 210 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.53(s，1H)，7.72-7.76(m，3H)，7.63(d，J＝7.6Hz，1H)，7.58(d，J＝5.2Hz，1H)，7.50(s，1H)，7.19-7.24(m，2H)，7.15-7.18(m，1H)，6.60(t，J＝5.2Hz，1H)，4.94(dd，J＝12.4Hz，5.2Hz，1H)，4.54(d，J＝5.6Hz，2H)，3.45(q，J＝6.8Hz，2H)，2.67-2.88(m，3H)，2.25(t，J＝7.2Hz，2H)，2.10-2.13(m，1H)，1.56-1.70(m，4H)，1.26-1.42(m，6H)。
Example 211: n- [10- ({ [2- (2, 6-Dioxon-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -10-oxon-dec ] -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 211 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.60(s，1H)，7.71-7.75(m，3H)，7.62(d，J＝7.2Hz，1H)，7.59(d，J＝4.8Hz，1H)，7.55(s，1H)，7.19-7.23(m，2H)，7.15-7.17(m，1H)，6.58(t，J＝6.0Hz，1H)，4.94(dd，J＝12.0Hz，5.2Hz，1H)，4.53(d，J＝6.4Hz，2H)，3.44(q，J＝7.2Hz，2H)，2.71-2.88(m，3H)，2.23(t，J＝7.6Hz，2H)，2.08-2.14(m，1H)，1.57-1.68(m，4H)，1.22-1.40(m，10H)。
Example 212:7- (chlorodifluoromethyl) -N- [10- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -10-oxodec ] -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
Method for synthesizing Compound of example 212The synthesis of the compound of example 209 was identical. 1 H NMR(400MHz，CDCl 3 )，8.57(s，1H)，7.73-7.77(m，3H)，7.64(d，J＝8.0Hz，1H)，7.58(d，J＝5.2Hz，1H)，7.51(s，1H)，7.21-7.25(m，2H)，7.16-7.18(m，1H)，6.52(t，J＝6.0Hz，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.55(d，J＝6.0Hz，2H)，3.45(q，J＝6.8Hz，2H)，2.68-2.89(m，3H)，2.25(t，J＝7.6Hz，2H)，2.10-2.14(m，1H)，1.58-1.69(m，4H)，1.22-1.41(m，10H)。
Example 213: n- [4- ({ [2- (2, 6-Dioxon-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -4-oxon-butyl ] -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 213 was carried out in the same manner as the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.22(s，1H)，7.82(s，1H)，7.79(d，J＝8.0Hz，1H)，7.76(d，J＝4.0Hz，1H)，7.70-7.72(m，1H)，7.61(d，J＝4.8Hz，1H)，7.57(s，1H)，7.45(t，J＝6.4Hz，1H)，7.38(t，J＝6.4Hz，1H)，7.26(s，1H)，7.18-7.20(m，1H)，4.96(dd，J＝12.4Hz，5.2Hz，1H)，4.59(d，J＝5.6Hz，2H)，3.57(q，J＝6.4Hz，2H)，2.68-2.91(m，3H)，2.38(t，J＝6.8Hz，2H)，2.11-2.16(m，1H)，1.98-2.05(m，2H)。
Example 214:7- (chlorodifluoromethyl) -N- [4- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -4-oxon-butyl ] -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 214 was the same as that of the compound of example 209And the same is true. 1 H NMR(400MHz，CDCl 3 )，8.16(s，1H)，7.83(s，1H)，7.79(d，J＝8.0Hz，1H)，7.76(d，J＝3.6Hz，1H)，7.70-7.73(m，1H)，7.61(d，J＝4.8Hz，1H)，7.53(s，1H)，7.46(t，J＝6.4Hz，1H)，7.37-7.43(brs，1H)，7.28(s，1H)，7.18-7.20(m，1H)，4.96(dd，J＝12.4Hz，5.2Hz，1H)，4.60(d，J＝6.0Hz，2H)，3.58(q，J＝6.8Hz，2H)，2.68-2.92(m，3H)，2.39(t，J＝6.8Hz，2H)，2.12-2.16(m，1H)，1.99-2.05(m，2H)。
Example 215: n- (10- { [2- (2, 6-Dioxon-ylpyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -10-oxon-dec-yl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 215 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.38(s，1H)，8.11(d，J＝1.6Hz，1H)，8.07(s，1H)，7.98(dd，J＝8.4Hz，1.6Hz，1H)，7.75-7.78(m，2H)，7.60(d，J＝5.2Hz，1H)，7.56(s，1H)，7.22-7.26(m，2H)，7.17-7.19(m，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.49(q，J＝7.2Hz，2H)，2.68-2.91(m，3H)，2.40(t，J＝7.2Hz，2H)，2.11-2.15(m，1H)，1.62-1.78(m，6H)，1.22-1.44(m，8H)。
Example 216: n- (8- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -8-oxon-ctyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 216 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.52(s，1H)，8.12-8.14(m，2H)，7.98(dd，J＝8.4Hz，1.6Hz，1H)，7.75-7.77(m，2H)，7.61(d，J＝5.2Hz，1H)，7.56(s，1H)，7.23-7.27(m，2H)，7.17-7.20(m，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.52(q，J＝6.8Hz，2H)，2.68-2.90(m，3H)，2.39(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.58-1.79(m，6H)，1.36-1.45(m，4H)。
Example 217:7- (chlorodifluoromethyl) -N- (8- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -8-oxolanctyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 217 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.60(s，1H)，8.21(s，1H)，8.11(d，J＝1.6Hz，1H)，7.98(dd，J＝8.4Hz，1.6Hz，1H)，7.74-7.76(m，2H)，7.60(d，J＝4.8Hz，1H)，7.52(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.52(q，J＝6.8Hz，2H)，2.69-2.90(m，3H)，2.39(t，J＝7.6Hz，2H)，2.10-2.16(m，1H)，1.60-1.78(m，6H)，1.35-1.44(m，4H).
Example 218: n- [6- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -6-oxon-exyl ] -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 218 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.00(s，1H)，7.75-7.80(m，3H)，7.66(d，J＝7.6Hz，1H)，7.61(d，J＝4.8Hz，1H)，7.56(s，1H)，7.22-7.26(m，2H)，7.18-7.20(m，1H)，6.23(t，J＝6.4Hz，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.57(d，J＝6.0Hz，2H)，3.50(q，J＝6.8Hz，2H)，2.68-2.91(m，3H)，2.31(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.67-1.80(m，6H)。
Example 219:7- (chlorodifluoromethyl) -N- [6- ({ [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] methyl } amino) -6-oxohexy-l ] -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 219 was identical to that of example 209. 1 H NMR(400MHz，CDCl 3 )，7.98(s，1H)，7.75-7.81(m，3H)，7.66(d，J＝8.0Hz，1H)，7.60(dd，J＝5.2Hz，1.2Hz，1H)，7.52(s，1H)，7.22-7.26(m，2H)，7.18-7.20(m，1H)，6.20(t，J＝5.6Hz，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.57(d，J＝6.4Hz，2H)，3.51(q，J＝6.8Hz，2H)，2.68-2.91(m，3H)，2.31(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.66-1.81(m，6H).
Example 220: n- (4- { [2- (2, 6-Dioxon-yl) hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -4-oxon-butyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 220 was identical to that of example 209. 1 H NMR(400MHz，CDCl 3 )，10.03(s，1H)，8.26(d，J＝2.0Hz，1H)，8.18(s，1H)，8.02(dd，J＝8.4Hz，2.0Hz，1H)，7.75-7.78(m，2H)，7.63(d，J＝5.2Hz，1H)，7.60(s，1H)，7.53(t，J＝6.8Hz，1H)，7.31(s，1H)，7.19-7.21(m，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，3.67(q，J＝6.4Hz，2H)，2.69-2.91(m，3H)，2.48-2.51(m，2H)，2.04-2.16(m，3H)。
Example 221:7- (chlorodifluoromethyl) -N- (4- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -4-oxomonobutyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 221 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，10.11(s，1H)，8.30(d，J＝1.6Hz，1H)，8.03-8.06(m，2H)，7.77-7.79(m，2H)，7.63(d，J＝4.8Hz，1H)，7.56(s，1H)，7.54(t，J＝6.4Hz，1H)，7.33(s，1H)，7.19-7.22(m，1H)，4.95(dd，J＝12.4Hz，4.8Hz，1H)，3.65-3.70(m，2H)，2.72-2.92(m，3H)，2.49-2.52(m，2H)，2.04-2.16(m，3H)。
Example 222:2- (2, 6-Dioxypyridin-3-yl) -5- {4- [2- (furan-2-yl) -6- (4-nitrophenyl) pyridin-4-yl ] phenyl } isoindole-1, 3-dione
Step 1: a solution of compound 222-1 (2.7 g), compound 222-2 (3 g), ammonium acetate (15 g) and glacial acetic acid (4 mL) in DMF (40 mL) was heated to 90℃and reacted overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give compound 222-3 (3 g).
Step 2: a solution of compound 222-3 (420 mg), pinacol diboronate (380 mg), pd (dppf) Cl2 (73 mg), anhydrous potassium acetate (197 mg) in 1, 4-dioxane (5 mL) was heated to 100℃under nitrogen and reacted overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate=3:1 to 1:1) to obtain compound 222-4 (400 mg).
Step 3: pd2 (dba) 3 (15 mg) was added to a solution of compound 222-4 (50 mg), compound 222-5 (20 mg), X-phos (30 mg), and anhydrous potassium acetate (31 mg) in 1, 4-dioxane/water (2 mL/0.5 mL) under nitrogen. The reaction solution was heated to 130℃by microwaves and reacted for 0.5h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to obtain the compound of example 222 (23 mg). 1 H NMR(400MHz，CDCl 3 )，8.32-8.39(m，4H)，8.17(s，1H)，8.04(dd，J＝7.6Hz，1.2Hz，1H)，7.99-8.01(m，3H)，7.90-7.92(m，3H)，7.82(d，J＝8.8Hz，2H)，7.61(s，1H)，7.29(d，J＝3.6Hz，1H)，6.61-6.62(m，1H)，5.03(dd，J＝8.4Hz，5.2Hz，1H)，2.72-2.97(m，3H)，2.17-2.22(m，1H)。
Example 223: n- (6- { [2- (2, 6-dioxo-hexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -6-oxon-exyl) -5- (thiophen-2-yl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 223 was identical to the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.59(s，1H)，8.45(s，1H)，8.06(s，1H)，7.93(dd，J＝8.0Hz，1.6Hz，1H)，7.75(d，J＝3.6Hz，1H)，7.69(d，J＝8.0Hz，1H)，7.61(d，J＝4.8Hz，1H)，7.56(s，1H)，7.34(t，J＝6.0Hz，1H)，7.27(s，1H)，7.18-7.20(m，1H)，4.96(dd，J＝12.4Hz，5.2Hz，1H)，4.52(q，J＝7.2Hz，2H)，2.70-2.91(m，3H)，2.43(t，J＝7.2Hz，2H)，2.10-2.16(m，1H)，1.80-1.88(m，2H)，1.69-1.76(m，2H)，1.45-1.53(m，2H).
Example 224:7- (chlorodifluoromethyl) -N- (6- { [2- (2, 6-dioxohexahydropyridin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl ] amino } -6-oxoniexyl) -5- (thiophen-2-yl) pyrazolo [1,5-a ] pyrimidine-2-carboxamide
The synthesis of the compound of example 224 was carried out in the same manner as the synthesis of the compound of example 209. 1 H NMR(400MHz，CDCl 3 )，8.52(s，1H)，8.43(s，1H)，8.06(d，J＝2.0Hz，1H)，7.93(dd，J＝8.0Hz，2.0Hz，1H)，7.75(dd，J＝4.0Hz，1.2Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.60(d，J＝5.2Hz，1H)，7.52(s，1H)，7.35(t，J＝6.0Hz，1H)，7.29(s，1H)，7.17-7.20(m，1H)，4.96(dd，J＝12.4Hz，5.2Hz，1H)，3.53(q，J＝6.8Hz，2H)，3.70-3.91(m，3H)，2.44(t，J＝7.6Hz，2H)，2.10-2.16(m，1H)，1.80-1.88(m，2H)，1.70-1.78(m，2H)，1.46-1.53(m，2H)。
Biological testing
1. Activity assay of Compounds for inhibiting proliferation of HL-60 cells
Human acute promyelocytic leukemia cell line HL-60 cells were cultured using RPMI-1640 medium plus 20% fetal bovine serum (FBS, available from Gibco) and 1% penicillin/streptomycin (P/S, available from Thermo Fisher Scientific) at 37℃with 5% CO 2 . HL-60 cells were plated in 96-well plates (# 3917, available from CORNING) at a concentration of 5000 cells/195 μl/well. After 24 hours, the compounds were mixed by 3-fold gradient dilution with 100% DMSO starting at 10mM (total of 10 concentrations), and then 4. Mu.L of each concentration of the compound was added to 96. Mu.L of serum-free RPMI-1640 medium for dilution and mixing. The diluted compounds were added to the plated cell suspension at 5 μl per concentration, and the compounds were incubated with the cells in a cell incubator for 3 days. Then 35. Mu.L of Cell-Titer was added
(G7571, from Promega) reagent, shaking table and mixing for 5 min. Reading chemiluminescence values on BMG CLARIO star, processing data by using GraphPad Prism software, and calculating to obtain the compoundIC for inhibiting cell proliferation 50 Values (table 1.).
TABLE 1 Activity assay of Compounds for inhibiting HL-60 cell proliferation
2. Method for detecting degradation activity of compound on HL-60 cell MYC protein
The modulation of MYC protein expression levels in Human acute promyelocytic leukemia Cell line HL-60 cells was determined using the Human c-MYC Cell-Based kit (63 ADK053PEH, available from Cisbio). The experimental method and the kit instruction are as follows: HL-60 cells were cultured using RPMI-1640 medium plus 20% fetal bovine serum (FBS, available from Gibco) and 1% penicillin/streptomycin (P/S, available from Thermo Fisher Scientific) at 37℃under 5% CO 2 HL-60 cells were plated in 96-well plates (# 3917, available from CORNING) at a concentration of 20000 cells/57 μl/well. Compounds were mixed by 10-fold gradient dilution (total 5 concentrations) in DMSO starting at 10mM, and then 2. Mu.L of each concentration was added to 98. Mu.L of serum-free RPMI-1640 medium for dilution and mixing. The diluted compounds were added to the plated cell suspension at 3. Mu.L for 4 hours in an incubator, after which 20. Mu.L of 4 Xlysis buffer (final concentration 1X) was added directly to the cell suspension, and the 96-well plate was placed in a shaker at room temperature for 30min, 10. Mu.L of cell lysate was transferred from the 96-well plate to a white 384-well plate (6007290, available from Perkin Elmer) with 10. Mu.L of diluted Cryptate-anti-ibody and d 2-anti-ibody added. After incubation for 3h at room temperature, fluorescence signals at 665nm and 620nm were read using an Envision microplate reader. Data were processed using GraphPad Prism software and calculated to obtain compound IC for modulation of MYC protein expression 50 Values (table 2).
TABLE 2 Compounds IC degradation of MYC in HL-60 50
| Examples | IC 50 (nM) | Examples | IC 50 (nM) | Examples | IC 50 (nM) |
| Example 84 | 344 | Example 168 | 751 | EXAMPLE 209 | 191 |
| Example 89 | 425 | Example 169 | 980 | Example 210 | 88.8 |
| Example 90 | 1538 | Example 172 | 67.6 | Example 211 | 64.7 |
| Example 92 | 1382 | Example 173 | 142 | Example 212 | 25.1 |
| Example 104 | 1455 | Example 174 | 428 | Example 215 | 97.8 |
| Example 119 | 1492 | Example 177 | 99.5 | Example 216 | 126 |
| Example 120 | 1076 | Example 178 | 317 | Example 217 | 192 |
| Example 144 | 12.9 | Example 179 | 1087 | Example 223 | 861 |
| Example 153 | 317 | Example 183 | 67.7 | Example 224 | 838 |
| Example 161 | 161 | Example 197 | 529 |
Claims (12)
1. A compound of formula (I), or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is CR 8 R 9 Or (c=o),
R 8 and R is 9 Each independently selected from halogen, -CF 3 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl and-NHC 1-6 An alkyl group, a hydroxyl group,
L 1 is-O-CH 2 CH 2 -, wherein C 2 H 2 Optionally by halogen, CF 3 Or C 1-6 An alkyl group is substituted and a substituent is substituted,
L 2 、L 3 、L 4 and L 5 Each independently selected from the group consisting of bond, - (O-CH) 2 CH 2 ) 1-8 -、-(CH 2 ) 1-12 -、-(CH 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-CR 12 ＝CR 12 -、-CO-CR 12 ＝CR 12 -、-C≡C-、-CO-C≡C-、
-O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 NR 10 -、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-(CO)-NR 10 -CH 2 -、-CH 2 -(CO)-NR 10 -、-CH 2 -(CO)-NR 10 -CH 2 -、-O-(CO)-NR 10 -、-O-CH 2 -(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH2-(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (5-12 membered heteroarylene) - (CO) -, - (3-12 membered carbocycle) - (CO) -, - (3-12 membered heterocycle) - (CO) -, - (C) 6 H 4 )-(CO)-、-(C 6 H 4 )-(CO)-NR 10 -、-CH 2 -(C 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -、-CH 2 -(C 6 H 4 )-CH 2 -、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) O-, wherein C 6 H 4 Is phenylene, C 2 H 2 、C 6 H 4 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, CF 3 Or C 1-6 Alkyl substitution, L 2 、L 3 、L 4 And L 5 The group selection of (c) does not include the case of chemical failure,
ar is a small molecule ligand capable of binding to a target protein, preferably a small molecule ligand capable of targeted binding to c-Myc or GSPT1,
R 10 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 12 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 2 Instead of the above-mentioned,
R 2 selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR 13 、-NR 13 R 14 、-(CO)-R 15 、-(CO)-NR 13 R 14 、-NH-(CO)-R 15 、-S(O)R 15 、-S(O) 2 R 15 、-S(O) 2 NR 13 R 14 or-NR 14 S(O) 2 R 15 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be R 3 Instead of the above-mentioned,
R 13 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being substituted by R 3 Instead of the above-mentioned,
R 14 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 15 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 3 Instead of the above-mentioned,
R 3 selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, - (CO) -C 1-6 Alkyl, - (CO) -NHC 1-6 Alkyl, -NH- (CO) -C 1-6 Alkyl, -S (O) C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl, -S (O) 2 NHC 1-6 Alkyl, or-NHC 1-6 Alkyl S (O) 2 C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, - (CO) -C 1-6 Alkyl, - (CO) -NHC 1-6 Alkyl, -NH- (CO) -C 1-6 Alkyl, -S (O) C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl, -S (O) 2 NHC 1-6 Alkyl, or-NHC 1-6 Alkyl S (O) 2 C 1-6 An alkyl group is substituted and a substituent is substituted,
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
2. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or any of the foregoing Pharmaceutically acceptable salts, wherein L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (CH) 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-CR 12 ＝CR 12 -、-CO-CR 12 ＝CR 12 -、-C≡C-、-CO-C≡C-、
-O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 NR 10 -、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-(CO)-NR 10 -CH 2 -、-CH 2 -(CO)-NR 10 -、-CH 2 -(CO)-NR 10 -CH 2 -、-O-(CO)-NR 10 -、-O-CH 2 -(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (C) 6 H 4 )-(CO)-NR 10 -、-CH 2 -(C 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -、-(C 6 H 4 )-CH 2 -(CO)-NR 10 -CH 2 -(C 6 H 4 )-、-(C 6 H 4 )-CH 2 -、-CH 2 -(C 6 H 4 )-CH 2 -、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) O-, wherein C 6 H 4 Is phenylene, C 2 H 2 、C 6 H 4 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, CF 3 Or C 1-6 Alkyl substitution, L 2 、L 3 、L 4 And L 5 The group selection of (c) does not include the case of chemical failure,
R 10 and R is 12 As defined in claim 1.
3. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ar is a 6-10 membered aryl or a 5-12 membered heteroaryl, the aryl and heteroaryl optionally being substituted with 1-4R 1 Instead of the above-mentioned,
R 1 each independently selected from halogen, -CF 3 、-CN、-OH、-NH 2 、-NO 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR 11 、-NR 10 R 11 、-(CO)-R 12 、-(CO)-NR 10 R 11 、-NR 11 -(CO)-R 12 、-S(O)R 12 、-S(O) 2 R 12 、-S(O) 2 NR 10 R 11 or-NR 10 S(O) 2 R 12 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be R 2 Instead of the above-mentioned,
R 10 each independently selected from H and C 1-6 Alkyl, which alkyl is optionally substituted by halogen,
R 11 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl being optionallyQuilt R 2 Instead of the above-mentioned,
R 12 each independently selected from-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being R 2 Instead of the above-mentioned,
R 2 as defined in claim 1.
4. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 8 And R is 9 Each independently selected from halogen, -CF 3 、-C 1-6 Alkyl and 3-12 membered cycloalkyl.
5. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is CH 2 Or (c=o).
6. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 is-O-CH 2 CH 2 -。
7. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein q is 0, 1, 2, 3, or 4.
8. The compound of claim 1, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 2 、L 3 、L 4 And L 5 Each independently selected from the group consisting of bond, - (CH) 2 ) 1-4 -、-NR 10 -CH 2 CH 2 -、-NR 10 -CH 2 CH 2 -NR 10 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 -O-、-C≡C-、-CO-C≡C-、-O-、-S-、-NR 10 -、-(CO)-、-(CO)-NR 10 -、-O-(CO)-NR 10 -、-NR 10 -(CO)-NR 10 -、-NR 10 -CH 2 -(CO)-NR 10 -, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, 3-12 membered heterocycle, - (C) 6 H 4 )-(CO)-NR 10 -、-(CO)-NR 10 -(C 6 H 4 )-、-(C 6 H 4 )-NR 10 -、-NR 10 -(C 6 H 4 )-NR 10 -、-(C 6 H 4 ) -O-and-O- (C) 6 H 4 ) -O-, wherein R 10 As defined in claim 1.
9. An intermediate of bifunctional small molecule PROTACs having a structure represented by formula (II):
each substituent group is defined in claim 1.
10. A compound, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing,
11. a pharmaceutical composition comprising a compound according to any one of claims 1-8, 10, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing, and optionally a pharmaceutically acceptable adjuvant.
12. Use of a compound according to any one of claims 1-8, 10, or a prodrug, solvate, polymorph, isomer, ester, deuterated compound or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the treatment of a disease associated with abnormal cell proliferation; preferably, the disease associated with abnormal cell proliferation is acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-hodgkin's lymphoma, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, or multiple myeloma.
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