Substituted 4-aminoisoindoline compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The present application relates to a kind of substituted 4-aminoisoindoline compound, its preparation method, pharmaceutical composition and application, the compound has the structure shown in formula (I). Specifically, the substituted 4-aminoisoindoline compound provided by the present application is used as CRL4 CRBN E3 ubiquitin ligase modulator has good antitumor activity, can be used for preparing the drug for treating CRL4 CRBN E3 ubiquitin ligase related disease.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to a class of substituted 4-aminoisoindoline compounds, their preparation methods, pharmaceutical compositions, and applications. Background Technology

[0002] To address the drug resistance issues of small molecule inhibitors and the development of effective drug molecules targeting "undruggable" proteins, a strategy for regulating protein function—targeted protein degradation technology—has been developed in recent years. Targeted protein degradation technology is a rapidly evolving technique in drug development. It utilizes the ubiquitin-proteasome (UPS)-mediated protein degradation pathway in the body to degrade disease-related proteins, thereby achieving therapeutic effects. Targeted protein degradation technology has become a research hotspot in drug development, with broad application prospects in both drug discovery and biomedicine. Currently, targeted protein degradation technologies based on the ubiquitin-proteasome system (UPS) mainly include protein hydrolysis-targeting chimeras (PROTACs) and molecular glutens. Despite the booming development of the PROTAC field, there are still many challenges: 1) Most PROTACs have a molecular weight greater than 1000 Da, which makes their bioavailability and membrane permeability poor, does not conform to Lipinski's rule, and has poor bioavailability and pharmacokinetic properties; 2) PROTAC molecules are complex to synthesize and have high synthesis costs; 3) PROTACs exert their effects through catalytic cycling, so traditional methods cannot accurately evaluate the PK and PD properties of PROTACs. Currently, there is no mature PK and PD evaluation system for PROTAC molecules.

[0003] Molecular glues are small molecules that induce protein-protein interactions, enabling precise time-dependent control of various biological processes. They act on protein interfaces to form new protein-protein interactions. By bringing target proteins into the physical vicinity of regulatory proteins, molecular glues reduce the need for active linker pockets on target proteins, potentially greatly expanding the druggable proteome. Molecular glue-mediated proximity-induced protein degradation offers inherent advantages over PROTACs: 1) Compared to PROTACs, molecular glues have smaller molecular weights, facilitating optimization of physicochemical properties and better conforming to the "five principles of drug-likeness"; 2) Compared to PROTACs, molecular glues are easier to improve bioavailability and pharmacokinetic properties; 3) Molecular glue synthesis is relatively simpler; 4) From a functional perspective, the mechanisms of action of target proteins and PROTACs are usually well-defined, while the discovery of molecular glues is often accompanied by the discovery of new modes of action and new drug targets.

[0004] Thalidomide, lenalidomide, and pomalidomide, among others, are collectively known as immunomodulatory drugs (IMiDs). Recent studies have shown that these immunomodulatory drugs, as a clinical treatment strategy, operate through a molecular mechanism, directly targeting CRL4 (Science, 2010, 327, 1345; Science, 2014, 343, 301; Science, 2014, 343, 305; Nature, 2015, 523, 183). Immunomodulatory drugs target CRL4. CRBN E3 ubiquitin ligases bind to CEBN, causing conformational fine-tuning of the protein-binding interface, thereby recruiting different substrate proteins and ubiquitinizing them. The ubiquitin-labeled substrate proteins are then degraded by the proteasome. The downstream effects of these protein degradations mediate the antitumor proliferation and immunomodulatory activities of immunomodulatory drugs. These results indicate that different lenalidomide drug molecules, after interacting with the target CRBN, exhibit different substrate protein degradation specificities, meaning the compounds possess different pharmacological activities and entirely different therapeutic effects, thus allowing for clinical applications in treating various indications. For example, lenalidomide is used to treat multiple myeloma by degrading IKZF1 and IKZF3; while it achieves therapeutic efficacy in treating 5q deletion myelodysplastic syndrome (MDS) by degrading CK1α. With the development of new lenalidomide compounds, their indications are continuously expanding, and several molecular gel degraders are currently in clinical trials.

[0005]

[0006] Lenalidomide is currently mainly used to treat multiple myeloma and myelodysplastic syndromes, but its efficacy for other indications is not ideal; while its analogues, such as CC-122, CC-220, CC-92480, and CC-90009, are still in the clinical research stage. Therefore, developing a novel CRL4 analogue is crucial. CRBN E3 ubiquitin ligase molecular gel degraders utilize structural modifications and adjustments to enhance ligand interactions and affinity with ligases, thereby increasing substrate degradation rates and potentially improving tumor treatment efficacy and expanding the indications for molecular gel degraders. Research into the molecular mechanisms of molecular gel degraders reveals that structural changes in amine drugs, leading to alterations in CRBN conformation, often result in the discovery of new mechanisms of action and novel drug targets. Therefore, the development of novel CRL4... CRBN E3 ubiquitin ligase molecular gel degraders can recruit and degrade novel substrate proteins, potentially enabling further exploration for new therapeutic indications. In summary, the development of novel CRL4... CRBN E3 ubiquitin ligases are molecular gel degraders that can improve the therapeutic effect on tumors and broaden new indications. They can be used to further address unmet medical needs and have important research value and practical significance. Summary of the Invention

[0007] The purpose of this invention is to provide a novel CRL4CRBNE3 ubiquitin ligase molecular gel degrader, which improves the therapeutic effect on tumors and broadens the indications for molecular gel degraders.

[0008] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof:

[0009]

[0010] Where n is 0 or 1;

[0011] X and Y are each independently selected from CH or N, and X and Y are not both CH at the same time;

[0012] Z is selected from: O, S, or NH;

[0013] Selected from: C6-C10 aryl, C4-C10 cycloalkyl, 4-10 heterocyclic, 5-10 heteroaryl, wherein the C6-C10 aryl, C4-C10 cycloalkyl, 4-10 heterocyclic, and 5-10 heteroaryl are optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 heterocyclic, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic oxy, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, –C(O)-R1, -(CH2)m-R2; wherein the substituted or unsubstituted phenyl group is optionally substituted by one or more of the following groups: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0014] R1 is selected from: halogen-substituted or unsubstituted C1-C6 alkyl, C4-C12 cycloalkyl, C6-C10 aryl, 4-10 membered heterocyclic, -CH2-(C4-C12 cycloalkyl), and said C4-C12 cycloalkyl, C6-C10 aryl, 4-10 membered heterocyclic, -CH2-(C4-C12 cycloalkyl) is optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted or unsubstituted phenyl;

[0015] R2 is a C6-C10 aryl group, and the C6-C10 aryl group is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy.

[0016] m is 0 or 1;

[0017] R3 is hydrogen or halogen;

[0018] R4 can be hydrogen, deuterium, or fluorine.

[0019] In another preferred example, n is 0.

[0020] In another preferred embodiment, Z is selected from O or S.

[0021] In another preferred embodiment, X is N, Y is C, and Z is O; or X is N, Y is C, and Z is S.

[0022] In another preferred embodiment, Selected from:

[0023] In another preferred embodiment, for Wherein, A1 is selected from: phenyl, C4-C6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl group;

[0024] L represents none, CO, or CH2;

[0025] A2 is selected from: none, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, phenyl, C4-C6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl;

[0026] Ra1 and Ra2 are each independently selected from: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic alkyloxy, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy; wherein the substituted or unsubstituted phenyl is optionally substituted by one or more groups selected from: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0027] p and q are each independently 0, 1, 2, 3, 4 or 5.

[0028] In another preferred embodiment, Selected from: phenyl, 5-6-membered heteroaryl, nitrogen-containing 4- or 6-membered heterocyclic group, and said phenyl, 5-6-membered heteroaryl, nitrogen-containing 4- or 6-membered heterocyclic group optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, cyano, morpholino, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic oxy, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, –C(O)-R1, -(CH2)-R2, wherein said substituted or unsubstituted phenyl is optionally substituted by one or more of the following groups: hydrogen, Halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; R1 and R2 are defined as above; preferably, R1 is selected from: halogen-substituted or unsubstituted C1-C6 alkyl, C4-C12 cycloalkyl, phenyl, -CH2-(C4-C12 cycloalkyl), and the C4-C12 cycloalkyl, phenyl, -CH2-(C4-C12 cycloalkyl) is optionally substituted by one or more groups selected from: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted or unsubstituted phenyl;

[0029] R2 is a phenyl group, and the phenyl group is optionally substituted by one or more of the following groups: halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy.

[0030] In another preferred embodiment, the compound has the structure shown in Formula II.

[0031]

[0032] Where n is 0 or 1;

[0033] X and Y are each independently selected from CH or N, and X and Y are not both CH at the same time;

[0034] Z is selected from: O, S, or NH;

[0035] R3 is hydrogen or halogen;

[0036] R4 is hydrogen, deuterium, or fluorine;

[0037] A1 is selected from: phenyl, C4-C6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl group;

[0038] L represents none, CO, or CH2;

[0039] A2 is selected from: none, C1-C6 alkyl, phenyl, C4-C10 cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl;

[0040] Ra1 and Ra2 are each independently selected from: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic alkyloxy, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy; wherein the substituted or unsubstituted phenyl is optionally substituted by one or more groups selected from: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0041] p and q are each independently 0, 1, 2, 3, 4 or 5.

[0042] In another preferred embodiment, A1 is selected from: phenyl, pyridyl, piperidyl, cyclohexyl, piperazinyl, acridineyl.

[0043] In another preferred embodiment, both L and A2 are zero.

[0044] In another preferred embodiment, the compound has the structures shown in formulas (I-1)-(I-4):

[0045]

[0046] in, Selected from:

[0047] R3 is hydrogen or halogen;

[0048] R4 is hydrogen, deuterium, or fluorine;

[0049] R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19R 20 R 21 Each is independently selected from: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, phenyl, vinyl, C3-C8 heterocyclic alkyloxy, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

[0050] In another preferred embodiment, R5, R6, R7, R8 and R9 are all H or deuterium, or one of them is not hydrogen or deuterium, or two of them are not H or deuterium.

[0051] In another preferred embodiment, the compound has the structure shown in formula (I-5) or (I-6):

[0052]

[0053] in, Selected from:

[0054] R1 is selected from: tert-butyl, cyclobutyl, cyclohexyl, phenyl, Furthermore, the cyclobutyl, cyclohexyl, and phenyl groups are optionally substituted by one or more of the following groups: halogen, cyano, C1-C3 alkyl, trifluoromethyl, trifluoromethoxy, halogen-substituted or unsubstituted phenyl groups;

[0055] R2 is a phenyl group, and the phenyl group is optionally substituted by one or more groups selected from the following: fluorine, cyano, trifluoromethoxy.

[0056] R3 is hydrogen or halogen;

[0057] R4 can be hydrogen, deuterium, or fluorine.

[0058] In another preferred embodiment, in formula (I-5), R1 is selected from: tert-butyl, cyclobutyl, cyclohexyl, phenyl, Furthermore, the cyclobutyl and phenyl groups are optionally substituted with one or more of the following groups: halogen, cyano, trifluoromethyl, trifluoromethoxy, halogen-substituted or unsubstituted phenyl groups.

[0059] In another preferred embodiment, the prodrug has the structure shown in Formula III.

[0060]

[0061] in,

[0062] R p It is CH2OCOC(CH3)3;

[0063] R3 is hydrogen or halogen;

[0064] R4 is hydrogen, deuterium, or fluorine;

[0065] The definitions of X, Y, Z, A, and n are as described above.

[0066] In another preferred embodiment, Selected from:

[0067] In another preferred embodiment, the compound is one of the following compounds:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] In a second aspect, the present invention provides a method for preparing the compound of the first aspect, wherein the method is selected from one of the following methods:

[0074] Synthesis Method 1:

[0075]

[0076] X and Y are each selected from CH or N, and X and Y cannot be CH at the same time;

[0077] Z is selected from O, S, or NH;

[0078] The definitions of R3, R4, R5, R6, R7, R8, and R9 are as described above;

[0079] Step 1-1: Compound 1A reacts with Compound 1B in the presence of phenylsilane and dichlorodibutyltin to give Compound 1C; or Compound 1A reacts with Compound 1B in the presence of acetic acid and sodium borohydride to give Compound 1C.

[0080] Synthesis Method 2:

[0081]

[0082] X is N, Y is CH;

[0083] Z is O;

[0084] The definitions of R1, R3, and R4 are as described above;

[0085] Step 2-1: Compound 2A reacts with 1,2-diiodoethane to give compound 2B;

[0086] Step 2-2: Compound 2B and compound 2C undergo a coupling reaction to obtain compound 2D;

[0087] Steps 2-3: Compound 2D is hydrogenated and reduced to obtain compound 2F;

[0088] Steps 2-4: Compound 2F is reduced with sodium borohydride to obtain compound 2G;

[0089] Steps 2-5: Compound 2G reacts with an oxidizing agent to give compound 2H;

[0090] Steps 2-6: Compounds 2H and 1B react in the presence of phenylsilane and dibutyltin dichloro to give compound 2I;

[0091] Steps 2-7: Compound 2I is reacted with hydrochloric acid to obtain compound 2J;

[0092] Steps 2-8: Compound 2K and compound 2J react in the presence of HATU and N,N-diisopropylethylamine to give compound 2L;

[0093] Synthesis Method 3:

[0094]

[0095] X is N, Y is CH;

[0096] Z is O;

[0097] The definitions of R2, R3, and R4 are as described above;

[0098] Step 3-1: Compound 3A and compound 2J react in the presence of zinc chloride, triethylamine and sodium cyanoborohydride to give compound 3B;

[0099] Synthesis Method 4:

[0100]

[0101] X is N, Y is CH;

[0102] Z is O;

[0103] The definition is as described above, preferably. It is a nitrogen-containing 4- or 6-membered heterocyclic group;

[0104] Step 4-1: Compound 4A reacts with lithium aluminum hydride to give compound 4B;

[0105] Step 4-2: Compound 4B reacts with tert-butyldiphenylchlorosilane to give compound 4C;

[0106] Step 4-3: In the presence of boranetetrahydrofuran complex and n-butyllithium, compound 4C reacts with 4-formylmorpholine to give compound 4D;

[0107] Step 4-4: Compound 4D is oxidized with Dess-Martin oxidant to obtain compound 4E;

[0108] Steps 4-5: Compound 4E and In the presence of sodium borohydride acetate, compound 4F is obtained by reductive amination.

[0109] Steps 4-6: In the presence of tetrabutylammonium fluoride in tetrahydrofuran solution, compound 4F is deprotected to give compound 4G;

[0110] Steps 4-7: Compound 4G is oxidized with Dess-Martin oxidant to give compound 4H;

[0111] Steps 4-8: In the presence of acetic acid and sodium borohydride, compound 4H reacts with compound 1B to give compound 4I;

[0112] Synthesis Method 5:

[0113]

[0114] X and Y are each selected from CH or N, and X and Y cannot be CH at the same time;

[0115] Z is selected from O, S, or NH;

[0116] The definitions of R3, R4, Ra2, and q are as described above;

[0117] Step 5-1: In the presence of a palladium catalyst, compound 5A and compound 5B undergo a Buchwald-Hartwig amination reaction to give compound 5C;

[0118] Step 5-2: In the presence of acetic acid and sodium borohydride, compound 5C undergoes a reductive amination reaction with compound 1B to obtain compound 5D.

[0119] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the compound of the first aspect, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a prodrug, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0120] In another preferred embodiment, the pharmaceutical composition further comprises one or more other pharmaceutically therapeutically active ingredients that produce a synergistic effect in the prevention or treatment of a specific disease or functional disorder; or reduce or eliminate the toxic side effects produced by one or more other pharmaceutically therapeutically active ingredients in the prevention or treatment of a specific disease or functional disorder.

[0121] In another preferred embodiment, the pharmaceutical composition further comprises one or more selected from dexamethasone, rituximab, trastuzumab, PD-1 inhibitors, PDL-1 inhibitors, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofarabine injection, HDAC inhibitors, kinase-targeting inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, erythrocyte growth hormone, minocycline, elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, ubliximab, romidepsin, eltrombopag, CAR-T, and melphalan.

[0122] In a fourth aspect, the present invention provides a compound as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, for the preparation of a compound for the prevention or treatment of CRL4. CRBN Use in medicines for diseases related to E3 ubiquitin ligases, preferably, those related to CRL4 CRBN Diseases associated with E3 ubiquitin ligase include cancer, pain, central nervous system disorders, or immune system disorders.

[0123] In another preferred embodiment, the disease is a solid tumor or hematologic malignancy. Preferably, the disease is selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, etc. Monocytic and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, type I complex regional pain syndrome, malignant melanoma, radiculopathy, glioblastoma, glioma, malignant glioma, refractory plasmacytoma, extraocular melanoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, or primary macroglobulinemia.

[0124] In a fifth aspect, the present invention provides a method for preventing or treating CRL4. CRBN A method for treating E3 ubiquitin ligase-related diseases, comprising the steps of administering to a subject in need a compound as described in the first aspect of the invention, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer thereof, or a prodrug thereof, or a pharmaceutical composition as described in the third aspect of the invention, thereby preventing or treating the disease.

[0125] In another preferred embodiment, the subject is a human or a non-human mammal, such as a rat or mouse.

[0126] In another preferred embodiment, the disease is a solid tumor, hematologic malignancy, etc.

[0127] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0128] Figure 1 The diagrams show the structure and stereoconformation of the compounds of the present invention, which can form intramolecular hydrogen bonds and form a special dihedral angle with a five-membered heteroaromatic ring through alkylene groups. Detailed Implementation

[0129] Through extensive and in-depth research, the inventors unexpectedly developed a novel CRL4 structure. CRBN E3 ubiquitin ligases, being gel-like degraders, exhibit superior activity on cells such as multiple myeloma MM.1S cells, mantle cell lymphoma Mino cells, and acute myeloid leukemia cell line (MV-4-11) compared to marketed drugs, clinically investigated drugs, and structurally comparable amines that do not form intramolecular hydrogen bonds or specific dihedral angles, due to the formation of intramolecular hydrogen bonds. Based on this, the inventors completed this invention.

[0130] the term

[0131] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0132] Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Substitution in the relevant structure in this invention includes both substitution and non-substitution; for example, "optionally" or "optionally" substituted by a substituent means both substitution and non-substitution.

[0133] The statement in this invention that when the number of substituents is greater than 1, the substituents R can be the same or different substituents means that when there are multiple substituents in a certain structure, the combination of substituents R can be selected from a variety of different types of substituents.

[0134] The term "substitution" applies only to sites that can be replaced by a substituent and does not include substitutions that are not achievable with existing chemical knowledge. The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. A specific substituent is a substituent described above or that appears in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic alkyl groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a single carbon atom.

[0135] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0136] The term "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms on the chain, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0137] The term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0138] The term "aryl" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6- to 10-membered ring (i.e., C6-C10 aryl), more preferably phenyl and naphthyl, and most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0139] The term "halogen-substituted C1-C6 alkoxy" refers to a straight-chain or branched C1-C6 alkoxy group substituted with one or more halogens, including, without limitation, -OCH2F, -OCHF2, and -OCF3.

[0140] The term "halogen-substituted C1-C6 alkyl" refers to straight-chain or branched C1-C6 alkyl groups substituted with one or more halogens, including, without limitation, 2-bromoethyl, 2-bromopropyl, etc.

[0141] The term "cycloalkyl" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. Cycloalkyl groups include C4-C12 cycloalkyl groups, preferably C4-C10, C4-C6, or C10-C12 cycloalkyl groups. Monocyclic cycloalkyl groups are not limited to cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl groups, while polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, such as...

[0142] The term "4-10 membered heterocyclic group" refers to a heterocyclic group containing one or more saturated and / or partially saturated rings comprising 4 to 10 ring atoms, wherein one or more (e.g., 2, 3) ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. The 4-10 membered heterocyclic group is preferably a 4-6 membered heterocyclic group, for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl. The term "C3-C8 heterocyclic group" refers to a saturated and / or partially saturated ring containing 3-8 ring carbon atoms, wherein it also includes one or more (e.g., 2, 3) heteroatoms selected from nitrogen, oxygen, sulfur or S(O)m (where m is an integer from 0 to 2). C3-C8 heterocyclic groups include heterocyclic groups containing 3-5 ring carbon atoms, which also include one or more (e.g., 2, 3) heteroatoms selected from nitrogen, oxygen or sulfur, such as oxo-heterobutyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0143] The term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having 2 to 6 carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, vinyl, propenyl, butenyl, styrene, and styrene-propenyl.

[0144] The term "heteroaryl" refers to a 5-14 membered aryl group having 1 to 4 heteroatoms as ring atoms and the remaining ring atoms being carbon. The heteroatoms include oxygen, sulfur, and nitrogen, preferably 5-10 members, more preferably 5 or 6 members, such as thiophene, furanyl, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0145] "Hydrate" refers to a compound that contains water.

[0146] "Pharmaceutically acceptable salts" refer to drug molecules that form corresponding salts with organic acids, inorganic acids, or organic bases, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, and methanesulfonates.

[0147] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0148] Active ingredients

[0149] As used herein, “compound of the invention” or “active ingredient” refers to a compound of formula I and also includes a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug.

[0150] The compound shown in formula (I) may also exist in different tautomer forms, all of which are included within the scope of this invention.

[0151] The term "tautomer" refers to structural isomers with different energies that interconvert via a low energy barrier. The reaction generally results in the movement of hydrogen atoms or protons, accompanied by the transformation of single bonds and adjacent double bonds.

[0152] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds contemplated by this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, non-corresponding isomers, racemates, and other mixtures, are within the scope of this invention. Additional asymmetric carbon atoms may be present in alkyl or other substituents. All such isomers and mixtures thereof are included within the scope of this invention.

[0153] The compounds represented by formula (I) may contain one or more asymmetric or chiral centers, and therefore may exist in different stereoisomer forms. The compounds of this invention include all stereoisomer forms, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof (such as racemates), all of which are included within the scope of this invention.

[0154] Unless otherwise stated, the term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0155] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0156] A racemic mixture is a stereoisomer that is a mirror image of another, with opposite optical rotations that cancel each other out.

[0157] The compounds in the general formula and examples of this invention contain chiral centers; therefore, the single configuration or racemate of the compounds of this invention is also within the scope of this application. Furthermore, prior art evidence indicates that compounds with a amine structure, in their R configuration, S configuration, and racemate, are converted to a 1:1 racemate in vivo after entering cells from in vitro cell experiments. Therefore, those skilled in the art can expect that the technical solutions corresponding to the enantiomers or racemates of the compounds of this invention can achieve comparable technical effects. To obtain a single configuration of the example compounds in this invention, a single configuration example compound can be obtained through synthesis method 1 in the compound preparation method using the single configuration intermediate 1B; thus, an enantiomer can be obtained. Alternatively, diastereomeric example compounds can be obtained through the preparation of the single configuration intermediate 1B; therefore, diastereomeric compounds can also be obtained in this invention, such as compounds 48 and 54, which can form diastereomeric forms. These different isomer forms all belong to stereoisomers.

[0158] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be radiolabeled with isotopes such as deuterium (D) and tritium (T). 12 C 13 C and 14 C, etc. For example, deuterium can replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations in the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0159] As used herein and unless otherwise specified, the term "prodrug" refers to a derivative of a compound containing a bioreactive functional group, such that, under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide said compound. Typically, prodrugs are inactive, or at least less active than the compound itself, such that the compound does not exert its activity until the bioreactive functional group is cleaved from it. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide said compound. For example, a prodrug may contain a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureas. For reviews of prodrugs, see, for example, J. Rautio et al., Nature Reviews Drug Discovery 2008, 7, 255-270 and Prodrugs: Challenges and Rewards (V. Stella et al. ed., Springer, 2007).

[0160] When the compounds of this invention contain a basic group, they can be prepared into pharmaceutically acceptable salts, including inorganic acid salts and organic acid salts. Suitable acids for salt formation are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0161] This invention also includes any of the novel intermediates disclosed herein.

[0162] Pharmaceutical Compositions and Administration

[0163] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0164] The compound of formula (I) can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I is preferred. Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of either drug alone.

[0165] As used herein, the term "pharmaceutically acceptable" means a substance (such as a 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., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0166] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0167] Drugs or active ingredients that can be used in combination with compounds of general formula (I) include, but are not limited to, dexamethasone, rituximab, trastuzumab, PD-1 inhibitors, PDL-1 inhibitors, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofarabine injection, HDAC inhibitors, kinase-targeting inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, erythrocyte growth hormone, minocycline, elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, ubliximab, romidepsin, eltrombopag, CAR-T, and melphalan.

[0168] Typical formulations are prepared by mixing compounds of general formula (I) of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, and water. The specific carrier, diluent, or excipient used will depend on the manner and purpose of use of the compound according to the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, as well as other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, seasonings or other known additives, so that the compound represented by formula (I) is manufactured or used in an acceptable form.

[0169] When the compounds of formula (I) of the present invention are used in combination with at least one other drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of formula (I) of the present invention can be administered to the subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic forms of administration.

[0170] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, or other known additives to make or use the pharmaceutical composition in an acceptable form.

[0171] The preferred route of administration for the pharmaceutical products of this invention is oral administration. Solid dosage forms for oral administration may include capsules, tablets, powders, or granules. In solid dosage forms, the compounds or pharmaceutical compositions of this invention are mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerin, etc.; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, specific complex silicates, sodium carbonate, etc.; solution blocking agents such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using lactose and high molecular weight polyethylene glycol as excipients.

[0172] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds or compositions thereof of the present invention, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerin; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitol; or mixtures of several of these substances.

[0173] In addition to these inert diluents, the composition may also include one or more excipients, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0174] In the case of suspensions, in addition to the compounds or combinations of the present invention, they may further contain carriers such as suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, or mixtures of several of these substances.

[0175] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds or combinations of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at normal room temperature and liquid at body temperature, and can melt in the rectum or vagina to release the active compound.

[0176] The compounds or pharmaceutical compositions of this invention can be administered in other topical dosage forms, including ointments, powders, sprays, and inhalers. The drug can be mixed under sterile conditions with pharmaceutically acceptable excipients, diluents, or carriers, and any desired preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be covered within the scope of this invention.

[0177] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0178] The terms "drug combination," "drug co-administration," "combined drug therapy," "administration of other treatments," and "administration of other therapeutic agents" used in this invention refer to drug therapy obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0179] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0180] The compounds or pharmaceutical compositions of the present invention can be used to prepare treatments or preventative medications for CRL4. CRBN Drugs for diseases involving E3 ubiquitin ligases. This invention describes a drug involving CRL4. CRBN Diseases involving E3 ubiquitin ligase, without limitation, include tumors, central nervous system diseases, and immune diseases.

[0181] In a preferred embodiment, the diseases include, but are not limited to: cancer, pain (including but not limited to complex regional pain syndrome), skin diseases, immunodeficiency diseases, and damage and dysfunction of the central nervous system.

[0182] In another preferred embodiment, the cancers include (but are not limited to): skin cancers (such as melanoma), lymphatic system cancers, breast cancer, cervical cancer, uterine cancer, digestive tract cancers, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain tumors, head and neck cancer, pharyngeal cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer, and cancers related to AIDS. The compounds provided by this invention are also effective against hematologic malignancies and myeloma, such as for the treatment of multiple myeloma, lymphoma, and acute and chronic leukemia. The compounds provided by this invention can also be used for the prevention or treatment of primary and metastatic tumors.

[0183] The uses of the drug molecules of this invention include, but are not limited to, the diseases selected from: myelodysplastic syndromes, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic lymphoma. Monocytic and cytoplasmic leukemia, myeloid leukemia, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, type I complex regional pain syndrome, malignant melanoma, radiculopathy, glioblastoma, glioma, malignant glioma, refractory plasmacytoma, extraocular melanoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, or primary macroglobulinemia.

[0184] Preparation methods of compounds

[0185] The following describes a method for preparing the compound of Formula I. In some cases, the order of steps in the reaction scheme can be changed to promote the reaction or avoid unwanted byproducts. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, such combinations being readily performed by those skilled in the art.

[0186] Typically, in the preparation process, the reactions are carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C-150°C, preferably 10°C-100°C). The reaction time is typically 0.1 h to 60 h, preferably 0.5 h to 48 h.

[0187] Preferably, the method is selected from one of the following methods:

[0188] For the synthesis of starting compounds 1A, 2B, 2D, and 2F, refer to CN111285850A and WO2017193063 A1.

[0189] Synthesis Method 1:

[0190]

[0191] X and Y are each selected from CH or N, and X and Y cannot be CH at the same time;

[0192] Z is selected from O, S, or NH;

[0193] The definitions of R3, R4, R5, R6, R7, R8, and R9 are as described above;

[0194] Step 1-1: Compound 1A reacts with Compound 1B in the presence of phenylsilane and dichlorodibutyltin to give Compound 1C; or Compound 1A reacts with Compound 1B in the presence of acetic acid and sodium borohydride to give Compound 1C.

[0195] Synthesis Method 2:

[0196]

[0197] X is N, Y is CH;

[0198] Z is O;

[0199] The definitions of R1, R3, and R4 are as described above;

[0200] Step 2-1: Compound 2A reacts with 1,2-diiodoethane to give compound 2B;

[0201] Step 2-2: Compound 2B and compound 2C undergo a coupling reaction to obtain compound 2D;

[0202] Steps 2-3: Compound 2D is hydrogenated and reduced to obtain compound 2F;

[0203] Steps 2-4: Compound 2F is reduced with sodium borohydride to obtain compound 2G;

[0204] Steps 2-5: Compound 2G reacts with an oxidizing agent to give compound 2H;

[0205] Steps 2-6: Compounds 2H and 1B react in the presence of phenylsilane and dibutyltin dichloro to give compound 2I;

[0206] Steps 2-7: Compound 2I is reacted with hydrochloric acid to obtain compound 2J;

[0207] Steps 2-8: Compound 2K and compound 2J react in the presence of HATU and N,N-diisopropylethylamine to give compound 2L;

[0208] Synthesis Method 3:

[0209]

[0210] X is N, Y is CH;

[0211] Z is O;

[0212] The definitions of R2, R3, and R4 are as described above;

[0213] Step 3-1: Compound 3A and compound 2J react in the presence of zinc chloride, triethylamine and sodium cyanoborohydride to give compound 3B;

[0214] Synthesis Method 4:

[0215]

[0216] X is N, Y is CH;

[0217] Z is O;

[0218] The definition is as described above, preferably. It is a nitrogen-containing 4- or 6-membered heterocyclic group;

[0219] Step 4-1: Compound 4A reacts with lithium aluminum hydride to give compound 4B;

[0220] Step 4-2: Compound 4B reacts with tert-butyldiphenylchlorosilane to give compound 4C;

[0221] Step 4-3: In the presence of boranetetrahydrofuran complex and n-butyllithium, compound 4C reacts with 4-formylmorpholine to give compound 4D;

[0222] Step 4-4: Compound 4D is oxidized with Dess-Martin oxidant to obtain compound 4E;

[0223] Steps 4-5: Compound 4E and In the presence of sodium borohydride acetate, compound 4F is obtained by reductive amination.

[0224] Steps 4-6: In the presence of tetrabutylammonium fluoride in tetrahydrofuran solution, compound 4F is deprotected to give compound 4G;

[0225] Steps 4-7: Compound 4G is oxidized with Dess-Martin oxidant to give compound 4H;

[0226] Steps 4-8: In the presence of acetic acid and sodium borohydride, compound 4H reacts with compound 1B to give compound 4I;

[0227] Synthesis Method 5:

[0228]

[0229] X and Y are each selected from CH or N, and X and Y cannot be CH at the same time;

[0230] Z is selected from O, S, or NH;

[0231] The definitions of R3, R4, Ra2, and q are as described above;

[0232] Step 5-1: In the presence of a palladium catalyst, compound 5A and compound 5B undergo a Buchwald-Hartwig amination reaction to give compound 5C;

[0233] Step 5-2: In the presence of acetic acid and sodium borohydride, compound 5C undergoes a reductive amination reaction with compound 1B to obtain compound 5D.

[0234] Main advantages of this invention:

[0235] 1. The compounds of this invention have excellent cellular activity, especially in cells such as multiple myeloma MM.1S cells, mantle cell lymphoma Mino cells, and acute myeloid leukemia cell line (MV-4-11), which are superior to marketed drugs, clinical investigation drugs, and compounds that are structurally comparable to those disclosed in the prior art but do not have intramolecular hydrogen bonds or specific dihedral angles.

[0236] 2. The compounds of this invention exhibit superior pharmacokinetics and efficacy. Pharmacokinetic and pharmacodynamic experiments in mice have shown that the compounds of this invention, for which testing results have been obtained, are superior to structurally comparable compounds disclosed in the prior art that lack intramolecular hydrogen bonds. These examples are intended to illustrate the advantages of forming intramolecular hydrogen bonds or specific dihedral angles in this invention and are not limited to other compounds of this invention possessing the same advantages.

[0237] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0238] In all embodiments, 1 The 1H NMR spectrometry was performed using a 400MHz and a 500MHz Bruker NMR spectrometer, with chemical shifts expressed as δ (ppm). Mass spectrometry was performed using UPLC-MS (ESI) mass spectrometry; the UPLC model was Waters HPLC H-CLASS, and the MS (ESI) model was Waters SQ Detector 2. Anhydrous tetrahydrofuran was prepared by reflux drying of benzophenone / sodium metal to remove oxygen, and anhydrous toluene and anhydrous dichloromethane were prepared by reflux drying of calcium chloride. Solvents used as mobile phases for column chromatography, such as petroleum ether, ethyl acetate, and dichloromethane, were purchased from Sinopharm Chemical Reagent Co., Ltd. The thin-layer chromatography silica gel plates (HSGF254) used for reaction detection were from Sinopharm Chemical Reagent Co., Ltd. 200-300 mesh silica gel from Sinopharm Chemical Reagent Co., Ltd. was used for compound separation. The raw materials used in this invention can be obtained commercially, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods of inhibition in the art, or prepared according to the methods described in this invention.

[0239] Example

[0240] Synthesis of key intermediates:

[0241] Intermediate 1: Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)oxazol-5-carboxylate

[0242]

[0243] Compounds 2-iodoxazole-5-carboxylic acid ethyl ester (500 mg, 1.87 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (636 mg, 2.06 mmol), and tetraphenylphosphine palladium (216 mg, 0.187 mmol) were dissolved in 16 mL of dioxane. 4 mL of Na₂CO₃ (396 mg, 3.74 mmol) aqueous solution was added. The reaction system was purged with nitrogen three times, and then heated to 90 °C for 4 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature. The reaction system was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated with acid under reduced pressure and subjected to silica gel column chromatography to obtain 424 mg of a brown oily substance, with a yield of 70%.1 H NMR(400MHz, CDCl3)δ7.73(s,1H),6.91(s,1H),4.43–4.33(m,2H),4.15(s, 2H), 3.61 (t, J = 4.8Hz, 2H), 2.64 (s, 2H), 1.48 (s, 9H), 1.38 (t, J = 6.7Hz, 3H).

[0244] Intermediate 2: Ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)oxazol-5-carboxylate

[0245]

[0246] 420 mg of ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)oxazol-5-carboxylate was dissolved in 5 mL of tetrahydrofuran. A catalytic amount of Raney nickel was added, and the mixture was purged with nitrogen and then purged with hydrogen three times. The reaction system was hydrogenated overnight at room temperature and atmospheric pressure. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter residue was washed with 30 mL of tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain the product, which was directly added to the next step.

[0247] Intermediate 3: 4-(5-(hydroxymethyl)oxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0248]

[0249] Ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)oxazol-5-carboxylic acid (437 mg, 1.67 mmol) was dissolved in 10 mL of anhydrous ethanol, and sodium borohydride (256 mg, 6.68 mmol) was added. After reacting at room temperature for 4 hours, the reaction was quenched with water, extracted with ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated with acid under reduced pressure and subjected to silica gel column chromatography to give 300 mg of a colorless oil, with a yield of 64%. 1 H NMR (500MHz, CDCl3) δ6.90(s,1H),4.64(s,2H),4.12(dd,J=14.3,7.1Hz,2H),2.98-2.85(m,3H),2.04-1.95(m,2H),1.81–1.72(m,2H),1.46(s,9H).

[0250] Intermediate 4: 4-(5-formyloxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0251]

[0252] 300 mg (1.06 mmol) of 4-(5-(hydroxymethyl)oxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 8 mL of dry dichloromethane solution. Under ice bath conditions, 541 mg (1.28 mmol) of Dys-Martin oxidant was added. After the addition was complete, the mixture was brought to room temperature and reacted for 3 hours. After the reaction was complete, sodium thiosulfate solution was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with dichloromethane. The layers were separated, and the organic layer was washed successively with sodium thiosulfate solution and saturated sodium bicarbonate solution. The mixture was dried, concentrated under reduced pressure, and purified by silica gel column chromatography to give 290 mg of white solid, with a yield of 98%. 1 H NMR (400MHz, CDCl3) δ9.74(s,1H),7.78(s,1H),4.11(s,2H),3.00(dt,J=23.4,1 1.2Hz, 3H), 2.08 (d, J=12.9Hz, 2H), 1.83 (dd, J=22.3, 10.3Hz, 2H), 1.47 (s, 9H).

[0253] Intermediate 5: 4-(5-(((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)oxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0254]

[0255] 4-(5-formyloxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.07 mmol), racemic pomalidomide (292 mg, 1.07 mmol), phenylsilane (132 μL, 1.07 mmol), and dichlorodibutyltin (232 μL, 1.07 mmol) were dissolved in 8 mL of dry tetrahydrofuran. The reaction system was heated to 80 °C and reacted overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 262 mg of yellow solid, yield 46%. 1 H NMR (400MHz, DMSO) δ11.10(s,1H),7.59(t,J=7.6Hz,1H),7.21(d,J=8.4Hz,1H),7.08(d ,J=6.9Hz,1H),7.02(d,J=5.8Hz,1H),6.97(s,1H),5.06(dd,J=12.5,4.8Hz,1H),4.60(d ,J=5.7Hz,2H),3.85(d,J=12.6Hz,2H),2.93(dt,J=24.9,11.5Hz,4H),2.64-2.53(m,1H) ,2.08–1.98(m,1H),1.91(d,J=12.6Hz,2H),1.49(dd,J=23.5,11.9Hz,2H),1.39(s,9H).

[0256] Intermediate 6: 2-(2,6-dioxadiazin-3-yl)-4-((2-(piperidin-4-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione hydrochloride

[0257]

[0258] 178 mg of compound 4-(5-(((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)oxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 6 mL of dioxane hydrochloride and reacted at room temperature for 5 hours. After the reaction was monitored to be complete, the product was concentrated under reduced pressure to obtain the product.

[0259] Intermediate 7: N-(prop-2-en-1-yl)-4-(trifluoromethoxy)benzamide

[0260]

[0261] p-Trifluoromethoxybenzoic acid (2 g, 9.7 mmol), propargylamine (445 mg, 8.1 mmol), and HATU (3.7 g, 9.7 mmol) were dissolved in 30 mL of DMF. N,N-diisopropylethylamine (8 mL, 48.6 mmol) was added with stirring at room temperature. After reacting for approximately 0.5 hours, the reaction was monitored by TLC until complete. The reaction was then quenched with water, extracted with ethyl acetate, and the organic phase was washed several times with saturated sodium chloride solution. The phase was dried, concentrated, and column chromatography was performed to give 1.6 g of the product, with a yield of 68%.

[0262] Intermediate 8: 2-(4-(trifluoromethoxy)phenyl)oxazol-5-carboxaldehyde

[0263]

[0264] N-(prop-2-en-1-yl)-4-(trifluoromethoxy)benzamide (671 mg, 2.76 mmol) and iodine (140 mg, 0.55 mol) were added to a 100 mL round-bottom flask. The mixture was purged with oxygen three times and the reaction was irradiated with 420 nm LED light for 10 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and precipitated by column chromatography to obtain 488 mg of a yellow solid, with a yield of 69%. 1 H NMR (500MHz, DMSO) δ9.80 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 8.9Hz, 2H), 7.57 (d, J = 8.1Hz, 2H).

[0265] Intermediate 9: 2-([1,1'-biphenyl]-3-yl)oxazol-5-carboxaldehyde

[0266]

[0267] The synthesis method was the same as that for intermediate 8, using N-(1-yl-2-propanediol)-[1,1'-biphenyl]-3-carboxamide (300 mg, 1.28 mmol) as the starting material, to obtain 93 mg of yellow solid, with a yield of 31%. 1 H NMR (400MHz, CDCl3) δ9.84(s,1H),8.42(s,1H),8.17(d,J=7.7Hz,1H),7.98(s,1H),7.79(d,J =7.7Hz,1H),7.67(s,2H),7.60(t,J=7.8Hz,1H),7.49(t,J=7.5Hz,2H),7.41(t,J=7.3Hz,1H).

[0268] Intermediate 10: 2-(p-Tolyl)oxazole-5-carboxaldehyde

[0269]

[0270] Using 4-methyl-N-(1-yl-2-propanediol)benzamide (500 mg, 2.89 mmol) as a starting material, the same method as intermediate 8 was used to synthesize 0.255 g of a yellow solid, with a yield of 51%. 1 H NMR (400MHz, DMSO) δ9.79 (s, 1H), 8.32 (s, 1H), 7.99 (d, J = 7.6Hz, 2H), 7.42 (d, J = 7.7Hz, 2H).

[0271] Intermediate 11: 2-(4-methoxyphenyl)oxazole-5-carboxaldehyde

[0272]

[0273] Using 4-methoxy-N-(1-yl-2-propanediol)benzamide (500 mg, 2.46 mmol) as the starting material, the same method as intermediate 8 was used to synthesize 0.402 g of a pale yellow solid, with a yield of 51%. The theoretical value of UPLC-MS (ESI) was C0.05. 11 H9NO3[M+H] + 204.20, Measured value: 204.06

[0274] Intermediate 12: 2-(4-chlorophenyl)oxazole-5-carboxaldehyde

[0275]

[0276] Using 4-chloro-N-(prop-2-yn-1-yl)benzamide (500 mg, 2.58 mmol) as a starting material, the same synthesis method as intermediate 8 was used to obtain 289 mg of a pale yellow solid, with a yield of 52%.

[0277] 1 H NMR (400MHz, DMSO) δ9.82 (s, 1H), 8.35 (s, 1H), 8.10 (d, J = 7.5Hz, 2H), 7.68 (d, J = 7.6Hz, 2H).

[0278] Intermediate 13: 2-(4-fluorophenyl)oxazole-5-carboxaldehyde

[0279]

[0280] Using 4-fluoro-N-(1-yl-2-propanediol)benzamide (1 g, 5.64 mmol) as the starting material, the same synthesis method as intermediate 8 was used to obtain 647 mg of pale yellow solid, with a yield of 60%. 1 H NMR (400MHz, DMSO) δ9.81 (s, 1H), 8.34 (s, 1H), 8.15 (d, J = 6.0Hz, 2H), 7.45 (s, 2H).:

[0281] Intermediate 14: 2-(2-chlorophenyl)oxazole-5-carboxaldehyde

[0282]

[0283] Using 2-chloro-N-(prop-2-yn-1-yl)benzamide (500 mg, 2.58 mmol) as a starting material, the synthesis method was the same as that for intermediate 8, yielding 230 mg of a pale yellow solid, with a yield of 43%. The theoretical value of UPLC-MS (ESI) was C1. 10 H6ClNO2[M+H] + 208.61, Measured value: [M+H] + 208.12

[0284] Intermediate 15: 5-(p-Tolyl)oxazole-2-carboxaldehyde

[0285]

[0286] p-Tolualdehyde (3 g, 24.97 mmol) and p-Toluenesulfonylmethylisocyanate (5.12 g, 26.22 mmol) were dissolved in 50 mL of methanol, and potassium carbonate (4.14 g, 29.96 mmol) was added. The mixture was refluxed for 1.5 h. After the reaction was completed by TLC monitoring, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to give 2.5 g of the product, with a yield of 63%.

[0287] 5-(p-Tolyl)oxazole (1 g, 6.28 mmol) was dissolved in 20 mL of diethyl ether. Under nitrogen protection at -78 °C, a 2.4 mol / L n-butyllithium (2.88 mL, 6.91 mmol) hexane solution was slowly added dropwise. After reacting for 30 minutes, a 2 mL solution of DMF (535 μL, 6.91 mmol) in diethyl ether was added dropwise. The reaction was continued at the same temperature for 30 minutes, then allowed to return to room temperature for 1.5 hours. After the reaction was complete as monitored by TLC, the pH was adjusted to approximately 5–6 with 2 M HCl. The mixture was extracted with dichloromethane, separated, dried under reduced pressure, and concentrated. Column chromatography yielded 650 mg of a yellow solid (55% yield). The theoretical value of UPLC-MS (ESI) was C1. 11 H9NO2[M+H] + :188.20, Measured value: 188.16.

[0288] Intermediate 16: 5-(4-fluorophenyl)thiazole-2-carboxaldehyde

[0289]

[0290] p-Fluorophenylboronic acid, 5-bromothiazole, and tetra-triphenylphosphine palladium were added to a 100 mL two-necked flask. 24 mL of dioxane and 6 mL of potassium carbonate (2.79 g, 20.13 mmol) aqueous solution were added. After purging with nitrogen three times, the mixture was refluxed at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, the reaction was quenched with water, and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with saturated sodium chloride, dried, concentrated, and column chromatography was performed to obtain 1.19 g of a brownish-red oil.

[0291] 5-(4-fluorophenyl)thiazole (1.19 g, 6.64 mmol) was dissolved in 25 mL of ultra-dry tetrahydrofuran. Under nitrogen protection at -78 °C, a 2.5 mol / L n-butyllithium (2.92 mL, 7.3 mmol) hexane solution was slowly added dropwise. After reacting for 30 minutes, a 5 mL solution of DMF (568 μL, 7.30 mmol) in tetrahydrofuran was added dropwise. After reacting at the same temperature for 2 hours, the pH was adjusted to approximately 5–6 with 2 M HCl. The mixture was extracted with dichloromethane, separated, dried under reduced pressure, and concentrated. Column chromatography yielded 743 mg of a yellow solid, with a yield of 54%. 1 H NMR (400MHz, CDCl3) δ9.96 (s, 1H), 8.21 (s, 1H), 7.64 (dd, J = 8.7, 5.1Hz, 2H), 7.17 (t, J = 8.5Hz, 2H).

[0292] Intermediate 17: 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde

[0293]

[0294] p-Trifluoromethoxyphenylboronic acid (355 mg, 1.72 mmol), 2-bromo-5-carboxythiazole (300 mg, 1.56 mmol), and tetra-triphenylphosphine palladium (180 mg, 0.156 mmol) were added to a 100 mL two-necked flask. 10 mL of dioxane and 3 mL of potassium carbonate (647 mg, 4.68 mmol) aqueous solution were added. After purging with nitrogen three times, the mixture was refluxed at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, the reaction was quenched with water, and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with saturated sodium chloride, dried, concentrated, and column chromatography was performed to give 220 mg of a yellow solid, with a yield of 52%. 1 HNMR (400MHz, DMSO) δ10.09 (s, 1H), 8.80 (s, 1H), 8.21 (d, J = 8.7Hz, 2H), 7.56 (d, J = 8.4Hz, 2H).

[0295] Intermediate 18: 3-(5-formylthiazolyl-2-yl)benzylnitrile

[0296]

[0297] Using (3-cyanophenyl)boronic acid (253 mg, 1.72 mmol) and 2-bromo-5-carboxythiazole (300 mg, 1.56 mmol) as raw materials, the same synthesis method as intermediate 17 was used to obtain 216 mg of brown solid, with a yield of 65%. 1 H NMR (400MHz, DMSO) δ10.07(s,1H),8.79(s,1H),8.48(s,1H),8.36(d,J=8.0Hz,1H),8.02(d,J=7.7Hz,1H),7.74(t,J=7.9Hz,1H).

[0298] Intermediate 19: 4-(5-formylthiazolyl-2-yl)benzylnitrile

[0299]

[0300] Using (4-cyanophenyl)boronic acid (253 mg, 1.72 mmol) and 2-bromo-5-carboxythiazole (300 mg, 1.56 mmol) as raw materials, the same synthesis method as intermediate 17 was used to obtain 235 mg of brown solid, with a yield of 66%. 1 H NMR (400MHz, DMSO) δ10.12(s,1H),8.86(s,1H),8.26(d,J=8.3Hz,2H),8.04(d,J=8.3Hz,2H).

[0301] Intermediate 20: 2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxaldehyde

[0302]

[0303] Using (4-(trifluoromethyl)phenyl)boronic acid (218 mg, 1.15 mmol) and 2-bromo-5-carboxythiazole (200 mg, 1 mmol) as raw materials, the same synthesis method as intermediate 17 was used to obtain 162 mg of yellow solid, with a yield of 40%. 1 H NMR (400MHz, CDCl3) δ10.08(s,1H),8.48(s,1H),8.15(d,J=6.8Hz,2H),7.75(d,J=6.8Hz,2H).

[0304] Intermediate 21: 2-(2,4-dimethoxyphenyl)thiazole-5-carboxaldehyde

[0305]

[0306] Using (2,4-dimethoxyphenyl)boric acid (313 mg, 1.72 mmol) and 2-bromo-5-carboxymethylthiazole (300 mg, 1.56 mmol) as starting materials, the synthesis method was the same as that for intermediate 17, yielding 249 mg of a yellow solid in 64% yield. The theoretical value of UPLC-MS (ESI) was C1. 12 H 11 NO3S[M+H] + 250.28, measured value: 250.52.

[0307] Intermediate 22: 2-(3-fluorophenyl)thiazole-5-carboxaldehyde

[0308]

[0309] Using (3-fluorophenyl)boronic acid (88 mg, 0.63 mmol) and 2-bromo-5-carboxythiazole (110 mg, 0.57 mmol) as raw materials, the same synthesis method as intermediate 17 was used to obtain 94 mg of pale yellow solid, with a yield of 72%. 1 H NMR (500MHz, DMSO) δ10.10(s,1H),8.81(s,1H),7.95–7.92(m,1H),7.92–7.89(m,1H),7.62(td,J=8.0,5.9Hz,1H),7.50–7.44(m,1H).

[0310] Intermediate 23: 2-(p-Tolyl)thiazole-5-carboxaldehyde

[0311]

[0312] Using p-toluylboronic acid (156 mg, 1.14 mmol) and 2-bromo-5-carboxythiazole (200 mg, 1.04 mmol) as raw materials, the same synthesis method as intermediate 17 was used to obtain 162 mg of yellow solid, with a yield of 70%. 1 H NMR (500MHz, DMSO) δ10.07 (s, 1H), 8.75 (s, 1H), 7.99–7.96 (m, 2H), 7.38 (d, J = 7.9Hz, 2H), 2.39 (s, 3H).

[0313] Intermediate 24: N-methyl-1-(2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methylamine

[0314]

[0315] Using 2-(4-(trifluoromethoxy)phenyl)oxazole-5-carboxaldehyde (200 mg, 0.778 mmol) as a starting material, the intermediate 2-(4-(trifluoromethoxy)phenyl)oxazole-5-carboxaldehyde from the previous step was dissolved in 10 mL of methanol. Methylamine (40% methanol solution) was added, and the reaction was carried out at room temperature for one hour. Sodium borohydride (59 mg, 1.55 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the mixture was quenched with acetone (10 mL), and concentrated under reduced pressure to give 190 mg of white solid, with a yield of 90%. ¹H NMR (500 MHz, DMSO) δ 8.06 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H), 3.76 (s, 2H), 2.30 (s, 3H).

[0316] Intermediate 25: Oxazole-5-Methanol

[0317]

[0318] At 0 °C, 10 mL of a THF solution of oxazol-5-carboxylic acid ethyl ester (9 g, 63.78 mmol) was added dropwise to 100 mL of a THF suspension of LiAlH4 (2.548 g, 63.78 mmol). The mixture was stirred for 30 minutes. After the reaction was complete, the mixture was quenched with water at 0 °C, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 3.039 g of a red oily product, with a yield of 48.09%. 1 H NMR (500MHz, DMSO) δ8.28(s,1H),7.04(s,1H),5.37(t,J=5.8Hz,1H),4.47(d,J=5.8Hz,2H).

[0319] Intermediate 26: 5-((((tert-butyldiphenylsilyl)oxy)methyl)oxazole

[0320]

[0321] The compounds oxazole-5-methanol (1.15 g, 11.61 mmol) and imidazole (1.580 g, 23.21 mmol) were dissolved in 20 mL of dry DMF, and tert-butyldiphenylchlorosilane (3.142 mL, 12.77 mmol) was added. The mixture was stirred for 1 hour, and after the reaction was complete, water was added to quench the reaction. The reaction system was extracted with ethyl acetate, and the organic phase was washed several times with saturated sodium chloride. After drying and concentration, column chromatography was performed to give 3.918 g of a colorless oily product, with a yield of 100%. 1 H NMR (500MHz, DMSO) δ8.33(s,1H),7.66–7.61(m,4H),7.51–7.43(m,6H),7.01(s,1H),4.74(s,2H),0.99(s,9H).

[0322] Intermediate 27: (5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-yl)methanol

[0323]

[0324] Compound 5-((((tert-butyldiphenylsilyl)oxy)methyl)oxazole (3.918 g, 11.61 mmol) was dissolved in 30 mL of dry THF, and the mixture was purged with nitrogen three times. A boranetetrahydrofuran complex (15.3 mL, 15.30 mmol) was added at 0 °C, and the reaction was maintained at 0 °C for 1 hour. The reaction system was then cooled to -78 °C, and a hexane solution of n-butyllithium (6.116 mL, 15.29 mmol) was added dropwise, maintaining the reaction at -78 °C for 2 hours. Then, 4-formylmorpholine (1.6 mL, 15.29 mmol) was added dropwise and the reaction was slowly raised to -25 °C. After the reaction was complete, the reaction was quenched with 35 mL of 5% v / v acetic acid in ethanol solution. The reaction was then raised to room temperature and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.724 g of colorless oily product, with a yield of 63.84%. 1 H NMR(500MHz,DMSO)δ7.65–7.62(m,4H),7.50–7.43(m,6H),6.91(s,1H),5.63 (t,J=6.2Hz,1H),4.71(s,2H),4.46(d,J=6.2Hz,2H),0.99(d,J=5.0Hz,9H).

[0325] Intermediate 28: 5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-carboxaldehyde

[0326]

[0327] The compound (5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-yl)methanol (1.254 g, 3.412 mmol) was dissolved in 10 mL of dichloromethane. Dess-Martin oxidant (1.592 g, 3.753 mmol) was added at 0 °C, and the mixture was heated to room temperature for 1 hour. After the reaction was complete, the reaction was quenched with 1 N NaOH. The aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then subjected to silica gel column chromatography to give 500 mg of a colorless oily product, with a yield of 40.09%. 1 H NMR (500MHz, DMSO) δ9.66 (s, 1H), 7.64 (dd, J = 7.9, 1.5Hz, 4H), 7.49–7.43 (m, 7H), 4.85 (s, 2H), 1.01 (s, 9H).

[0328] Intermediate 29: (2R,6S)-4-((5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-yl)methyl)-2,6-dimethylmorpholine

[0329]

[0330] Compound 5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-carboxaldehyde (500 mg, 1.368 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and cis-2,6-dimethylmorpholine (204 μL, 1.642 mmol) was added. Sodium borohydride acetate (580 mg, 2.736 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction was quenched with ice water, extracted twice with dichloromethane, and the combined organic phases were washed with saturated sodium chloride. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was then purified by silica gel column chromatography to obtain 527 mg of an oily product, with a yield of 82.60%. 1H NMR (500MHz, CDCl3) δ7.67(dd,J=8.0,1.4Hz,4H),7.47–7.37(m,6H),6.77(s,1H),4.67(s,2H),3.72(dt,J=13. 6,6.9Hz,2H),3.65(s,2H),2.75(d,J=10.8Hz,2H),1.91(t,J=10.6Hz,2H),1.14(d,J=6.3Hz,6H),1.05(s,9H).

[0331] Intermediate 30: (2-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-5-yl)methanol

[0332]

[0333] The compound (2R,6S)-4-((5-(((tert-butyldiphenylsilyl)oxy)methyl)oxazol-2-yl)methyl)-2,6-dimethylmorpholine (527 mg, 1.13 mmol) was dissolved in 5 mL of dry tetrahydrofuran solution. The reaction system was cooled to 0 °C, and a tetrahydrofuran solution of tetrabutylammonium fluoride (1.7 mL, 1.70 mmol) was added. The reaction was brought to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 170 mg of oily product; yield 66.49%. 1 H NMR (500MHz, CDCl3) δ6.96 (s, 1H), 4.67 (s, 2H), 3.72 (dqd, J = 12.5, 6.3, 2.0Hz, 2H ),3.66(s,2H),2.76(d,J=10.4Hz,2H),1.94–1.87(m,2H),1.15(d,J=6.3Hz,6H).

[0334] Intermediate 31: 2-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-5-carboxaldehyde

[0335]

[0336] The compound (2-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-5-yl)methanol (170 mg, 0.7513 mmol) was dissolved in 3 mL of dichloromethane. Dess-Martin oxidant (351 mg, 0.8264 mmol) was added at 0 °C, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with 1 N NaOH. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then subjected to silica gel column chromatography to obtain 151 mg of a colorless oily product; yield 89.62%. 1 H NMR(500MHz, CDCl3)δ9.79(s,1H),7.82(s,1H),3.79(s,2H),3.73(dqd,J=12.5,6 .3,2.1Hz,2H),2.79(d,J=10.2Hz,2H),1.99–1.93(m,2H),1.15(d,J=6.3Hz,6H).

[0337] Intermediate 32: 3-Fluoro-4-(4-(5-formylthiazo-2-yl)piperazin-1-yl)benzylnitrile

[0338]

[0339] Compounds 2-bromothiazol-5-carboxaldehyde (100 mg, 0.521 mmol), 3-fluoro-4-(piperazin-1-yl)benzyl nitrile (128 mg, 0.625 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (30 mg, 0.0521 mmol), tris(dibenzylacetone)dipalladium (15 mg, 0.0261 mmol), and cesium carbonate (238 mg, 0.729 mmol) were dissolved in 10 mL of toluene. The reaction system was purged with nitrogen three times, and then heated to 100 °C for 12 hours under nitrogen protection. After the reaction was complete, it was cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 102 mg of brown solid, yield 62%.

[0340] Synthesis of the compounds in the example:

[0341] Synthesis Route 1:

[0342]

[0343] Wherein, R1 is the same as defined above, S-2 is the aforementioned intermediate, and the reaction conditions are described in the following specific embodiments.

[0344] Example 1: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0345]

[0346] Compounds 2-(2,6-dioxadiazin-3-yl)-4-((2-(piperidin-4-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione hydrochloride (40 mg, 0.084 mmol), 1-methylcyclobutanecarboxylic acid (11 mg, 0.092 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (35 mg, 0.092 mmol) were dissolved in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (42 μL, 0.252 mmol) was added under stirring. The reaction was carried out at room temperature for 1 hour. After the reaction was completed as monitored by LC-Mas, 21 mg of a yellow solid was obtained by HPLC purification, with a yield of 47%. 1 H NMR (600MHz, DMSO) δ11.10(s,1H),7.62–7.55(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6 .1Hz,1H),6.98(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.61(d,J=6.0Hz,2H),4.19(s,1H),3.51(s,1H),3.05(td, J = 10.8, 5.4 Hz, 2H), 2.92–2.83 (m, 1H), 2.77 (s, 1H), 2.59 (d, J = 18.1 Hz, 1H), 2.55–2.51 (m, 1H), 2.37 (q, J = 9.5 Hz, 2H), 2.06–1.99 (m, 1H), 1.97–1.85 (m, 3H), 1.78 (t, J = 9.5 Hz, 2H), 1.57 (dt, J = 69.6, 34.8 Hz, 3H), 1.32 (s, 3H). The theoretical value of UPLC-MS (ESI) is C. 28 H 31 N5O6[M+H] + :534.23, measured value: 534.36.

[0347] Example 2: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(1-(1-((4-fluorophenyl)cyclobutane-1-carbonyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0348]

[0349] Using 1-(4-fluorophenyl)cyclobutane-1-carboxylic acid and intermediate 6 as raw materials, the same route as synthetic route 1 and Example 1 was followed to obtain 18 mg of yellow solid, with a yield of 35%. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),7.61–7.54(m,1H),7.38(dd,J=8.6,5.4Hz,2H),7.23–7.14(m,3H),7.07(d,J=7.1Hz,1H) ,7.02-6.97(t,1H),6.92(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.57(d,J=6.2Hz,2H),4.26(d,J=11.6Hz,1H),3.23(d,J=13 .1Hz, 1H), 2.96–2.84(m, 2H), 2.83–2.73(m, 3H), 2.68–2.55(m, 2H), 2.44–2.34(m, 2H), 2.26–2.15(m, 1H), 2.05–1.97(m, 1H), 1.87(dd, J = 18.2, 9.8Hz, 2H), 1.76(dt, J = 15.3, 7.3Hz, 1H), 1.54(d, J = 9.8Hz, 1H), 1.43–1.33(m, 1H). The theoretical value of UPLC-MS (ESI) is C 33 H 32 FN5O6[M+H] + Measured value: 614.23, Actual value: 614.45

[0350] Example 3: 4-((2-(1-((3r,5r,7r)-adamantane-1-carbonyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadipinidin-3-yl)isoindole-1,3-dione

[0351]

[0352] Using 1-adamantanecarboxylic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 25 mg of yellow solid, with a yield of 50%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.59(dd,J=14.0,6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02 (dd,J=12.6,6.4Hz,1H),6.98(s,1H),5.06(dd,J=12.8,5.3Hz,1H),4.61(d,J=6.2Hz,1H),4.25(d,J=13.2Hz,2H),3 .12–3.05(m,1H), 2.99(t,J=12.2Hz,2H), 2.93–2.84(m,1H), 2.65–2.52(m,2H), 2.06–1.99(m,1H), 1.99–1.91(m,5H), 1.88(s,5H), 1.80(dd,J=18.5,8.2Hz,2H), 1.73–1.61(m,7H), 1.49(dd,J=21.3,10.9Hz,2H). The theoretical value of UPLC-MS (ESI) is C 33 H 37 N5O6[M+H] + Measured value: 600.27; Actual value: 600.41

[0353] Example 4: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(1-(1-((trifluoromethoxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0354]

[0355] Using 2-bromo-6-trifluoromethylpyridine and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 20.5 mg of a yellow solid, with a yield of 42%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.62–7.55(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H ),7.03(t,J=6.1Hz,1H),6.98(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.26( d,J=12.5Hz,1H), 3.50(d,J=12.3Hz,1H), 3.17–3.05(m,2H), 2.94–2.82(m,2H), 2.7–2.53(m,4H), 2.46–2.32(m,3H), 2.06–1.90(m,5H), 1.8–1.71(m,1H), 1.63–1.49(m,2H). The theoretical value of UPLC-MS (ESI) is C 28 H 28 F3N5O7[M+H] + :588.20, Measured value: 588.41

[0356] Example 5: 2-(2,6-dioxadiazin-3-yl)-4-((2-(1-(4-fluorobenzoyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0357]

[0358] Using p-fluorobenzoic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 20 mg of yellow solid, with a yield of 43%. 1 H NMR (600MHz, DMSO) δ11.10(s,1H),7.62–7.57(m,1H),7.48–7.43(m,2H),7.26(t,J=8.9Hz,2H),7.21( d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.3Hz,1H),6.99(s,1H),5.06(dd,J=12.9,5.4Hz,1H ), 4.61 (d, J = 6.2 Hz, 2H), 4.32 (s, 1H), 3.55 (s, 1H), 3.17–3.01 (m, 3H), 2.88 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.62–2.56 (m, 1H), 2.56–2.52 (m, 1H), 2.07–1.87 (m, 3H), 1.68–1.57 (m, 2H). The theoretical value of UPLC-MS (ESI) is C 29 H 26FN5O6[M+H]+: 560.19, Measured value: 560.73

[0359] Example 6: 4-(4-(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindol-4-yl)amino)methyl)oxazol-2-yl)piperidine-1-carbonyl)-3-fluorobenzonitrile

[0360]

[0361] Using 4-cyano-2-fluorobenzoic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 13 mg of yellow solid, with a yield of 26%. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),8.00(d,J=9.2Hz,1H),7.79(d,J=7.8Hz,1H),7.63–7.55(m,2H),7.21( d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=5.9Hz,1H),6.99(s,1H),5.06(dd,J=12.8,5.4Hz,1H), 4.61 (d, J = 6.2 Hz, 2H), 4.37 (d, J = 13.3 Hz, 1H), 3.36 (s, 1H), 3.22–3.12 (m, 2H), 3.06 (dd, J = 17.7, 7.0 Hz, 1H), 2.93–2.82 (m, 1H), 2.64–2.52 (m, 2H), 2.11–1.86 (m, 3H), 1.56 (d, J = 10.1 Hz, 2H). The theoretical value of UPLC-MS (ESI) is C. 30 H 25 FN6O6[M+H] + Measured value: 585.18, Actual value: 585.25

[0362] Example 7: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0363]

[0364] Using p-trifluoromethoxybenzoic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 20 mg of yellow solid, with a yield of 38%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.60(s,1H),7.54(d,J=8.5Hz,2H),7.43(d,J=8.2Hz,2 H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(s,1H),6.99(s,1H),5.06(dd,J=12 .8, 5.4 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 4.34 (s, 1H), 3.51 (s, 1H), 3.20–2.98 (m, 3H), 2.94–2.81 (m, 1H), 2.63–2.52 (m, 2H), 2.08–1.87 (m, 3H), 1.70–1.55 (m, 2H). The theoretical value of UPLC-MS (ESI) is C 30 H 26 F3N5O7[M+H]+: 626.18, Measured value: 626.26

[0365] Example 8: 4-((2-(1-(2,4-dichlorobenzoyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxopiridine-3-yl)isoindoline-1,3-dione

[0366]

[0367] Using p-2,4-dichlorobenzoic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 20 mg of a yellow solid, with a yield of 39%. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),7.72(d,J=1.7Hz,1H),7.66–7.54(m,1H),7.50(ddd,J=8.0,3.8,1.8Hz,1H),7.42(dd ,J=27.4,8.2Hz,1H),7.21(d,J=7.8Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=6.2Hz,1H),6.99(s,1H),5.06(dd,J=12.8, 5.4Hz, 1H), 4.61(d, J = 6.2Hz, 2H), 4.37(d, J = 13.2Hz, 1H), 3.27(d, J = 14.1Hz, 1H), 3.10(ddt, J = 29.8, 21.2, 10.3Hz, 3H), 2.93–2.82(m, 1H), 2.65–2.55(m, 2H), 2.10–1.99(m, 2H), 1.89(t, J = 13.4Hz, 1H), 1.71–1.48(m, 2H). The theoretical value of UPLC-MS (ESI) is C29 H 25 Cl2N5O6[M+H]+: 610.12, measured value: 610.28.

[0368] Example 9: 2-(2,6-dioxadiazin-3-yl)-4-((2-(1-neovalerylpiperidin-4-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0369]

[0370] Using p-trimethylacetic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 20 mg of a yellow solid, with a yield of 46%. 1 H NMR (600MHz, DMSO) δ11.10(s,1H),7.59(s,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.0 2(s,1H),6.98(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.17(d,J=13.5Hz,2H) 3.12–3.04 (m, 1H), 2.99 (t, J = 12.0 Hz, 2H), 2.92–2.85 (m, 1H), 2.62–2.52 (m, 2H), 2.06–2.00 (m, 1H), 1.95 (dd, J = 13.1, 2.5 Hz, 2H), 1.51 (td, J = 14.5, 3.6 Hz, 2H), 1.18 (s, 9H). The theoretical value of UPLC-MS (ESI) is C. 27 H 31 N5O6[M+H] + Measured value: 522.23, Actual value: 522.44

[0371] Example 10: 2-(2,6-dioxadiazin-3-yl)-4-(((2-(1-(1-methylcyclohexane-1-carbonyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0372]

[0373] Using 1-methyl-1-cyclohexylcarboxylic acid and intermediate 6 as raw materials, the same route as in synthetic route 1 and Example 1 was followed to obtain 18 mg of yellow solid, with a yield of 38%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.62–7.57(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(s,1H) ,6.97(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.18(d,J=13.4Hz,2H),3.13–3.04(m,1H),2 .98 (t, J = 12.0 Hz, 2H), 2.92–2.82 (m, 1H), 2.57 (ddd, J = 17.7, 15.6, 9.9 Hz, 2H), 2.07–1.99 (m, 1H), 1.94 (d, J = 10.3 Hz, 4H), 1.54–1.43 (m, 4H), 1.39 (dd, J = 13.2, 6.2 Hz, 3H), 1.32–1.20 (m, 4H), 1.15 (s, 3H). The theoretical value of UPLC-MS (ESI) is C 30 H 35 N5O6[M+H]+: 562.26, Measured value: 562.82

[0374] Example 11: 4-((2-(1-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxoperidol-3-yl)isoindole-1,3-dione

[0375]

[0376] Using 1-adamantaneacetic acid and intermediate 6 as raw materials, the same synthetic route as in Example 1 was followed to obtain 26 mg of a yellow solid, with a yield of 50%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.62–7.56(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=6.3Hz,1H),6.9 8(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.30(d,J=13.1Hz,1H),3.93(d,J=14.0Hz,1H),3.15(t,J=11.4 Hz, 1H), 3.08–3.02(m, 1H), 2.92–2.83(m, 1H), 2.75(t, J = 12.0Hz, 1H), 2.65–2.52(m, 2H), 2.13(d, J = 13.5Hz, 1H), 2.04(dd, J = 18.4, 9.4Hz, 2H), 1.98–1.88(m, 5H), 1.64(d, J = 11.9Hz, 3H), 1.61–1.55(m, 10H), 1.43(d, J = 13.1Hz, 1H). The theoretical value of UPLC-MS (ESI) is C 34 H 39 N5O6[M+H] + Measured value: 614.29, Actual value: 614.37

[0377] Example 12: 2-(2,6-dioxadiazin-3-yl)-4-((2-(1-(4-fluorobenzyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0378]

[0379] A tetrahydrofuran solution of p-fluorobenzaldehyde (9 mg, 0.076 mmol), intermediate 6 (30 mg, 0.063 mmol), and ZnCl2 (1 M in THF, 66 μL) was stirred at room temperature for 3 hours. Sodium cyanoborohydride (8 mg, 0.126 mmol) was then added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete as monitored by LC-Mass, the solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. HPLC purification yielded 10 mg of a yellow solid, with a yield of 29%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.62–7.57(m,1H),7.32(s,2H),7.20(d,J=8.6Hz,1H),7.13( t,J=8.6Hz,2H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.2Hz,1H),6.96(s,1H),5.06(dd,J=12.9,5. 4Hz, 1H), 4.60 (d, J = 6.2Hz, 2H), 3.49–3.39 (m, 2H), 2.92–2.83 (m, 1H), 2.81–2.70 (m, 3H), 2.65–2.53 (m, 2H), 2.11–1.97 (m, 3H), 1.91 (d, J = 11.4Hz, 2H), 1.70–1.60 (m, 2H). The theoretical value of UPLC-MS (ESI) is C 29 H 28 FN5O5[M+H] + :546.21, Measured value: 546.84

[0380] Example 13: 4-((4-(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoquinoline-4-yl)amino)methyl)oxazol-2-yl)piperidine-1-yl)methyl)-3-fluorobenzonitrile

[0381]

[0382] Using 4-cyano-2-fluorobenzaldehyde and intermediate 6 as raw materials, the same synthetic route as in Example 12 was followed to obtain 13 mg of yellow solid, with a yield of 38%. 1 H NMR (500MHz, DMSO) δ11.10(s,1H),7.82(dd,J=9.8,1.3Hz,1H),7.68(dd,J=7.9,1.4Hz,1H),7.66–7.56(m,2H),7 .20(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.2Hz,1H),6.96(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4. 60 (d, J = 6.2 Hz, 2H), 3.58 (s, 2H), 2.88 (ddd, J = 17.1, 14.0, 5.4 Hz, 1H), 2.76 (dd, J = 7.6, 3.4 Hz, 3H), 2.65–2.55 (m, 2H), 2.13 (t, J = 10.4 Hz, 2H), 2.07–1.98 (m, 1H), 1.91 (d, J = 11.0 Hz, 2H), 1.73–1.61 (m, 2H). The theoretical value of UPLC-MS (ESI) is C.30 H 27 FN6O5[M+H] + Measured value: 571.20, Actual value: 571.72

[0383] Example 14: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0384]

[0385] Using p-trifluoromethoxybenzaldehyde and intermediate 6 as raw materials, the same synthetic route as in Example 12 was followed to obtain 23 mg of yellow solid, with a yield of 60%. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),7.62–7.56(m,1H),7.42(d,J=8.5Hz,2H),7.30(d,J=8.2Hz,2 H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.01(d,J=6.5Hz,1H),6.96(s,1H),5.06(dd,J= 12.8, 5.4 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 2.93–2.84 (m, 2H), 2.81–2.70 (m, 3H), 2.64–2.56 (m, 2H), 2.11–1.96 (m, 4H), 1.91 (d, J = 10.7 Hz, 2H), 1.66 (dd, J = 21.1, 11.1 Hz, 2H). The theoretical value of UPLC-MS (ESI) is C. 30 H 28 F3N5O6[M+H] + Measured value: 612.20, Actual value: 612.33

[0386] Example 15: 2-(2,6-dioxadiazin-3-yl)-4-((((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methyl)amino)isoindoline-1,3-dione

[0387]

[0388] A solution of 2-(4-(trifluoromethoxy)phenyl)oxazol-5-carboxaldehyde (46 mg, 0.18 mmol), racemic pomalidomide (50 mg, 0.18 mmol), phenylsilane (22 μL, 0.18 mmol), and dibutyltin dichloride (55 mg, 0.18 mmol) in tetrahydrofuran (6 mL) was heated under reflux overnight. After the reaction was completed by LC-Mass monitoring, the solution was concentrated under reduced pressure and purified by HPLC to give 12 mg of yellow solid, yield 13%. 1 ¹H NMR (500MHz, DMSO) δ 11.11 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.3Hz, 2H), 7.32–7.25 (m, 2H), 7.15 (s, 1H), 7.10 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.74 (d, J = 6.2Hz, 2H), 2.89 (dd, J = 22.4, 8.8Hz, 1H), 2.59 (d, J = 18.3Hz, 2H), 2.07–1.99 (m, 1H). The theoretical value of UPLC-MS (ESI) is C0. 24 H 17 F3N4O6[M+H] + Measured value: 515.11, Actual value: 515.29

[0389] Example 16: 2-(2,6-dioxadiazin-3-yl)-4-((2-(4-methoxyphenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0390]

[0391] Using 2-(4-methoxyphenyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 15. After HPLC purification, 8 mg of yellow powder was obtained, with a yield of 10%. 1 H NMR (500MHz, DMSO) δ11.12(s,1H),7.84(d,J=8.9Hz,2H),7.66–7.59(m,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H),7.13(s,1H),7.08(dd,J=14.6,8.0H z,3H),5.07(dd,J=12.8,5.4Hz,1H),4.71(d,J=6.2Hz,2H),3.81(s,3H),2 .95–2.84(m,1H),2.58(d,J=19.4Hz,2H),2.07–1.96(m,1H).UPLC-MS(ESI)

[0392] Theoretical value C 24 H 20 N4O6[M+H] + :461.45, measured value: 461.27.

[0393] Example 17: 2-(2,6-dioxadiazin-3-yl)-4-((2-(3-methoxyphenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0394]

[0395] A solution of 2-(3-methoxyphenyl)oxazol-5-carboxaldehyde (74 mg, 0.37 mmol), racemic pomalidomide (100 mg, 0.37 mmol), phenylsilane (45 μL, 0.37 mmol), and dibutyltin dichloride (112 mg, 0.27 mmol) in tetrahydrofuran (6 mL) was heated under reflux overnight. After the reaction was completed by LC-Mass monitoring, the solution was concentrated under reduced pressure and purified by HPLC to obtain 40 mg of yellow solution, with a yield of 23%. 1 H NMR (500MHz, DMSO) δ11.12(s,1H),7.63(dd,J=8.4,7.2Hz,1H),7.49(dd,J=7.7,1.1Hz,1H),7.44 (d,J=8.0Hz,1H),7.41–7.39(m,1H),7.31(d,J=8.6Hz,1H),7.23(s,1H),7.16(t,J=6.3Hz,1H),7 0.08 (ddd, J = 5.9, 4.0, 3.5 Hz, 2H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.73 (d, J = 6.1 Hz, 2H), 3.81 (s, 3H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.61–2.53 (m, 2H), 2.06–1.99 (m, 1H). The theoretical value of UPLC-MS (ESI) is C 24 H 20 N4O6[M+H] + :461.45, measured value: 461.38.

[0396] Example 18: 4-((2-([1,1'-biphenyl]-3-yl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxopiridine-3-yl)isoindole-1,3-dione

[0397]

[0398] Using 2-([1,1'-biphenyl]-3-yl)oxazol-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 28 mg of yellow substance was obtained, with a yield of 15%. 1 H NMR (500MHz, DMSO) δ11.12(s,1H),8.13(t,J=1.5Hz,1H),7.91(d,J=7.8Hz,1H),7.84–7.78(m,1H),7. 73–7.67(m,2H),7.62(q,J=8.3Hz,2H),7.51(t,J=7.7Hz,2H),7.43(d,J=7.4Hz,1H),7.33(d,J=8.7Hz ,1H), 7.27(s,1H), 7.18(s,1H), 7.10(d,J=7.1Hz,1H), 5.07(dd,J=12.8,5.4Hz,1H), 4.76(d,J=6.3Hz,2H), 2.88(ddd,J=17.0,13.9,5.4Hz,1H), 2.62–2.52(m,2H), 2.07–1.96(m,1H). The theoretical value of UPLC-MS (ESI) is C 29 H 22 N4O5[M+H] + :507.52, measured value: 507.28.

[0399] Example 19: 2-(2,6-dioxadiazin-3-yl)-4-((2-(p-tolyl)oxazol-5-yl)methyl)amino)isoindoline-1,3-dione

[0400]

[0401] Using 2-(p-tolyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 42 mg of yellow powder was obtained, with a yield of 26%. 1 ¹H NMR (500MHz, DMSO) δ 11.12 (s, 1H), 7.80 (d, J = 8.2Hz, 2H), 7.62 (dd, J = 8.5, 7.2Hz, 1H), 7.31 (dd, J = 12.2, 8.3Hz, 3H), 7.20 (s, 1H), 7.14 (s, 1H), 7.09 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.72 (s, 2H), 2.88 (ddd, J = 17.0, 14.0, 5.4Hz, 1H), 2.57 (dd, J = 25.6, 10.1Hz, 2H), 2.35 (s, 3H), 2.06–1.98 (m, 1H). The theoretical value of UPLC-MS (ESI) is C24 H 20 N4O5[M+H] + :445.45, Measured value: 445.33.

[0402] Example 20: 2-(2,6-dioxadiazin-3-yl)-4-((2-(m-tolyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0403]

[0404] Using 2-(m-tolyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 32 mg of yellow powder was obtained, with a yield of 20%. 1 H NMR(500MHz,DMSO)δ11.12(s,1H),7.73(s,1H),7.70(d,J=7.7Hz,1H),7.65–7.59(m, 1H),7.39(t,J=7.7Hz,1H),7.30(t,J=8.7Hz,2H),7.22(s,1H),7.15(t,J=6.2Hz,1H), 7.09 (d, J = 7.1 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.73 (d, J = 6.2 Hz, 2H), 2.93–2.82 (m, 1H), 2.58 (d, J = 19.8 Hz, 2H), 2.36 (s, 3H), 2.07–1.97 (m, 1H). The theoretical value of UPLC-MS (ESI) is C. 24 H 20 N4O5[M+H] + Measured value: 445.45, Actual value: 445.22

[0405] Example 21: 2-(2,6-dioxadiazin-3-yl)-4-((2-(o-tolyl)oxazol-5-yl)methyl)amino)isoindoline-1,3-dione

[0406]

[0407] Using 2-(o-tolyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthesis route was the same as in Example 17. After purification by HPLC, 25 mg of yellow solution was obtained, with a yield of 15%. 1H NMR (500MHz, DMSO) δ11.12(s,1H),7.85(d,J=7.7Hz,1H),7.65–7.58(m,1H),7.35(dt,J=16.6,8.0Hz,4H),7.26(s,1H),7.15(t,J=6.3Hz, 1H),7.09(d,J=7.0Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.75(d,J=6.2Hz,2H),2.94–2.81(m,1H),2.62-2.53(m,5H),2.06–1.95(m,1H).

[0408] The theoretical value of UPLC-MS (ESI) is C 24 H 20 N4O5[M+H] + :445.45, Measured value: 445.29.

[0409] Example 22: 2-(2,6-dioxadiazin-3-yl)-4-((2-phenyloxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0410]

[0411] Using 2-phenyloxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the same synthetic route as in Example 15 was used. After HPLC purification, 31 mg of yellow powder was obtained, with a yield of 20%. 1 H NMR(500MHz,DMSO)δ11.12(s,1H),7.94–7.89(m,2H),7.63(dd,J=8.4,7.3Hz,1H),7.5 5–7.48(m,3H),7.30(d,J=8.6Hz,1H),7.24(s,1H),7.15(t,J=6.3Hz,1H),7.10(d,J=7. 1Hz, 1H), 5.07(dd, J = 12.8, 5.4Hz, 1H), 4.74(d, J = 6.2Hz, 2H), 2.88(ddd, J = 17.0, 13.9, 5.4Hz, 1H), 2.65–2.52(m, 2H), 2.03(ddd, J = 10.5, 5.4, 3.1Hz, 1H). The theoretical value of UPLC-MS (ESI) is C. 23 H 18 N4O5[M+H] + :431.42, measured value: 431.28.

[0412] Example 23: 4-((2-(4-bromophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0413]

[0414] Using 2-(4-bromophenyl)oxazole-5-carboxaldehyde and racemic pomalidomide as starting materials, the same synthetic route as in Example 15 was followed. After HPLC purification, 21 mg of a yellow substance was obtained, with a yield of 11%. 1 ¹H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 7.84 (d, J = 8.4Hz, 2H), 7.73 (d, J = 8.5Hz, 2H), 7.66–7.59 (m, 1H), 7.33–7.23 (m, 2H), 7.18–7.06 (m, 2H), 5.07 (dd, J = 12.8, 5.3Hz, 1H), 4.73 (d, J = 4.7Hz, 2H), 2.94–2.79 (m, 1H), 2.69–2.55 (m, 2H), 2.08–1.97 (m, 1H). UPLC-MS (ESI) theoretical value is C1. 23 H 17 BrN4O5[M+H] + :510.32, measured value: 510.07.

[0415] Example 24: 2-(2,6-dioxadiazin-3-yl)-4-((5-(p-tolyl)oxazol-2-yl)methyl)amino)isoindoline-1,3-dione

[0416]

[0417] Using 5-(p-tolyl)oxazole-2-carboxaldehyde (55 mg, 0.294 mmol) and pomalidomide (80 mg, 0.294 mmol) as raw materials, the synthetic route was the same as in Example 15. After purification by HPLC, 14 mg of yellow carboxaldehyde was obtained, with a yield of 11%. 1 ¹H NMR (500MHz, DMSO) δ 11.13 (s, 1H), 7.61 (dd, J = 8.3, 7.3Hz, 1H), 7.55 (t, J = 4.1Hz, 3H), 7.30–7.20 (m, 4H), 7.10 (d, J = 7.1Hz, 1H), 5.09 (dd, J = 12.7, 5.5Hz, 1H), 4.78 (d, J = 6.2Hz, 2H), 2.95–2.82 (m, 1H), 2.66–2.53 (m, 2H), 2.32 (s, 3H), 2.08–2.01 (m, 1H). UPLC-MS (ESI) theoretical value is C0. 24 H20 N4O5[M+H] + :445.45, Measured value: 445.22.

[0418] Example 25: 4-((2-(4-chlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0419]

[0420] Using 2-(4-chlorophenyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 93 mg of yellow powder was obtained, with a yield of 55%. 1 ¹H NMR (500MHz, DMSO) δ 11.14 (s, 1H), 7.96–7.87 (m, 2H), 7.67–7.59 (m, 3H), 7.31 (d, J = 8.6Hz, 1H), 7.27 (s, 1H), 7.17 (t, J = 6.2Hz, 1H), 7.11 (d, J = 7.1Hz, 1H), 5.08 (dd, J = 12.8, 5.5Hz, 1H), 4.75 (d, J = 6.3Hz, 2H), 2.90 (ddd, J = 16.9, 14.0, 5.4Hz, 1H), 2.68–2.57 (m, 2H), 2.04 (dd, J = 10.7, 5.7Hz, 1H). The theoretical value of UPLC-MS (ESI) is C0. 23 H 17 ClN4O5[M+H] + 465.86, measured value: 465.37.

[0421] Example 26: 2-(2,6-dioxadiazin-3-yl)-4-((2-(4-fluorophenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0422]

[0423] Using 2-(4-fluorophenyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 92 mg of yellow powder was obtained, with a yield of 56%. 1H NMR(500MHz,DMSO)δ11.12(s,1H),8.00–7.91(m,2H),7.62(dd,J=8.4,7.2Hz,1H),7.41–7 .33(m,2H),7.30(d,J=8.6Hz,1H),7.23(s,1H),7.15(t,J=6.4Hz,1H),7.10(d,J=7.0Hz,1H ), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.73 (d, J = 6.3 Hz, 2H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.60 (dd, J = 17.5, 14.6 Hz, 2H), 2.06–1.98 (m, 1H). The theoretical value of UPLC-MS (ESI) is C23H17FN4O5[M+H] + :449.41, Measured value: 449.54.

[0424] Example 27: 4-((2-(2-chlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0425]

[0426] Using 2-(2-chlorophenyl)oxazole-5-carboxaldehyde and racemic pomalidomide as raw materials, the synthetic route was the same as in Example 17. After HPLC purification, 144 mg of yellow powder was obtained, with a yield of 86%. 1 H NMR (500MHz, DMSO) δ 11.10 (s, 1H), 7.92 (dd, J = 7.6, 1.9Hz, 1H), 7.64–7.59 (m, 2H), 7.50 (dtd, J = 18.4, 7.4, 1.6Hz, 2H), 7.31 (t, J = 4.3Hz, 2H), 7.14 (d, J = 6.4Hz, 1H), 7.10 (d, J = 7.0Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.76 (d, J = 6.2Hz, 2H), 2.88 (ddd, J = 17.0, 14.0, 5.4Hz, 1H), 2.65–2.54 (m, 2H), 2.06–1.96 (m, 1H). The theoretical value of UPLC-MS (ESI) is C. 23 H 17 ClN4O5[M+H] + :465.86, Measured value: 465.30.

[0427] Example 28: 2-(2,6-dioxadiazin-3-yl)-4-((2-(3-fluorophenyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0428]

[0429] An acetic acid suspension (4 mL) of 2-(3-fluorophenyl)thiazol-5-carboxaldehyde (45 mg, 0.22 mmol) and racemic pomalidomide (59 mg, 0.22 mmol) was heated under reflux overnight. The reaction was cooled to room temperature, and sodium borohydride (9 mg, 0.22 mmol) was added. After reacting at room temperature for two hours, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated, and purified by HPLC to give 5.5 mg of yellow product, with a yield of 15.4%. 1 H NMR(500MHz,DMSO)δ11.13(s,1H),7.94(s,1H),7.74–7.66(m,2H),7.61–7.55(m,1H),7.5 1(dt,J=14.0,7.0Hz,1H),7.38(t,J=6.3Hz,1H),7.30(td,J=8.4,2.1Hz,1H),7.21(d,J=8 0.6Hz, 1H), 7.07(d, J = 7.1Hz, 1H), 5.07(dd, J = 12.8, 5.4Hz, 1H), 4.85(d, J = 6.3Hz, 2H), 2.93–2.84(m, 1H), 2.65–2.55(m, 2H), 2.03(ddd, J = 7.5, 6.8, 3.9Hz, 1H). The theoretical value of UPLC-MS (ESI) is C 23 H 17 FN4O4S[M+H] + :465.47, measured value: 465.19.

[0430] Example 29: 2-(2,6-dioxadiazin-3-yl)-4-((2-(p-tolyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0431]

[0432] Using 2-(p-tolyl)thiazole-5-carboxaldehyde (80 mg, 0.39 mmol) and racemic pomalidomide (108 mg, 0.39 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 25.4 mg of yellow product was obtained, with a yield of 14%. 1H NMR (500MHz, DMSO) δ11.13(s,1H),7.86(s,1H),7.77(d,J=8.2Hz,2H),7.58(dd,J=8.5,7.2 Hz,1H),7.33(t,J=6.2Hz,1H),7.27(d,J=8.0Hz,2H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1 Hz, 1H), 5.07(dd, J = 12.8, 5.4Hz, 1H), 4.82(d, J = 6.1Hz, 2H), 2.89(ddd, J = 16.9, 13.9, 5.5Hz, 1H), 2.59(dd, J = 34.3, 14.6Hz, 2H), 2.33(s, 3H), 2.07–2.00(m, 1H). The theoretical value of UPLC-MS (ESI) is C 24 H 20 N4O4S[M+H] + :461.51, Measured value:461.23.

[0433] Example 30: 3-(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoquinoline-4-yl)amino)methyl)thiazolyl)benzonitrile

[0434]

[0435] Using 3-(5-formylthiazolyl-2-yl)benzyl nitrile (62 mg, 0.29 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 9 mg of yellow product was obtained, with a yield of 7%. 1 H NMR (500MHz, DMSO) δ11.13(s,1H),8.31(s,1H),8.21(d,J=8.4Hz,1H),7.98(s,1H),7. 91(d,J=7.8Hz,1H),7.67(t,J=7.9Hz,1H),7.62–7.55(m,1H),7.40(t,J=6.4Hz,1H),7. 22 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (d, J = 6.1 Hz, 2H), 2.94–2.83 (m, 1H), 2.65–2.55 (m, 2H), 2.07–1.99 (m, 1H). The theoretical value of UPLC-MS (ESI) is C. 24 H 17 N5O4S[M+H] + :472.49, Measured value: 472.20.

[0436] Example 31: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-vinylphenyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0437]

[0438] Using 2-(4-vinylphenyl)thiazol-5-carboxaldehyde (63 mg, 0.29 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 10 mg of yellow powder was obtained, with a yield of 7%. 1 H NMR (500MHz, DMSO) δ11.13(s,1H),7.90(s,1H),7.86(d,J=8.3Hz,2H),7.57(t,J=8.2Hz,3H) ,7.35(t,J=6.3Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),6.77(dd,J=17.6,11.0H z, 1H), 5.92 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.84 (d, J = 6.3 Hz, 2H), 2.96–2.80 (m, 1H), 2.65–2.53 (m, 2H), 2.10–2.00 (m, 1H). The theoretical value of UPLC-MS (ESI) is C 25 H 20 N4O4S[M+H] + :473.52, measured value: 473.19.

[0439] Example 32: 4-((2-(4-chlorophenyl)thiazo-5-yl)methyl)amino)-2-(2,6-dioxanidin-3-yl)isoindoline-1,3-dione

[0440]

[0441] Using 2-(4-chlorophenyl)thiazole-5-carboxaldehyde (66 mg, 0.29 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After HPLC purification, 12 mg of yellow powder was obtained, with a yield of 9%. 1¹H NMR (500MHz, DMSO) δ 11.13 (s, 1H), 7.96–7.85 (m, 3H), 7.58 (dd, J = 8.5, 7.2Hz, 1H), 7.54–7.49 (m, 2H), 7.36 (t, J = 6.1Hz, 1H), 7.21 (d, J = 8.6Hz, 1H), 7.07 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.84 (d, J = 5.6Hz, 2H), 2.89 (ddd, J = 17.1, 13.9, 5.4Hz, 1H), 2.65–2.52 (m, 2H), 2.07–1.99 (m, 1H). The theoretical value of UPLC-MS (ESI) is C0. 23 H 17 ClN4O4S[M+H] + 481.92, measured value: 481.13.

[0442] Example 33: 4-(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoquinoline-4-yl)amino)methyl)thiazolyl)benzonitrile

[0443]

[0444] Using 4-(5-formylthiazo-2-yl)benzyl nitrile (70 mg, 0.33 mmol) and racemic pomalidomide (90 mg, 0.33 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 28 mg of yellow product was obtained, with a yield of 18%. 1 ¹H NMR (400MHz, DMSO) δ 11.11 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 8.01 (s, 1H), 7.92 (d, J = 8.3Hz, 2H), 7.62–7.55 (m, 1H), 7.39 (t, J = 6.2Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 7.08 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.9, 5.3Hz, 1H), 4.87 (d, J = 6.2Hz, 2H), 2.95–2.83 (m, 1H), 2.70–2.57 (m, 2H), 2.09–1.98 (m, 1H). The theoretical value of UPLC-MS (ESI) is C1. 24 H 17 N5O4S[M+H] + :472.49, measured value: 472.19.

[0445] Example 34: 2-(2,6-dioxadiazin-3-yl)-4-((5-(4-fluorophenyl)thiazolyl-2-yl)methyl)amino)isoindole-1,3-dione

[0446]

[0447] Using 5-(4-fluorophenyl)thiazole-2-carboxaldehyde (72 mg, 0.348 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 10.5 mg of yellow product was obtained, with a yield of 8%. 1 ¹H NMR (500MHz, DMSO) δ 11.14 (s, 1H), 8.12 (s, 1H), 7.68 (dd, J = 8.6, 5.3Hz, 2H), 7.56 (dt, J = 12.1, 7.0Hz, 2H), 7.25 (t, J = 8.8Hz, 2H), 7.10 (dd, J = 7.5, 5.6Hz, 2H), 5.10 (dd, J = 12.7, 5.3Hz, 1H), 4.88 (d, J = 6.1Hz, 2H), 2.94–2.86 (m, 1H), 2.60 (dd, J = 28.6, 10.3Hz, 2H), 2.10–2.02 (m, 1H). UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O4S[M+H] + :465.47, measured value: 465.22.

[0448] Example 35: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(trifluoromethoxy)phenyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0449]

[0450] Using 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde (80 mg, 0.29 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 20 mg of yellow powder was obtained, with a yield of 13%. 1¹H NMR (500MHz, DMSO) δ 11.13 (s, 1H), 8.01 (dd, J = 8.7, 1.8Hz, 2H), 7.94 (s, 1H), 7.59 (t, J = 7.8Hz, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.37 (d, J = 5.8Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 7.07 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.3, 4.8Hz, 1H), 4.85 (d, J = 6.0Hz, 2H), 2.94–2.83 (m, 1H), 2.57 (d, J = 35.0Hz, 2H), 2.09–1.98 (m, 1H). UPLC-MS (ESI) theoretical value is C0. 24 H 17 F3N4O5S[M+H] + :531.48, measured value: 531.19.

[0451] Example 36: 4-((2-(2,4-dimethoxyphenyl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxanidin-3-yl)isoindole-1,3-dione

[0452]

[0453] Using 2-(2,4-dimethoxyphenyl)thiazole-5-carboxaldehyde (72 mg, 0.29 mmol) and racemic pomalidomide (80 mg, 0.29 mmol) as starting materials, the synthetic route was the same as in Example 28. After purification by HPLC, 19 mg of yellow powder was obtained, with a yield of 13%. 1 HNMR(500MHz,DMSO)δ11.12(s,1H),8.14(d,J=8.8Hz,1H),7.83(s,1H),7.60–7.55(m,1H),7.26(t ,J=5.7Hz,1H),7.21(d,J=8.6Hz,1H),7.07(t,J=7.1Hz,1H),6.74(d,J=2.3Hz,1H),6.68(dd,J=8.8 ,2.4Hz,1H), 5.07(dd,J=12.8,5.4Hz,1H), 4.80(d,J=5.0Hz,2H), 3.96(s,3H), 3.83(s,3H), 2.88(ddd,J=16.9,13.9,5.3Hz,1H), 2.58(dd,J=21.8,4.3Hz,2H), 2.07–1.95(m,1H). The theoretical value of UPLC-MS (ESI) is C 25 H 22 N4O6S[M+H] +:507.53, measured value: 507.61.

[0454] Example 37: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(trifluoromethyl)phenyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0455]

[0456] Using 2-(4-(trifluoromethyl)phenylthiazol-5-carboxaldehyde (75 mg, 0.29 mmol) and pomalidomide (80 mg, 0.29 mmol) as raw materials, the synthetic route was the same as in Example 28. After purification by HPLC, 6 mg of yellow carboxaldehyde was obtained, with a yield of 4%. 1 ¹H NMR (500MHz, DMSO) δ 11.11 (s, 1H), 8.10 (d, J = 8.2Hz, 2H), 8.00 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.63–7.56 (m, 1H), 7.39 (t, J = 6.3Hz, 1H), 7.23 (d, J = 8.6Hz, 1H), 7.08 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.8, 5.3Hz, 1H), 4.87 (d, J = 6.3Hz, 2H), 2.94–2.82 (m, 1H), 2.59 (d, J = 20.0Hz, 2H), 2.10–1.96 (m, 1H). The theoretical value of UPLC-MS (ESI) is C1. 24 H 17 F3N4O4S[M+H] + :515.48, measured value: 515.11.

[0457] Example 38: 2-(2,6-dioxadiazin-3-yl)-4-(5-(phenyl-d5)-1,3,4-thiadiazol-2-yl)methyl)amino)isoindole-1,3-dione

[0458]

[0459] Following the synthetic route of Example 32, compound 38 of Example 38 was obtained.

[0460] Example 39: Methyl (3-(1,3-dioxy-4-((2-(4-(trifluoromethyl)phenyl)thiazolyl-5-yl)methyl)amino)isoindol-2-yl)-2,6-dioxadiazin-1-yl)neopentate

[0461]

[0462] Compound 37, 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(trifluoromethyl)phenyl)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione (70 mg, 0.11 mmol) was added to 2 mL of N,N-dimethylformamide at room temperature. Chloromethyl tervastatin (16 μL, 0.11 mmol) and cesium carbonate (43 mg, 0.13 mmol) were added. The reaction mixture was heated to 50 °C and reacted for one hour. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and separated. The organic layer was washed several times with saturated sodium chloride solution, dried, filtered, and concentrated. The crude product was purified by HPLC to give 7.6 mg of a yellow solid, with a yield of 11%. 1 H NMR(500MHz,DMSO)δ8.10(d,J=8.2Hz,2H),7.99(s,1H),7.82(d,J=8.4Hz,2H),7.60(dd ,J=8.5,7.2Hz,1H),7.36(t,J=6.3Hz,1H),7.24(d,J=8.6Hz,1H),7.09(d,J=7.1Hz,1H), 5.65(s,2H),5.26(dd,J=13.0,5.4Hz,1H),4.88(d,J=6.2Hz,2H),3.07(ddd,J=17.4,14 .0,5.4Hz,1H),2.87–2.80(m,1H),2.65–2.51(m,1H),2.11(tdd,J=7.6,5.0,2.6Hz,1H). 13 C NMR (126MHz, DMSO) δ 176.44, 171.12, 169.37, 168.42, 167.07, 164.71, 145.34, 142.47, 139.59, 136.59, 136.30, 132.25, 129.69, 126.65, 126.19, 126.17, 117.72, 111.41, 110.06, 63.18, 49.05, 38.46, 38.22, 31.05, 26.62, 21.07. UPLC-MS (ESI) theoretical value is C 30 H 27 F3N4O6S[M+H] + :629.62, Measured value: 629.28.

[0463] Example 40: (3-(4-(((2-(4-chlorophenyl)oxazol-5-yl)methyl)amino)-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiperidin-1-yl)methylneovalerate

[0464]

[0465] Referring to the synthetic routes of Example 25 and Example 39, compound 40 of Example was obtained as a yellow solid (50 mg, 26.7%). 1 H NMR(500MHz,DMSO)δ7.91(d,J=8.6Hz,2H),7.63(dd,J=8.4,7.3Hz,1H),7.61–7.57(m,2H),7.30( d,J=8.6Hz,1H),7.26(s,1H),7.13(d,J=5.7Hz,1H),7.11(d,J=7.1Hz,1H),5.64(s,2H),5.26(dd ,J=13.0,5.4Hz,1H), 4.74(d,J=5.8Hz,2H), 3.06(ddd,J=17.5,14.0,5.3Hz,1H), 2.83(dd,J=13.6,2.8Hz,1H), 2.56(dd,J=13.4,4.3Hz,1H), 2.12–2.04(m,1H), 1.09(s,9H). The theoretical value of UPLC-MS (ESI) is C 29 H 27 ClN4O7[M+H] + :579.16, measured value: 579.36.

[0466] Example 41: Methyl (3-(1,3-dioxy-4-((2-(1-valproylpiperidin-4-yl)oxazol-5-yl)methyl)amino)isoindol-2-yl)-2,6-dioxadiopidin-1-yl)valproate

[0467]

[0468] Following the synthetic routes of Example 38 and Example 39, compound 41 of Example 41 was obtained. 56.9 mg of a yellow solid was yielded, with a yield of 38%. 1H NMR(500MHz,DMSO)δ7.60(dd,J=8.5,7.2Hz,1H),7.22(d,J=8.6Hz,1H),7.09(d,J=7.1Hz,1H),7.02(s,1H),6 .98(s,1H),5.64(s,2H),5.26(dd,J=13.0,5.4Hz,1H),4.61(d,J=3.5Hz,2H),4.17(d,J=13.5Hz,2H),3.06(dd d,J=22.2,12.9,6.0Hz,2H),2.99(dd,J=13.1,10.8Hz,2H),2.83(dd,J=13.6,2.8Hz,1H),2.62–2.54(m,1H),2 .09(ddd,J=14.9,7.4,4.9Hz,1H),1.95(dd,J=13.4,3.0Hz,2H),1.55–1.46(m,2H),1.17(s,9H),1.10(s,9H). 13 C NMR (201MHz, DMSO) δ 176.45, 174.84, 171.11, 169.36, 168.53, 167.08, 165.57, 148.77, 145.69, 136.20, 132.11, 123.98, 117.74, 111.36, 109.90, 63.17, 49.05, 43.80, 40.43, 39.99, 38.23, 38.12, 36.82, 34.56, 31.04, 29.62, 28.07, 26.62, 21.08. UPLC-MS (ESI) theoretical value is C 33 H 41 N5O8[M+H] + :636.72, measured value: 636.36.

[0469] Example 42: 2-(2,6-dioxadiazin-3-yl)-4-((2-(4-(4-fluorobenzyl)cyclohexyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0470]

[0471] Following the synthetic route of Example 12, compound 42 was obtained. Compound 42 was a mixture of compounds 105 and 106 before separation, and the NMR and mass spectrometry data correspond to the respective compounds 105 and 106.

[0472] Example 43: 4-((2-(5-chloropyridin-2-yl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindole-1,3-dione

[0473]

[0474] Following the synthetic route of Example 32, compound 43 of Example was obtained, and after HPLC purification, 58 mg of yellow compound was obtained, with a yield of 33%. 1 ¹H NMR (600MHz, DMSO) δ 11.10 (s, 1H), 8.65 (d, J = 0.9Hz, 1H), 8.09–8.02 (m, 2H), 7.97 (s, 1H), 7.59 (t, J = 7.8Hz, 1H), 7.35 (t, J = 6.3Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 7.07 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.85 (d, J = 6.4Hz, 2H), 2.93–2.84 (m, 1H), 2.62–2.51 (m, 2H), 2.08–2.00 (m, 1H). UPLC-MS (ESI) theoretical value is C 22 H 16 ClN5O4S[M+H] + 482.06, measured value: 482.25.

[0475] Example 44: 4-((2-(6-chloropyridin-3-yl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0476]

[0477] Following the synthetic route of Example 25, compound 44 of Example 44 was obtained. 49.3 mg of a yellow solid was given, with a yield of 53%. 1H NMR(500MHz,DMSO)δ11.10(s,1H),8.91(d,J=2.0Hz,1H),8.29(dd,J=8.4,2.5Hz,1H),7.69 (d,J=8.4Hz,1H),7.62(dd,J=8.4,7.2Hz,1H),7.32(s,1H),7.29(d,J=8.6Hz,1H),7.16(t, J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.75(d,J=6.2Hz,2H),2 .88(ddd,J=17.0,13.9,5.4Hz,1H),2.65–2.52(m,2H),2.03(ddd,J=10.5,5.4,3.1Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.82, 170.07, 168.64, 167.22, 157.37, 151.58, 150.94, 146.91, 145.52, 136.60, 136.19, 132.21, 126.17, 124.97, 122.54, 117.72, 111.41, 110.16, 48.59, 36.94, 30.97, 22.12. UPLC-MS (ESI) theoretical value is C 22 H 16 ClN5O5[M+H] + 466.85, Measured value: 466.23. Example 45: 2-(2,6-dioxadiazin-3-yl)-4-((2-(phenyl-d5)oxazol-5-yl)methyl)amino)isoindoline-1,3-dione

[0478]

[0479] Following the synthetic route of Example 22, compound 45 of Example was obtained as a yellow solid (110 mg, 69%). 1 ¹H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 7.63 (s, 1H), 7.30 (d, J = 7.4Hz, 1H), 7.23 (s, 1H), 7.10 (s, 2H), 5.07 (d, J = 8.0Hz, 1H), 4.74 (s, 2H), 2.86 (d, J = 12.4Hz, 1H), 2.59 (d, J = 17.8Hz, 2H), 2.04 (s, 1H). UPLC-MS (ESI) theoretical value is C 23 H 13 D5N4O5[M+H] +436.16, measured value: 436.28.

[0480] Example 46: 2-(2,6-dioxadiazin-3-yl)-4-((2-(phenyl-d5)thiazolyl-5-yl)methyl)amino)isoindole-1,3-dione

[0481]

[0482] Following the synthetic route of Example 32, Compound 46 of Example was obtained. Compound 46 was obtained from 2-(phenyl-d5)thiazol-5-carboxaldehyde (134 mg, 0.69 mmol) and racemic pomalidomide (188 mg, 0.69 mmol). After HPLC purification, 88 mg of a yellow solid was obtained, with a yield of 28%. 1 ¹H NMR (600MHz, DMSO) δ 11.11 (s, 1H), 7.90 (s, 1H), 7.59 (t, J = 7.8Hz, 1H), 7.33 (t, J = 6.2Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 7.07 (d, J = 7.1Hz, 1H), 5.07 (dd, J = 12.9, 5.4Hz, 1H), 4.84 (d, J = 6.2Hz, 2H), 2.89 (ddd, J = 17.3, 14.1, 5.3Hz, 1H), 2.62–2.51 (m, 2H), 2.07–2.01 (m, 1H). UPLC-MS (ESI) theoretical value is C0. 23 H 13 D5N4O4S[M+H] + :452.14, measured value: 452.31.

[0483] Example 47: 2-(2,6-dioxadiazol-3-yl)-4-(5-(phenyl-d5)-1,3,4-oxadiazol-2-yl)methyl)amino)isoindole-1,3-dione

[0484]

[0485] Following the synthetic route of Example 32, compound 47 of Example was obtained.

[0486] Example 48: 2-(2,6-dioxopiperidin-3-yl)-4-(((2-(4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0487]

[0488] Following the synthetic route of Example 22, compound 48 of Example 48 was obtained. 65.3 mg of a yellow solid was given, with a yield of 55%. 1 HNMR(500MHz,DMSO)δ11.08(s,1H),7.83(d,J=8.9Hz,2H),7.65–7.60(m,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H) ,7.10(t,J=6.5Hz,2H),7.05(d,J=8.9Hz,2H),5.12–5.08(m,1H),5.06(dd,J=12.9,5.5Hz,1H),4.71(d,J=6.3Hz ,2H),3.90(dd,J=10.2,4.5Hz,1H),3.84(dd,J=15.4,8.0Hz,1H),3.79(d,J=10.3Hz,1H),3.78–3.72(m,1H),2.9 3–2.83(m,1H),2.58(dt,J=18.0,9.6Hz,2H),2.25(td,J=14.3,8.1Hz,1H),2.06–2.00(m,1H),1.99–1.94(m,1H). 13 CNMR (126MHz, DMSO) δ 172.77, 170.02, 168.66, 167.20, 160.35, 158.89, 149.12, 145.61, 136.11, 132.18, 127.48, 125.53, 119.65, 117.72, 115.78, 111.30, 110.05, 77.40, 72.20, 66.39, 48.57, 36.90, 32.40, 30.95, 22.09. UPLC-MS (ESI) theoretical value is C 27 H 24 N4O7[M+H] + :517.51, measured value: 517.41.

[0489] Example 49: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(oxetan-3-oxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0490]

[0491] Following the synthetic route of Example 22, compound 49 of Example 49 was obtained. 14.3 mg of a yellow solid was given, with a yield of 23%. 1HNMR (500MHz, DMSO) δ11.09(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.6H z,1H),7.17(s,1H),7.10(t,J=6.0Hz,2H),6.92(d,J=8.9Hz,2H),5.37–5.30(m,1H),5.06(dd,J=12.8,5 4.4Hz, 1H), 4.94(t, J = 6.8Hz, 2H), 4.71(d, J = 6.2Hz, 2H), 4.55(dd, J = 7.4, 5.1Hz, 2H), 2.88(ddd, J = 17.0, 13.8, 5.4Hz, 1H), 2.57(dt, J = 12.8, 9.4Hz, 2H), 2.02(ddd, J = 7.4, 5.2, 2.7Hz, 1H). The theoretical value of UPLC-MS (ESI) is C. 26 H 22 N4O7[M+H] + :503.48, measured value: 503.39.

[0492] Example 50: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(2-hydroxyethoxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0493]

[0494] Following the synthetic route of Example 22, compound 50 of Example 50 was obtained. 47 mg of a yellow solid was yielded, with a yield of 37%. 1 HNMR(500MHz,DMSO)δ11.09(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.4,7.2Hz,1H),7. 30(d,J=8.6Hz,1H),7.16(s,1H),7.09(d,J=7.0Hz,2H),7.06(d,J=8.9Hz,2H),5.06(dd,J =12.8,5.4Hz,1H),4.71(d,J=5.8Hz,2H),4.04(t,J=4.9Hz,2H),3.72(t,J=4.9Hz,2H),2. 88(ddd,J=17.0,13.9,5.4Hz,1H),2.57(ddd,J=19.7,14.6,9.2Hz,2H),2.06–2.00(m,1H). 13C NMR (126MHz, DMSO) δ 172.82, 170.07, 168.68, 167.23, 160.46, 160.44, 149.06, 145.62, 136.14, 132.20, 127.43, 125.54, 119.46, 117.74, 115.05, 111.31, 110.04, 69.75, 59.44, 48.58, 36.91, 30.97, 22.11. UPLC-MS (ESI) theoretical value is C 25 H 22 N4O7[M+H] + :491.15, Measured value: 491.41.

[0495] Example 51: 4-((2-(4-cyclopropoxyphenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0496]

[0497] Following the synthetic route of Example 22, compound 51 of Example 51 was obtained. 82.3 mg of a yellow solid was given, with a yield of 45%. 1 HNMR(500MHz,DMSO)δ11.08(s,1H),7.85(d,J=8.9Hz,2H),7.63(dd,J=8.4,7.2Hz,1H) ,7.30(d,J=8.6Hz,1H),7.19–7.15(m,3H),7.09(d,J=7.0Hz,2H),5.06(dd,J=12.8,5.4 Hz,1H),4.71(d,J=5.2Hz,2H),3.90(tt,J=6.0,2.9Hz,1H),2.88(ddd,J=17.1,13.9,5 .4Hz,1H),2.65–2.51(m,2H),2.06–1.99(m,1H),0.84–0.78(m,2H),0.70–0.65(m,2H). 13 CNMR (126MHz, DMSO) δ 172.82, 170.06, 168.68, 167.23, 160.41, 160.40, 149.15, 145.62, 136.14, 132.19, 127.38, 125.55, 119.95, 117.75, 115.50, 111.32, 110.05, 51.06, 48.58, 36.92, 30.97, 22.11, 5.94. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O6[M+H]+ :487.48, Measured value: 487.39.

[0498] Example 52: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(2-methoxyethoxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0499]

[0500] Following the synthetic route of Example 22, compound 52 of Example 52 was obtained. 72.4 mg of a yellow solid was given, in 59% yield. 1 H NMR(600MHz,DMSO)δ11.10(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.5,7.2Hz,1H),7.30 (d,J=8.6Hz,1H),7.16(s,1H),7.13–7.03(m,4H),5.06(dd,J=12.9,5.4Hz,1H),4.71(d,J=5 .6Hz,2H),4.16–4.12(m,2H),3.69–3.64(m,2H),3.30(s,3H),2.88(ddd,J=17.1,13.9,5.4H z,1H),2.59(dd,J=17.2,2.4Hz,1H),2.56–2.51(m,1H),2.03(ddd,J=10.4,5.4,3.0Hz,1H). 13 CNMR (151MHz, DMSO) δ 172.86, 170.09, 168.71, 167.26, 160.45, 160.26, 149.12, 145.65, 136.18, 132.22, 127.47, 125.57, 119.61, 117.77, 115.06, 111.36, 110.07, 70.25, 67.16, 58.20, 48.61, 36.93, 30.99, 22.14. UPLC-MS (ESI) theoretical value is C 26 H 24 N4O7[M+H] + :505.50, measured value: 505.41.

[0501] Example 53: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(tetrahydro-2H-pyran-4-yl)oxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0502]

[0503] Following the synthetic route of Example 22, compound 53 of Example 53 was obtained. 70 mg of a yellow solid was yielded, with a yield of 60%. 1 HNMR (500MHz, DMSO) δ11.09(s,1H),7.82(d,J=8.8Hz,2H),7.62(dd,J=8.4,7.3Hz,1H),7.29(d,J=8.6 Hz,1H),7.16(s,1H),7.12–7.06(m,4H),5.06(dd,J=12.8,5.4Hz,1H),4.71(d,J=4.6Hz,2H),4.68–4.6 2(m,1H),3.85(dt,J=11.4,4.3Hz,2H),3.51–3.47(m,2H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.59(d d,J=17.7,1.9Hz,1H),2.53(d,J=4.4Hz,1H),2.05–2.00(m,1H),2.00–1.95(m,2H),1.64–1.53(m,2H). 13 C NMR (126MHz, DMSO) δ 172.82, 170.06, 168.70, 167.24, 160.44, 158.76, 149.09, 145.64, 136.15, 132.20, 127.51, 125.54, 119.54, 117.75, 116.14, 111.34, 110.07, 71.55, 64.51, 48.61, 36.93, 31.66, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C 28 H 26 N4O7[M+H] + :531.54, measured value: 531.40.

[0504] Example 54: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-((R)-tetrahydrofuran-3-yl)oxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0505]

[0506] Following the synthetic route of Example 22, compound 54 of Example 54 was obtained. 77.5 mg of a yellow solid was given, with a yield of 65%. 1HNMR (600MHz, DMSO) δ11.10(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.5,7.1Hz,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H),7.10(d d,J=10.4,6.4Hz,2H),7.05(d,J=8.9Hz,2H),5.10–5.08(m,1H),5.08–5.04(m,1H),4.71(d,J=5.4Hz,2H),3.89(dd,J=10.2,4.5Hz, 1H),3.84(dd,J=15.3,8.1Hz,1H),3.79(d,J=10.2Hz,1H),3.75(td,J=8.4,4.6Hz,1H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.62–2 .56(m,1H),2.53(ddd,J=9.8,6.7,3.2Hz,1H),2.25(dtd,J=14.4,8.2,6.3Hz,1H),2.06–2.00(m,1H),1.96(dt,J=12.1,5.7Hz,1H). 13 C NMR (151MHz, DMSO) δ 172.86, 170.10, 168.72, 167.26, 160.40, 158.93, 149.16, 145.65, 136.18, 132.22, 127.54, 125.58, 119.68, 117.77, 115.83, 111.36, 110.07, 77.44, 72.25, 66.45, 48.61, 36.93, 32.45, 30.99, 22.14. UPLC-MS (ESI) theoretical value is C 27 H 26 N4O6[M+H] + :517.51, Measured value: 517.26.

[0507] Example 55: 2-(2,6-dioxadiazin-3-yl)-4-(2-(3-(trifluoromethoxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0508]

[0509] Following the synthetic route of Example 22, compound 55 of Example 55 was obtained. 64.4 mg of a yellow solid was given, with a yield of 64%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),7.94(d,J=7.9Hz,1H),7.79(s,1H),7.68(t,J=8.0Hz,1H ),7.62(dd,J=8.4,7.3Hz,1H),7.53(d,J=8.3Hz,1H),7.30(d,J=8.6Hz,1H),7.29(s,1H),7.1 5(t,J=6.1Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.75(d,J=5.6Hz,2H) ,2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.03(ddd,J=10.4,5.4,3.2Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.63, 167.19, 158.80, 150.65, 148.74, 145.55, 136.11, 132.19, 131.62, 128.82, 126.03, 124.68, 122.97, 117.73, 111.37, 110.15, 48.58, 36.95, 30.95, 22.09. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O6[M+H] + :515.42, measured value: 515.33.

[0510] Example 56: 2-(2,6-dioxadiazin-3-yl)-4-(2-(2-(2-(trifluoromethoxy)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0511]

[0512] Following the synthetic route of Example 22, compound 56 of Example 56 was obtained. 66.4 mg of a yellow solid was yielded, with a yield of 66%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),8.04(dd,J=7.8,1.6Hz,1H),7.65(td,J=8.0,1.6Hz, 1H),7.62–7.58(m,1H),7.58–7.51(m,2H),7.33(s,1H),7.26(d,J=8.6Hz,1H),7.12(d,J= 6.3Hz,1H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.75(d,J=6.3Hz,2H),2 .89(ddd,J=17.0,13.8,5.4Hz,1H),2.64–2.51(m,2H),2.02(ddd,J=7.4,5.4,2.7Hz,1H). 13 CNMR (126MHz, DMSO) δ 172.76, 169.98, 168.61, 167.21, 156.80, 150.52, 145.53, 144.89, 136.09, 132.28, 132.16, 129.96, 128.30, 125.92, 122.96, 120.82, 117.55, 111.33, 110.12, 48.56, 36.88, 30.94, 22.10. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O6[M+H]+: 515.42, measured value: 515.34.

[0513] Example 57: 2-(2,6-dioxadiazin-3-yl)-4-(2-(4-(trifluoromethyl)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0514]

[0515] Following the synthetic route of Example 22, compound 57 of Example 57 was obtained. 46.5 mg of a yellow solid was given, with a yield of 37%. 1HNMR (500MHz, DMSO) δ11.11(s,1H),8.11(d,J=8.0Hz,2H),7.89(d,J=7.9Hz,2H),7.62(t,J=7.7Hz,1H),7.32(s,1H),7.30(d,J=8.6Hz,1H),7.17(t ,J=5.9Hz,1H),7.10(d,J=6.9Hz,1H),5.06(dd,J=12.8,5.0Hz,1H),4.76( d,J=5.5Hz,2H),2.92–2.83(m,1H),2.65–2.53(m,2H),2.07–1.99(m,1H). 13 C NMR (151MHz, DMSO) δ 172.88, 170.11, 168.69, 167.27, 159.06, 150.94, 145.59, 136.25, 132.25, 130.40, 130.15, 126.47, 126.30, 126.26, 124.86, 123.06, 117.76, 111.47, 110.18, 48.63, 37.02, 31.00, 22.16. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.35.

[0516] Example 58: 2-(2,6-dioxadiazin-3-yl)-4-(2-(3-(trifluoromethyl)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0517]

[0518] Following the synthetic route of Example 22, compound 58 of Example 58 was obtained. 58.9 mg of a yellow solid was given, with a yield of 57%. 1HNMR (500MHz, DMSO) δ11.08 (s, 1H), 8.20 (d, J = 7.8Hz, 1H), 8.15 (s, 1H), 7.89 (d, J = 7. 9Hz,1H),7.78(t,J=7.8Hz,1H),7.62(dd,J=8.3,7.3Hz,1H),7.31(t,J=4.3Hz,2H),7. 17(t,J=6.2Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.76(d,J=6 .1Hz,2H),2.88(ddd,J=16.9,14.3,5.4Hz,1H),2.65–2.52(m,2H),2.06–2.00(m,1H). 13 CNMR (126MHz, DMSO) δ 172.77, 170.02, 168.62, 167.19, 158.88, 150.70, 145.54, 136.10, 132.20, 130.65, 129.52, 127.73, 126.98, 126.07, 124.83, 122.66, 121.92, 121.89, 117.74, 111.37, 110.16, 48.58, 36.96, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.18.

[0519] Example 59: 2-(2,6-dioxadiazin-3-yl)-4-(2-(2-(2-(trifluoromethyl)phenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0520]

[0521] Following the synthetic route of Example 22, compound 59 of Example 59 was obtained. 42.6 mg of a yellow solid was given, with a yield of 45%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),7.97(d,J=7.7Hz,1H),7.91(d,J=7.8Hz,1H),7 .82(t,J=7.5Hz,1H),7.75(t,J=7.6Hz,1H),7.63–7.58(m,1H),7.32(s,1H),7.25(d ,J=8.6Hz,1H),7.10(t,J=6.7Hz,2H),5.07(dd,J=12.7,5.4Hz,1H),4.75(d,J=6.0 Hz,2H),2.89(ddd,J=16.9,13.8,5.3Hz,1H),2.65–2.52(m,2H),2.06–1.99(m,1H). 13 C NMR (126MHz, DMSO) δ 172.81, 170.03, 168.63, 167.23, 158.02, 151.05, 145.58, 136.10, 132.93, 132.16, 131.30, 131.05, 127.08, 127.03, 126.99, 126.95, 125.90, 117.71, 111.38, 110.15, 48.57, 36.87, 30.96, 22.12. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.34.

[0522] Example 60: 2-(2,6-dioxadiazin-3-yl)-4-(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)methyl)amino)isoindole-1,3-dione

[0523]

[0524] Following the synthetic route of Example 24, compound 60 of Example 60 was obtained. 17.6 mg of a yellow solid was given, with a yield of 17%. 1HNMR (500MHz, DMSO) δ11.10 (s, 1H), 7.88 (d, J = 8.4Hz, 2H), 7.83 (t, J = 4.2Hz, 3H),7.61(dd,J=8.1,7.5Hz,1H),7.25(d,J=6.1Hz,1H),7.22(d,J=8.6Hz,1H ),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.2Hz,2H) ,2.94–2.85(m,1H),2.63–2.58(m,1H),2.57–2.51(m,1H),2.06–2.01(m,1H). 13 C NMR (126MHz, DMSO) δ 172.78, 170.03, 168.65, 167.21, 162.01, 149.46, 145.71, 136.16, 132.10, 131.09, 130.09, 128.43, 128.17, 126.14, 126.11, 125.11, 124.81, 124.34, 122.95, 117.84, 111.50, 110.19, 48.62, 30.97, 22.11. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.35.

[0525] Example 61: 2-(2,6-dioxadiazin-3-yl)-4-(5-(3-(trifluoromethyl)phenyl)oxazol-2-yl)methyl)amino)isoindole-1,3-dione

[0526]

[0527] Following the synthetic route of Example 24, compound 61 of Example 61 was obtained. 54.6 mg of a yellow solid was given, with a yield of 53%. 1HNMR(500MHz,DMSO)δ11.10(s,1H),7.99(s,1H),7.96(dd,J=4.2,3.1Hz,1H),7.84(s,1H), 7.74–7.70(m,2H),7.64–7.59(m,1H),7.24(dd,J=12.9,7.4Hz,2H),7.11(d,J=7.0Hz,1H),5 .08(dd,J=12.8,5.4Hz,1H),4.82(d,J=6.3Hz,2H),2.89(ddd,J=16.9,13.8,5.2Hz,1H),2.6 0(dd,J=15.0,3.3Hz,1H),2.54(dd,J=13.5,4.4Hz,1H),2.04(ddd,J=12.4,5.3,2.2Hz,1H). 13 CNMR (126MHz, DMSO) δ 172.77, 170.01, 168.64, 167.20, 161.66, 149.36, 145.71, 136.12, 132.09, 130.39, 128.39, 127.56, 124.85, 124.20, 120.21, 120.18, 117.88, 111.48, 110.18, 48.61, 30.96, 22.10. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.31.

[0528] Example 62: 2-(2,6-dioxadiazin-3-yl)-4-(5-(2-(trifluoromethyl)phenyl)oxazol-2-yl)methyl)amino)isoindole-1,3-dione

[0529]

[0530] Following the synthetic route of Example 24, compound 62 of Example 62 was obtained. 20.6 mg of a yellow solid was given, with a yield of 20%. 1HNMR(500MHz,DMSO)δ11.09(s,1H),7.88(d,J=7.9Hz,1H),7.81–7.76(m,2H),7.66(dd,J= 10.9,5.1Hz,1H),7.62–7.57(m,1H),7.43(s,1H),7.23(t,J=6.3Hz,1H),7.19(d,J=8.6Hz ,1H),7.11(d,J=7.0Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.82(d,J=6.3Hz,2H),2.89(dd d,J=16.6,13.7,5.3Hz,1H),2.60(d,J=18.4Hz,1H),2.56–2.51(m,1H),2.07–2.01(m,1H). 13 CNMR (126MHz, DMSO) δ 172.77, 169.99, 168.62, 167.21, 162.06, 147.66, 145.71, 136.09, 132.97, 132.07, 130.39, 129.73, 126.86, 126.81, 126.77, 126.72, 126.10, 126.08, 125.46, 124.70, 122.53, 117.77, 111.47, 110.21, 48.59, 30.95, 22.11. UPLC-MS (ESI) theoretical value is C 24 H 17 F3N4O5[M+H] + :499.42, measured value: 499.24.

[0531] Example 63: 4-((2-(3-chlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0532]

[0533] Following the synthetic route of Example 22, compound 63 of Example 63 was obtained. 76.1 mg of a yellow solid was given, with a yield of 68%. 1H NMR (500MHz, DMSO) δ11.08(s,1H),7.89(d,J=1.7Hz,1H),7.87(dt,J=7.0,1.5Hz,1H),7.63(dd ,J=8.4,7.2Hz,1H),7.60–7.55(m,2H),7.30(d,J=8.6Hz,1H),7.28(s,1H),7.15(t,J=5.9Hz,1 H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.74(d,J=4.8Hz,2H),2.88(ddd,J=16 .9,13.9,5.4Hz,1H),2.61(ddd,J=33.5,17.4,7.5Hz,2H),2.03(ddd,J=12.1,6.2,3.9Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.63, 167.20, 158.90, 150.48, 145.54, 136.13, 133.84, 132.20, 131.26, 130.33, 128.69, 126.00, 125.18, 124.29, 117.72, 111.37, 110.14, 48.58, 36.95, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O5[M+H]+: 465.86, measured value: 465.31.

[0534] Example 64: 4-((5-(4-chlorophenyl)oxazol-2-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0535]

[0536] Following the synthetic route of Example 24, compound 64 of Example 64 was obtained. 10.2 mg of a yellow solid was yielded, with a yield of 9%. 1HNMR(500MHz,DMSO)δ11.10(s,1H),7.68(d,J=8.7Hz,2H),7.67(s,1H),7.63–7 .59(m,1H),7.53(d,J=8.6Hz,2H),7.25–7.20(m,2H),7.11(d,J=7.0Hz,1H),5.0 8(dd,J=12.7,5.4Hz,1H),4.80(d,J=6.3Hz,2H),2.89(ddd,J=16.7,13.6,5.3H z,1H),2.57(ddd,J=18.0,13.9,3.5Hz,2H),2.04(ddd,J=12.8,5.6,2.3Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.78, 170.02, 168.65, 167.21, 161.23, 149.82, 145.72, 136.15, 132.87, 132.09, 129.20, 126.25, 125.53, 123.19, 117.83, 111.47, 110.16, 48.61, 30.96, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O5[M+H]+: 465.86, measured value: 465.29.

[0537] Example 65: 4-((5-(3-chlorophenyl)oxazol-2-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0538]

[0539] Following the synthetic route of Example 24, compound 65 of Example 65 was obtained. 5.1 mg of a yellow solid was given, with a yield of 5%. 1 HNMR(500MHz,DMSO)δ11.10(s,1H),7.76–7.73(m,2H),7.63–7.60(m,2H),7.49 (t,J=7.9Hz,1H),7.42(dd,J=8.0,1.0Hz,1H),7.23(dd,J=11.1,7.4Hz,2H),7.1 1(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.80(d,J=6.2Hz,2H),2.95–2 .83(m,1H),2.60(dd,J=14.8,3.5Hz,1H),2.57–2.52(m,1H),2.08–2.01(m,1H). 13C NMR (126MHz, DMSO) δ 172.78, 170.02, 168.64, 167.21, 161.48, 149.39, 145.70, 136.14, 133.88, 132.09, 131.10, 129.33, 128.20, 123.88, 123.42, 122.30, 117.85, 111.47, 110.17, 48.61, 30.96, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O5[M+H] + :465.86, Measured value: 465.28.

[0540] Example 66: 4-((5-(2-chlorophenyl)oxazol-2-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0541]

[0542] Following the synthetic route of Example 24, compound 66 of Example 66 was obtained. 21.6 mg of a yellow solid was given, with a yield of 19%. 1 HNMR(500MHz,DMSO)δ11.10(s,1H),7.74(dd,J=7.8,1.5Hz,1H),7.72(s,1H),7.64–7.60(m,1H) ,7.59(d,J=1.0Hz,1H),7.48(td,J=7.7,1.2Hz,1H),7.40(td,J=7.8,1.6Hz,1H),7.26(d,J=6.3 Hz,1H),7.22(s,1H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.3Hz,2H) ,2.89(ddd,J=16.7,13.7,5.2Hz,1H),2.63–2.57(m,1H),2.57–2.52(m,1H),2.06–2.02(m,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.64, 167.21, 161.28, 147.37, 145.73, 136.15, 132.09, 130.67, 129.88, 129.44, 127.80, 126.61, 125.87, 117.88, 111.49, 110.20, 48.61, 30.96, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17ClN4O5[M+H] + 465.86, measured value: 465.32.

[0543] Example 67: 4-((2-(4-chlorophenyl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxorphyrin-3-yl)isoindole-1,3-dione

[0544]

[0545] Following the synthetic route of Example 32, compound 67 of Example 67 was obtained.

[0546] Example 68: 4-((2-(3-chlorophenyl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxorphyrin-3-yl)isoindole-1,3-dione

[0547]

[0548] Following the synthetic route of Example 32, compound 68 of Example 68 was obtained. 10.8 mg of a yellow solid was yielded, with a yield of 55%. 1 HNMR(500MHz,DMSO)δ11.09(s,1H),7.94(s,1H),7.90(d,J=1.7Hz,1H),7.85–7.81(m ,1H),7.62–7.56(m,1H),7.54–7.46(m,2H),7.35(t,J=6.3Hz,1H),7.22(d,J=8.6Hz,1 H),7.08(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.86(d,J=6.3Hz,2H),2.89( ddd,J=17.1,13.8,5.4Hz,1H),2.64–2.52(m,2H),2.04(ddd,J=17.4,7.8,4.8Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.78, 170.05, 168.57, 167.19, 164.75, 145.30, 142.13, 138.95, 136.20, 134.94, 133.91, 132.28, 131.15, 129.82, 125.20, 124.77, 117.61, 111.30, 110.11, 48.59, 38.45, 30.96, 22.11. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O4S[M+H] + :481.92, measured value: 481.15.

[0549] Example 69: 4-((2-(2-chlorophenyl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxorphyrin-3-yl)isoindole-1,3-dione

[0550]

[0551] Following the synthetic route of Example 32, compound 69 of Example 69 was obtained. 20.3 mg of a yellow solid was given, with a yield of 12%. 1 HNMR(500MHz,DMSO)δ11.09(s,1H),8.18–8.11(m,1H),8.01(s,1H),7.61(ddd, J=12.4,6.5,5.1Hz,2H),7.50–7.44(m,2H),7.35(t,J=6.2Hz,1H),7.24(d,J=8. 6Hz,1H),7.08(d,J=7.0Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.88(d,J=5.9Hz, 2H), 2.89 (ddd, J=16.9, 13.8, 5.4Hz, 1H), 2.64–2.53 (m, 2H), 2.07–1.99 (m, 1H). 13 C NMR (126MHz, DMSO) δ 172.78, 170.05, 168.58, 167.20, 161.71, 145.36, 140.97, 139.38, 136.20, 132.30, 131.25, 131.03, 130.72, 130.47, 130.42, 127.71, 117.61, 111.27, 110.08, 48.59, 38.31, 30.96, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O4S[M+H] + 481.92, measured value: 481.14.

[0552] Example 70: 2-(2,6-dioxadiazin-3-yl)-4-((2-(3-fluorophenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0553]

[0554] Following the synthetic route of Example 22, compound 70 of Example 70 was obtained. 79.1 mg of a yellow solid was given, with a yield of 73%. 1HNMR (500MHz, DMSO) δ11.09 (s, 1H), 7.76 (d, J = 7.8Hz, 1H), 7.67–7.61 (m, 2H), 7.58 (td, J = 8. 0,6.0Hz,1H),7.36(td,J=8.4,2.1Hz,1H),7.30(d,J=8.6Hz,1H),7.27(s,1H),7.14(t,J=5.9 Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.74(d,J=5.5Hz,2H),2.88(ddd ,J=16.9,13.8,5.3Hz,1H),2.58(dt,J=17.7,9.4Hz,2H),2.03(ddd,J=10.8,5.6,3.3Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.63, 167.19, 163.25, 161.31, 159.13, 159.11, 150.40, 145.55, 136.14, 132.19, 131.57, 131.50, 128.93, 128.86, 125.96, 121.87, 117.71, 117.53, 117.36, 112.39, 112.20, 111.37, 110.13, 48.58, 36.94, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.41, Measured value: 449.32.

[0555] Example 71: 2-(2,6-dioxadiazin-3-yl)-4-((2-(2-fluorophenyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0556]

[0557] Following the synthetic route of Example 22, compound 71 of Example was obtained. 54.6 mg of a yellow solid was given, with a yield of 51%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),7.95(td,J=7.7,1.6Hz,1H),7.62(dd,J=8.4,7.3Hz,1H),7.5 6(tdd,J=7.1,5.1,1.7Hz,1H),7.42–7.37(m,1H),7.35(dd,J=11.2,3.9Hz,1H),7.29(t,J=4.3Hz ,2H),7.13(t,J=5.8Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.75(d,J=4.9H z,2H),2.88(ddd,J=17.0,13.8,5.4Hz,1H),2.65–2.53(m,2H),2.03(ddd,J=7.2,5.3,2.5Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.64, 167.20, 159.99, 157.96, 156.70, 150.24, 145.56, 136.12, 132.65, 132.58, 132.17, 129.19, 125.72, 125.03, 117.72, 117.06, 116.89, 114.98, 114.89, 111.35, 110.09, 48.57, 36.91, 30.95, 22.09. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.41, Measured value: 449.27.

[0558] Example 72: 2-(2,6-dioxadiazin-3-yl)-4-((5-(4-fluorophenyl)oxazol-2-yl)methyl)amino)isoindole-1,3-dione

[0559]

[0560] Following the synthetic route of Example 24, compound 72 of Example 72 was obtained. 10.5 mg of a yellow solid was given, with a yield of 10%. 1HNMR(500MHz,DMSO)δ11.10(s,1H),7.73–7.68(m,2H),7.61(dd,J=8.4,7.3Hz,1H),7.59(s,1H),7.31(t,J=8.9Hz,2H),7.22(t,J=6.7Hz,2H),7.1 1(d,J=7.1Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.79(d,J=6.1Hz,2H),2 .89(ddd,J=16.8,13.8,5.2Hz,1H),2.64–2.52(m,2H),2.07–2.02(m,1H). 13 C NMR (126MHz, DMSO) δ 172.78, 170.03, 168.66, 167.21, 162.90, 160.94, 160.89, 150.03, 145.73, 136.15, 132.09, 126.12, 126.06, 124.08, 124.05, 122.31, 117.83, 116.28, 116.11, 111.46, 110.15, 48.61, 30.97, 22.11. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.41, Measured value: 449.38.

[0561] Example 73: 4-((2-(3,4-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0562]

[0563] Following the synthetic route of Example 22, compound 73 of Example 73 was obtained. 77 mg of a yellow solid was given, with a yield of 62%. 1HNMR(500MHz,DMSO)δ11.11(s,1H),8.06(d,J=1.9Hz,1H),7.86(dd,J=8.4,2.0Hz,1 H),7.80(d,J=8.4Hz,1H),7.65–7.60(m,1H),7.31-7.26(m,2H),7.16(t,J=6.3Hz,1H ),7.10(d,J=7.0Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.74(d,J=6.1Hz,2H),2.88( ddd,J=17.3,14.0,5.5Hz,1H),2.64–2.53(m,2H),2.02(ddd,J=7.7,6.4,2.1Hz,1H). 13 C NMR (151MHz, DMSO) δ 172.87, 170.11, 168.68, 167.26, 158.27, 150.80, 145.56, 136.22, 133.19, 132.25, 132.09, 131.70, 127.28, 127.24, 126.22, 125.79, 117.76, 111.46, 110.19, 48.63, 36.98, 31.00, 22.16. UPLC-MS (ESI) theoretical value is C 23 H 16 Cl2N4O5[M+H] + Measured value: 499.05; Actual value: 499.25.

[0564] Example 74: 4-((2-(2,3-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0565]

[0566] Following the synthetic route of Example 22, compound 74 of Example 74 was obtained. 64.8 mg of a yellow solid was given, with a yield of 63%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),7.89(dd,J=7.9,1.5Hz,1H),7.81(dd,J=8.1,1.5Hz,1H ),7.62(dd,J=8.4,7.3Hz,1H),7.51(t,J=8.0Hz,1H),7.34(s,1H),7.30(d,J=8.6Hz,1H),7 .14(t,J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.77(d,J=6.0Hz ,2H),2.88(ddd,J=17.0,13.8,5.4Hz,1H),2.58(dt,J=17.9,9.3Hz,2H),2.06–2.00(m,1H). 13 CNMR (126MHz, DMSO) δ 172.77, 170.01, 168.63, 167.19, 157.45, 150.77, 145.56, 136.13, 133.48, 132.28, 132.16, 129.55, 129.31, 128.63, 127.94, 125.73, 117.83, 111.39, 110.14, 48.58, 36.89, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 26 H 24 N4O7[M+H]+: 499.05, measured value: 499.12.

[0567] Example 75: 4-((2-(3,5-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0568]

[0569] Following the synthetic route of Example 22, compound 75 of Example 75 was obtained. 47.2 mg of a yellow solid was given, with a yield of 38%. 1HNMR (500MHz, DMSO) δ11.11(s,1H),7.86(d,J=1.9Hz,2H),7.79(t,J=1.9Hz,1H),7.62(dd, J=8.4,7.3Hz,1H),7.31(s,1H),7.29(d,J=8.6Hz,1H),7.17(t,J=6.3Hz,1H),7.10(d,J=7.1 Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.74(d,J=6.1Hz,2H),2.88(ddd,J=17.0,14.1,5.5H z,1H),2.65–2.59(m,1H),2.56(dd,J=13.2,8.2Hz,1H),2.03(ddd,J=10.4,5.5,3.1Hz,1H). 13 C NMR (151MHz, DMSO) δ 172.87, 170.11, 168.67, 167.26, 157.76, 151.12, 145.54, 136.21, 135.07, 132.26, 129.91, 129.87, 126.31, 124.15, 117.78, 111.47, 110.22, 48.63, 36.98, 31.00, 22.16. UPLC-MS (ESI) theoretical value is C 23 H 16 Cl2N4O5[M+H] + :499.05, Measured value: 499.28.

[0570] Example 76: 4-((2-(2,4-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0571]

[0572] Following the synthetic route of Example 22, compound 76 of Example 76 was obtained. 55.5 mg of a yellow solid was given, with a yield of 45%. 1HNMR(500MHz,DMSO)δ11.11(s,1H),7.94(d,J=8.5Hz,1H),7.80(d,J=2.1Hz,1H),7.6 3-7.54(m,2H),7.32(s,1H),7.30(d,J=8.6Hz,1H),7.14(t,J=6.5Hz,1H),7.10(d,J= 7.1Hz, 1H), 5.06 (dd, J=12.8, 5.5Hz, 1H), 5.06 (dd, J=12.8, 5.5Hz, 1H), 4.75 (d, J=6. 3Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.05–2.00(m,1H). 13 CNMR (151MHz, DMSO) δ 172.87, 170.09, 168.69, 167.27, 157.34, 150.69, 145.62, 136.20, 135.64, 132.20, 132.04, 131.90, 130.69, 128.02, 125.83, 124.58, 117.91, 111.46, 110.17, 48.63, 36.92, 31.00, 22.16. UPLC-MS (ESI) theoretical value is C 23 H 16 Cl2N4O5[M+H] + :499.05, Measured value: 499.13.

[0573] Example 77: 4-((2-(2,5-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0574]

[0575] Following the synthetic route of Example 22, compound 77 of Example 77 was obtained. 53.1 mg of a yellow solid was given, with a yield of 51%. 1HNMR(500MHz,DMSO)δ11.08(s,1H),7.95(d,J=2.5Hz,1H),7.65(d,J=8.6Hz, 1H),7.63–7.58(m,2H),7.34(s,1H),7.30(d,J=8.6Hz,1H),7.15(t,J=6.4Hz, 1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.76(d,J=6.2Hz,2H ),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.62–2.53(m,2H),2.06–2.00(m,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.01, 168.62, 167.20, 156.79, 150.90, 145.56, 136.09, 132.93, 132.16, 132.08, 131.44, 129.81, 129.72, 127.03, 125.83, 117.87, 111.39, 110.17, 48.58, 36.88, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 16 Cl2N4O5[M+H] + :499.05, Measured value: 499.29.

[0576] Example 78: 4-((2-(2,6-dichlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0577]

[0578] Following the synthetic route of Example 22, compound 78 of Example 78 was obtained.

[0579] Example 79: 4-(((2-(((2R,6S)-2,6-dimethylmorpholine)methyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione

[0580]

[0581] Compound 2-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-5-carboxaldehyde (30 mg, 0.1338 mmol) and pomalidomide (37 mg, 0.1338 mmol) were dissolved in 3 mL of acetic acid and refluxed at 135 °C overnight. After cooling to room temperature, sodium borohydride (10 mg, 0.2675 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water under ice bath conditions, concentrated under reduced pressure, dissolved in ethyl acetate, washed three times with water, and washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The theoretical value of UPLC-MS (ESI) was C1. 24 H 27 N5O6[M+H] + :482.51, Measured value: 482.20. 1 H NMR (500MHz, DMSO) δ11.08(s,1H),7.61–7.56(m,1H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.1H z,1H),7.06–7.02(m,2H),5.06(dd,J=12.8,5.4Hz,1H),4.64(d,J=6.3Hz,2H),3.58(s,2H),3 .49(dd,J=13.8,6.6Hz,2H),2.88(ddd,J=17.2,13.9,5.4Hz,1H),2.63(d,J=11.5Hz,2H),2.6 1–2.51(m,2H),2.05–1.99(m,1H),1.70(td,J=10.7,4.9Hz,2H),0.97(dd,J=6.2,1.9Hz,6H). 13 C NMR (126MHz, DMSO) δ172.81,170.04,168.66,167.21,160.26,149.55,145.53,136.09,132.1 6,124.27,117.66,111.26,109.97,70.82,58.15,53.54,48.58,36.74,30.97,22.12,18.86.

[0582] Example 80: 2-(2,6-dioxadiazin-3-yl)-4-((2-((3-morpholinazo-1-yl)methyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0583]

[0584] Following the synthetic route of Example 79, compound 80 of Example was obtained. 16.8 mg of a yellow solid was given, with a yield of 6%.1 HNMR (500MHz, DMSO) δ11.09(s,1H),7.59(dd,J=8.3,7.4Hz,1H),7.21(d,J=8.6Hz,1H),7.07(d,J= 7.0Hz,1H),7.03(t,J=6.4Hz,1H),7.01(s,1H),5.05(dd,J=12.8,5.4Hz,1H),4.62(d,J=6.3Hz,2H ),3.61(s,2H),3.54–3.50(m,4H),3.44–3.37(m,2H),2.93(t,J=6.9Hz,2H),2.91–2.85(m,1H),2. 83(dd,J=12.9,6.4Hz,1H),2.62–2.56(m,1H),2.56–2.51(m,1H),2.17(s,4H),2.05–1.98(m,1H). 13 C NMR (126MHz, DMSO) δ 172.81, 170.03, 168.69, 167.22, 160.53, 149.42, 145.60, 136.11, 132.17, 124.17, 117.67, 111.28, 109.99, 65.86, 57.83, 55.11, 53.79, 49.65, 48.60, 36.71, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C 25 H 28 N 6 O 6 [M+H]+: 509.54, Measured value: 509.85.

[0585] Example 81: 4-(4-(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindol-4-yl)amino)methyl)oxazol-2-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile

[0586]

[0587] Following the synthetic route of Example 79, compound 81 of Example was obtained. 48 mg of a yellow solid was given, with a yield of 19%. 1HNMR(500MHz,DMSO)δ11.09(s,1H),7.66(dd,J=13.4,1.9Hz,1H),7.58(dd,J=8.3,7.4Hz,1H ),7.55(dd,J=8.5,1.7Hz,1H),7.20(d,J=8.6Hz,1H),7.11–7.03(m,4H),5.05(dd,J=12.8,5. 4Hz,1H),4.65(d,J=6.3Hz,2H),3.67(s,2H),3.16–3.09(m,4H),2.88(ddd,J=17.1,13.9,5. 4Hz,1H),2.60(d,J=2.7Hz,1H),2.58–2.55(m,4H),2.52(d,J=4.5Hz,1H),2.05–1.96(m,1H). 13 C NMR (126MHz, DMSO) δ172.81,170.06,168.66,167.20,160.32,154.11,152.1 5,149.60,145.56,143.75,143.69,136.10,132.17,129.89,129.87,124.29, 119.79, 119.59, 119.44, 119.42, 118.40, 117.68, 111.28, 110.02, 102.30, 102.22, 53.58, 51.80, 49.04, 48.58, 36.82, 30.97, 22.12. The theoretical value of UPLC-MS (ESI) is C. 29 H 26 FN7O5[M+H]+: 572.57, measured value: 572.61.

[0588] Example 82: 2-(2,6-dioxadiazin-3-yl)-4-(2-(morpholinomethyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0589]

[0590] Following the synthetic route of Example 79, compound 82 of Example was obtained. 5.4 mg of a yellow solid was yielded, with a yield of 7%. 1HNMR (600MHz, DMSO) δ11.10(s,1H),7.58(dd,J=8.4,7.2Hz,1H),7.20(d,J=8.6Hz,1H),7.08(d,J= 7.0Hz,1H),7.05(d,J=6.5Hz,2H),5.06(dd,J=12.9,5.4Hz,1H),4.64(d,J=6.3Hz,2H),3.78–3.58 (m,2H),3.51(dd,J=15.5,12.3Hz,4H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.62–2.57(m,1H),2. 53(ddd,J=6.0,5.0,3.7Hz,1H),2.45(dd,J=23.4,15.2Hz,4H),2.03(dtd,J=7.5,5.2,2.1Hz,1H). 13 C NMR (151MHz, DMSO) δ 172.86, 170.10, 168.69, 167.25, 145.58, 136.15, 132.19, 124.38, 117.72, 111.35, 110.07, 69.80, 65.76, 52.50, 48.61, 36.83, 31.00, 22.15. UPLC-MS (ESI) theoretical value is C 22 H 23 N5O6[M+H] + 454.46, Measured value: 454.67.

[0591] Example 83: 4-(4-(5-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisooctanol-4-yl)amino)methyl)thiazolyl-2-yl)piperazin-1-yl)-3-fluorobenzonitrile

[0592]

[0593] 3-Fluoro-4-(4-(5-formylthiazolyl-2-yl)piperazin-1-yl)benzyl nitrile (83 mg, 0.303 mmol) and racemic pomalidomide (96 mg, 0.303 mmol) were dissolved in 5 mL of glacial acetic acid and refluxed overnight at 130 °C. After cooling to room temperature, NaBH4 (23 mg, 0.606 mmol) was added and the reaction was carried out for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 50 mg of a green solid, with a yield of 28.7%. The theoretical value of UPLC-MS (ESI) was C1. 28 H 24 FN7O4S[M+H] + :574.60, measured value: 574.44.

[0594] Example 84: 4-(4-(5-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)oxazol-2-yl)piperazin-1-yl)-3-fluorobenzyl nitrile

[0595]

[0596] Following the synthetic route of Example 83, Compound 84 of Example was obtained.

[0597] Example 85: 2-(2,6-dioxadiazin-3-yl)-4-(2-(3-morpholinazabutan-1-yl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0598]

[0599] Following the synthetic route of Example 83, Compound 85 of Example was obtained.

[0600] Example 86: 2-(2,6-dioxadiazin-3-yl)-4-(2-(3-morpholinazabutan-1-yl)thiazolyl)methyl)amino)isoindole-1,3-dione

[0601]

[0602] Following the synthetic route of Example 83, Compound 86 of Example 86 was obtained.

[0603] Example 87: 2-(2,6-dioxadiazin-3-yl)-4-(2-((4-morpholinopadiazin-1-yl)methyl)oxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0604]

[0605] Following the synthetic route of Example 79, compound 87 of Example was obtained. 65.8 mg of a yellow solid was given, with a yield of 23%. 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.60(dd,J=8.3,7.3Hz,1H),7.23(s,1H),7.21(d,J=8.6Hz,1H), 7.11(t,J=6.6Hz,2H),5.07(dd,J=12.9,5.4Hz,1H),4.68(d,J=6.0Hz,2H),4.35(s,2H),3.98(dd,J= 14.9,8.7Hz,2H),3.75–3.59(m,2H),3.53–3.26(m,5H),3.18–3.00(m,2H),2.95–2.79(m,3H),2.63– 2.57(m,1H),2.53(s,1H),2.23(d,J=11.6Hz,2H),2.06–2.00(m,1H),1.79(dd,J=24.6,13.0Hz,2H).

[0606] 13 C NMR (201MHz, DMSO) δ 172.84, 170.13, 168.68, 167.21, 145.47, 136.18, 132.20, 125.03, 117.60, 117.13, 115.66, 111.42, 110.10, 63.54, 50.36, 48.62, 40.43, 39.99, 36.75, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C 27 H 32 N6O6[M+H] + :537.59, measured value: 537.45.

[0607] Example 88: 2-(2,6-dioxadiazin-3-yl)-6-fluoro-4-(2-phenyloxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0608]

[0609] Following the synthetic route of Example 22, compound 88 of Example 88 was obtained.

[0610] Example 89: 2-(2,6-dioxadiazin-3-yl-3-d)-4-((2-phenyloxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0611]

[0612] Following the synthetic route of Example 22, compound 89 of Example 89 was obtained.

[0613] Example 90: 2-(3-fluoro-2,6-dioxadiazin-3-yl)-4-((2-phenyloxazol-5-yl)methyl)amino)isoindole-1,3-dione

[0614]

[0615] Following the synthetic route of Example 22, compound 90 of Example 90 was obtained.

[0616] Example 91: 2-(2,6-dioxadiazin-3-yl)-4-((((2-((4-methylpiperazin-1-yl)methyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0617]

[0618] Following the synthetic route of Example 79, compound 91 of Example was obtained. 21.1 mg of a yellow solid was given, with a yield of 6%. 1 HNMR (600MHz, DMSO) δ11.11(s,1H),7.59(dd,J=8.5,7.1Hz,1H),7.20(d,J=8.6Hz,1H),7.09(d,J=7.4H z,1H),7.08(s,1H),7.05(t,J=6.1Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.64(d,J=5.6Hz,2H),3.73(s, 2H),3.36(d,J=10.4Hz,2H),2.98(dd,J=13.5,10.0Hz,4H),2.89(ddd,J=17.1,14.0,5.5Hz,1H),2.76( s,3H),2.63–2.57(m,1H),2.56–2.51(m,1H),2.45(t,J=10.4Hz,2H),2.03(dtd,J=7.8,5.3,2.3Hz,1H). 13 C NMR (151MHz, DMSO) δ 172.85, 170.11, 168.71, 167.22, 159.73, 149.73, 145.54, 136.18, 132.20, 124.44, 117.60, 111.36, 110.03, 52.61, 52.44, 48.84, 48.61, 42.13, 36.79, 30.99, 22.14. UPLC-MS (ESI) theoretical value is C 23 H 26 N6O5[M+H] + Measured value: 467.46 :467.50

[0619] Example 92: 4-(((2-(2-chlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione

[0620]

[0621] Following the synthetic route of Example 22, compound 92 of Example 92 was obtained. 57.9 mg of a yellow solid was given, with a yield of 52%. 1 H NMR (500MHz, DMSO) δ11.08(s,1H),7.92(dd,J=7.6,1.8Hz,1H),7.61(dd,J=12.5,5.0Hz,2H ),7.52(td,J=7.7,1.9Hz,1H),7.48(td,J=7.5,1.4Hz,1H),7.31(t,J=4.0Hz,2H),7.13(t, J=6.0Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.76(d,J=4.8Hz,2H),2 .88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.03(ddd,J=10.3,6.1,3.9Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.01, 168.64, 167.20, 158.10, 150.38, 145.60, 136.11, 132.15, 131.81, 131.08, 131.05, 130.72, 127.60, 125.67, 125.60, 117.85, 111.37, 110.12, 48.57, 36.90, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 ClN4O5[M+H] + :465.86, measured value: 465.33.

[0622] Example 93: 2-(2,6-dioxadiazin-3-yl)-4-(((2-(4-fluorophenyl)oxazol-5-yl)methyl)amino)isoindoline-1,3-dione

[0623]

[0624] Following the synthetic route of Example 22, compound 92 of Example 92 was obtained. 67.7 mg of a yellow solid was given, with a yield of 58%. 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.98–7.94(m,2H),7.62(dd,J=8.4,7.3Hz,1H) ,7.36(t,J=8.9Hz,2H),7.30(d,J=8.6Hz,1H),7.23(s,1H),7.12(t,J=4.8Hz,1H) ,7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.73(d,J=4.8Hz,2H),2.88 (ddd,J=17.0,13.9,5.4Hz,1H),2.57(dt,J=12.7,9.1Hz,2H),2.06–2.00(m,1H). 13 C NMR (126MHz, DMSO) δ 172.77, 170.02, 168.65, 167.20, 164.28, 162.30, 159.53, 149.91, 145.58, 136.14, 132.19, 129.63, 128.20, 128.13, 125.77, 123.56, 123.54, 117.70, 116.40, 116.23, 111.34, 110.10, 48.58, 36.92, 30.95, 22.10. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.41, measured value: 449.35.

[0625] Example 94: 2-(2,6-dioxadiazin-3-yl)-4-(((5-(3-fluorophenyl)oxazol-2-yl)methyl)amino)isodihydroindole-1,3-dione

[0626]

[0627] Following the synthetic route of Example 22, compound 94 of Example 94 was obtained. 10.5 mg of a yellow solid was yielded, with a yield of 10%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.72(s,1H),7.62(dd,J=8.5,7.2Hz,1H),7.54–7.48(m,3H),7.26–7.17(m,3H),7.11(d,J=7.1Hz, 1H),5.09(dd,J=12.8,5.4Hz,1H),4.80(d,J=5.9Hz,2H),2.89(ddd,J=16.6,13.7,5.2Hz,1H),2.64–2.52(m,2H),2.08–2.01(m,1H). 13 C NMR (126MHz, DMSO) δ 172.82, 170.06, 168.66, 167.24, 161.51, 161.43, 149.69, 149.67, 145.72, 136.17, 132.11, 131.44, 131.38, 129.56, 129.49, 123.82, 119.87, 119.86, 117.87, 115.35, 115.18, 111.49, 110.67, 110.48, 110.16, 48.62, 30.99, 22.12. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.41, measured value: 449.31.

[0628] Example 95: 2-(2,6-dioxadiazin-3-yl)-4-(((5-(2-fluorophenyl)oxazol-2-yl)methyl)amino)isodihydroindole-1,3-dione

[0629]

[0630] Following the synthetic route of Example 22, compound 95 of Example 95 was obtained. 20.3 mg of a yellow solid was given, with a yield of 17%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.70(td,J=7.7,1.7Hz,1H),7.62(dd,J=8.4,7.2Hz,1H) ,7.47(d,J=3.6Hz,1H),7.46–7.41(m,1H),7.40–7.31(m,2H),7.25(t,J=6.5Hz,1H),7.23(d ,J=8.6Hz,1H),7.11(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.3Hz,2H), 2.89(ddd,J=16.7,13.7,5.2Hz,1H),2.63–2.51(m,2H),2.05(ddt,J=12.7,5.4,2.6Hz,1H). 13 C NMR (126MHz, DMSO) δ 172.82, 170.07, 168.66, 167.24, 161.21, 158.85, 156.86, 145.74, 145.24, 145.23, 136.17, 132.11, 130.31, 130.25, 125.94, 125.85, 125.27, 125.25, 117.88, 116.33, 116.17, 115.51, 115.41, 111.50, 110.17, 48.62, 30.99, 22.12. UPLC-MS (ESI) theoretical value is C 23 H 17 FN4O5[M+H] + :449.51, measured value: 449.39.

[0631] Example 96: 4-(((2-(3-cyclopropoxyphenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0632]

[0633] Following the synthetic route of Example 22, compound 96 of Example 96 was obtained. 64.9 mg of a yellow solid was given, with a yield of 61%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.62(dd,J=8.5,7.2Hz,1H),7.57–7.55(m,1H),7.51(d,J=7.8Hz,1H),7.43( t,J=8.0Hz,1H),7.31(d,J=8.6Hz,1H),7.23(s,1H),7.18–7.13(m,2H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.8 ,5.4Hz,1H),4.74(d,J=3.3Hz,2H),3.90(ddd,J=8.9,5.9,2.9Hz,1H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.6 2–2.56(m,1H),2.54(dd,J=8.5,4.4Hz,1H),2.06–1.99(m,1H),0.80(dt,J=11.5,5.8Hz,2H),0.70–0.65(m,2H). 13 C NMR (151MHz, DMSO) δ 172.82, 170.06, 168.68, 167.23, 160.11, 158.98, 149.97, 145.62, 136.14, 132.21, 130.40, 128.04, 125.73, 118.41, 117.78, 117.53, 111.47, 111.36, 110.10, 50.90, 48.59, 36.95, 30.98, 22.12, 5.94. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O6[M+H]+: 487.48, measured value: 487.31.

[0634] Example 97: 4-(((2-(2-cyclopropoxyphenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0635]

[0636] Following the synthetic route of Example 22, compound 97 of Example 97 was obtained. 72.3 mg of a yellow solid was given, with a yield of 68%. 1HNMR (500MHz, DMSO) δ11.11(s,1H),7.75(dd,J=7.7,1.5Hz,1H),7.61(dd,J=8.4,7.2Hz,1H),7.51–7.47(m,1 H),7.44(d,J=7.7Hz,1H),7.28(d,J=8.6Hz,1H),7.20(s,1H),7.13–7.04(m,3H),5.07(dd,J=12.7,5.4Hz,1H ),4.70(d,J=2.3Hz,2H),3.90(dq,J=8.9,2.8Hz,1H),2.89(ddd,J=16.8,13.8,5.3Hz,1H),2.59(dd,J=15.7, 3.7Hz,1H),2.52(d,J=9.6Hz,1H),2.03(ddd,J=10.1,5.2,3.1Hz,1H),0.79–0.74(m,2H),0.62–0.58(m,2H). 13 CNMR (126MHz, DMSO) δ 172.84, 170.05, 168.71, 167.26, 159.20, 156.46, 149.47, 145.65, 136.15, 132.19, 131.85, 129.84, 125.25, 120.95, 117.69, 116.14, 114.44, 111.27, 109.94, 51.31, 48.59, 40.43, 36.81, 30.98, 22.15, 6.02. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O6[M+H]+: 487.48, Measured value: 487.31

[0637] Example 98: 2-(2,6-dioxadiazine-3-yl)-4-(((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)amino)isoindoline-1,3-dione

[0638] Synthesis route:

[0639]

[0640] Step 1: Compound 98-1 (300 mg, 1.70 mmol), compound 98-2 (501 mg, 3.4 mmol), and triphenylphosphine (893 mg, 3.4 mmol) were dissolved in 10 mL of dry tetrahydrofuran solution. DIAD (671 μL, 3.4 mmol) was added at room temperature. The reaction was carried out under nitrogen protection at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 600 mg of compound 98-3 as a pale yellow oil. The theoretical value of UPLC-MS (ESI) was C1. 17 H 11 N3O3[M+H] + 306.08, measured value: 306.15.

[0641] Step 2: Compound 98-3 (600 mg, 1.97 mmol) was dissolved in 8 mL of ethanol, and 80% hydrazine hydrate was added and refluxed for 1 hour. The reaction was monitored by LC-Mass to ensure complete reaction. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 185 mg of the target product compound 98-4 as a yellow oil. The theoretical value of UPLC-MS (ESI) is C9H9N3O[M+H]. + :176.07, Measured value: 176.15.

[0642] Step 3: Compound 98-4 (86 mg, 0.49 mmol), compound 98-5 (147 mg, 0.53 mmol), and DIEA (160 mL, 0.97 mmol) were dissolved in 3 mL of DMF. The mixture was heated to 90 °C and reacted overnight. After the reaction was complete as monitored by TLC, it was cooled to room temperature, diluted with ethyl acetate, washed several times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by HPLC to obtain 13.1 mg of compound 98 as a yellow solid, with a yield of 6%. 1 H NMR (500MHz, DMSO) δ11.13 (s, 1H), 7.96–7.94 (m, 2H), 7.63 (dd, J = 9.3, 6.6Hz, 2H), 7. 61(dd,J=7.1,4.6Hz,2H),7.31(t,J=6.4Hz,1H),7.27(d,J=8.6Hz,1H),7.14(d,J=7. 1Hz, 1H), 5.09 (dd, J=12.7, 5.4Hz, 1H), 4.96 (d, J=6.3Hz, 2H), 2.89 (ddd, J=16.8, 13. 7,5.2Hz,1H),2.60(dd,J=15.5,3.6Hz,1H),2.54(t,J=6.8Hz,1H),2.07–2.01(m,1H). 13C NMR (126MHz, DMSO) δ 172.84, 170.07, 168.59, 167.22, 164.37, 145.46, 136.24, 132.15, 132.06, 129.60, 129.51, 126.93, 126.47, 123.25, 117.87, 111.74, 110.42, 48.64, 37.41, 30.99, 22.12. UPLC-MS (ESI) theoretical value is C 22 H 17 N5O5[M+H] + Measured value: 432.41, Actual value: 432.21

[0643] Example 99: 2-(2,6-dioxadiazin-3-yl)-4-(((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)amino)isoindoline-1,3-dione

[0644]

[0645] The synthetic route of Example 99 is the same as that of Example 98. Using (5-phenyl-1,3,4-thiadiazol-2-yl)methylamine (200 mg, 1.04 mmol) and 2-(2,6-dioxadiazin-3-yl)-4-fluoroisoindoline-1,3-dione (144 mg, 0.52 mmol) as raw materials, Example 98 was obtained. After purification by HPLC, 5 mg of yellow solid was obtained, with a yield of 2%. 1 H NMR(500MHz,DMSO)δ11.13(s,1H),7.95(dd,J=7.9,1.4Hz,2H),7.62–7.59(m, 3H),7.55–7.53(m,2H),7.17(d,J=8.6Hz,1H),7.12(d,J=7.1Hz,1H),5.09(dd, J=12.8,5.4Hz,1H),5.05(d,J=6.5Hz,2H),2.90(ddd,J=16.8,13.8,5.3Hz,1H) ,2.60(dd,J=15.5,4.0Hz,1H),2.54(dd,J=8.1,5.5Hz,1H),2.07–2.03(m,1H). 13CNMR (126MHz, DMSO) δ 172.84, 170.02, 168.56, 167.19, 145.11, 136.39, 132.29, 132.06, 131.53, 131.45, 131.35, 129.43, 128.82, 128.72, 127.63, 117.57, 111.76, 110.46, 48.64, 41.44, 30.99, 22.12. UPLC-MS (ESI) theoretical value is C 22 H 17 N5O4S[M+H] + 448.47, Measured value: 448.20

[0646] Example 100: 2-(2,6-dioxopiperidin-3-yl)-4-((((2-(3-(oxecyclobutane-3-yloxy)phenyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0647]

[0648] Following the synthetic route of Example 22, compound 100 of Example 1 was obtained. 67.6 mg of a yellow solid was given, with a yield of 66%. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),7.63(dd,J=8.4,7.3Hz,1H),7.52(d,J=7.7Hz,1H),7.44(t,J=8.0Hz,1H),7.30( d,J=8.6Hz,1H),7.23(d,J=4.0Hz,2H),7.15(t,J=5.9Hz,1H),7.10(d,J=7.1Hz,1H),6.94(dd,J=8.2,2.3Hz,1H),5. 40–5.31(m,1H),5.07(dd,J=12.8,5.4Hz,1H),4.93(t,J=6.7Hz,2H),4.73(d,J=5.5Hz,2H),4.56(dd,J=7.2,5.0Hz ,2H),2.88(ddd,J=16.9,13.9,5.3Hz,1H),2.62–2.55(m,1H),2.54–2.51(m,1H),2.02(ddd,J=7.3,5.3,2.9Hz,1H). 13C NMR (126MHz, DMSO) δ 172.83, 170.08, 168.68, 167.23, 159.86, 156.66, 150.06, 145.60, 136.15, 132.22, 130.82, 128.35, 125.79, 118.75, 117.77, 116.77, 111.40, 110.12, 76.67, 70.12, 48.60, 36.94, 30.98, 22.12. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O7[M+H] + Measured value: 503.48, Actual value: 503.25

[0649] Example 101: 2-(2,6-dioxopiperidin-3-yl)-4-(((2-(2-((oxecyclobutane-3-yloxy)phenyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0650]

[0651] Following the synthetic route of Example 22, compound 101 of Example 1 was obtained. 2.1 mg of a yellow solid was given, with a yield of 39%. 1 HNMR(500MHz,DMSO)δ11.13(s,1H),8.22(s,1H),8.09(dd,J=8.2,1.4Hz,1H),7.77–7.72(m,1H),7.70–7.65(m ,1H),7.39–7.33(m,3H),7.28(d,J=8.4Hz,1H),7.16(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.89(d,J =6.5Hz,2H),4.82(d,J=15.1Hz,1H),4.53–4.47(m,1H),4.40(dd,J=15.1,8.3Hz,1H),3.85(dd,J=11.6,4.8Hz ,1H),3.78(dd,J=11.6,5.0Hz,1H),2.89(ddd,J=17.2,13.7,5.2Hz,1H),2.65–2.56(m,2H),2.06–2.01(m,1H). 13C NMR (201MHz, DMSO) δ 172.82, 170.07, 168.56, 167.17, 157.99, 157.91, 151.00, 145.06, 136.80, 136.34, 132.24, 129.43, 123.34, 121.53, 121.34, 117.78, 111.87, 110.56, 109.57, 77.64, 60.99, 52.53, 48.65, 36.53, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O7[M+H]+: 503.48, measured value: 503.29.

[0652] Example 102: 2-(2,6-dioxopiperidin-3-yl)-4-((((2-(4-(oxecyclobutane-3-yloxy)phenyl)thiazolyl)methyl)amino)isodihydroindole-1,3-dione

[0653]

[0654] Following the synthetic route of Example 22, compound 102 of Example 1 was obtained. 8.6 mg of a yellow solid was given, with a yield of 8%. 1 HNMR(500MHz,DMSO)δ11.12(s,1H),7.86–7.79(m,3H),7.60–7.56(m,1H),7.31(t,J=6.2Hz ,1H),7.21(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),6.87(d,J=8.8Hz,2H),5.36–5.30(m,1H ),5.07(dd,J=12.8,5.4Hz,1H),4.93(t,J=6.7Hz,2H),4.81(d,J=6.2Hz,2H),4.55(dd,J=7 .3,5.0Hz,2H),2.88(ddd,J=16.9,13.9,5.4Hz,1H),2.62–2.52(m,2H),2.07–2.00(m,1H). 13 C NMR (126MHz, DMSO) δ 172.84, 170.10, 168.62, 167.23, 166.34, 157.78, 145.40, 141.78, 136.91, 136.20, 132.28, 127.75, 126.68, 117.67, 115.13, 111.26, 110.05, 76.68, 70.15, 48.59, 38.47, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C26 H 22 N4O6S[M+H]+: 519.54, measured value: 519.22.

[0655] Example 103: 4-(((2-(4-cyclopropoxyphenyl)thiazolyl-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindoline-1,3-dione

[0656]

[0657] Following the synthetic route of Example 22, compound 103 of Example 1 was obtained. 6.6 mg of a yellow solid was yielded, representing a yield of 6%. 1 HNMR (500MHz, DMSO) δ11.12(s,1H),7.83(s,2H),7.81(d,J=2.5Hz,1H),7.59(dd,J=8.3,7.4Hz,1H ),7.31(t,J=6.1Hz,1H),7.22(d,J=8.6Hz,1H),7.12(d,J=8.8Hz,2H),7.07(d,J=7.1Hz,1H),5.07( dd,J=12.8,5.4Hz,1H),4.81(d,J=5.9Hz,2H),3.89(ddd,J=8.9,6.0,2.9Hz,1H),2.89(ddd,J=17.0 ,14.0,5.4Hz,1H),2.61–2.53(m,2H),2.07–2.00(m,1H),0.80(q,J=5.8Hz,2H),0.69–0.64(m,2H). 13 C NMR (201MHz, DMSO) δ 172.83, 170.09, 168.61, 167.23, 166.57, 160.19, 145.40, 141.70, 136.71, 136.19, 132.28, 128.89, 127.48, 126.35, 117.67, 115.46, 111.25, 110.04, 51.02, 48.59, 38.47, 30.98, 22.13, 5.94. UPLC-MS (ESI) theoretical value is C 26 H 22 N4O5S[M+H] + Measured value: 503.13, Actual value: 503.18

[0658] Example 104: 2-(2,6-dioxopiperidin-3-yl)-4-((((2-(4-(2-methoxyethoxy)phenyl)thiazolyl-5-yl)methyl)amino)isoindoline-1,3-dione

[0659]

[0660] Following the synthetic route of Example 22, compound 104 of Example 1 was obtained. 3.4 mg of a yellow solid was given, with a yield of 5%. 1 HNMR(500MHz,DMSO)δ11.12(s,1H),7.82(s,1H),7.81–7.78(m,2H),7.58(dd,J=8.3,7.3Hz,1H) ,7.31(t,J=6.2Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.0Hz,1H),7.02(t,J=5.8Hz,2H),5.07 (dd,J=12.8,5.5Hz,1H),4.81(d,J=6.2Hz,2H),4.13(dd,J=5.3,3.7Hz,2H),3.66(dd,J=5.3,3.7 Hz,2H),3.30(s,3H),2.89(ddd,J=17.3,13.8,5.3Hz,1H),2.61–2.53(m,2H),2.06–2.01(m,1H). 13 C NMR (126MHz, DMSO) δ 172.83, 170.10, 168.61, 167.23, 166.58, 160.01, 145.40, 141.70, 136.64, 136.18, 132.28, 127.52, 126.00, 117.68, 115.00, 111.25, 110.04, 70.25, 67.11, 58.18, 48.59, 38.47, 30.98, 22.13. UPLC-MS (ESI) theoretical value is C 26 H 24 N4O6S[M+H] + :521.14, measured value: 521.21.

[0661] Example 105: 2-(2,6-dioxadiazin-3-yl)-4-(((2-((1s,4s)-4-(4-fluorobenzyl)cyclohexyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0662]

[0663] Following the synthetic route of Example 12, compound 105 of Example 1 was obtained. 43.6 mg of a yellow solid was given, with a yield of 51%. 1H NMR (500MHz, DMSO) δ11.11(s,1H),7.60(dd,J=8.5,7.2Hz,1H),7.22(d,J=8.6Hz,1H),7.16–7.11(m, 2H),7.10–7.02(m,4H),6.98(s,1H),5.07(dd,J=12.7,5.4Hz,1H),4.62(d,J=1.4Hz,2H),3.00(p,J= 4.6Hz,1H),2.88(ddd,J=16.9,13.8,5.4Hz,1H),2.61–2.55(m,1H),2.53(d,J=4.5Hz,1H),2.39(d,J =7.4Hz,2H),2.04–1.94(m,3H),1.64–1.56(m,3H),1.47–1.39(m,2H),1.11(td,J=12.7,2.7Hz,2H).

[0664] Example 106: 2-(2,6-dioxadiazin-3-yl)-4-(((2-((1r,4r)-4-(4-fluorobenzyl)cyclohexyl)oxazol-5-yl)methyl)amino)isodihydroindole-1,3-dione

[0665]

[0666] Following the synthetic route of Example 22, compound 106 of Example 1 was obtained. 10.8 mg of a yellow solid was given, with a yield of 55%. 1 HNMR (500MHz, DMSO) δ11.11(s,1H),7.59(dd,J=8.4,7.2Hz,1H),7.18(dd,J=8.3,6.2Hz,3H),7.10–7.05(m,3H),7. 01(t,J=6.9Hz,1H),6.93(s,1H),5.06(dd,J=12.8,5.5Hz,1H),4.58(d,J=5.6Hz,2H),2.88(ddd,J=17.2,14.0,5.4H z, 1H), 2.70–2.63(m, 1H), 2.61–2.53(m, 2H), 2.47(d, J = 7.1 Hz, 2H), 2.06–1.94(m, 3H), 1.67(dd, J = 12.7, 1.9 Hz, 2H), 1.52–1.43(m, 1H), 1.35(ddd, J = 15.8, 13.2, 3.4 Hz, 2H), 1.04(ddd, J = 15.7, 13.1, 3.3 Hz, 2H). The theoretical value of UPLC-MS (ESI) is C. 30 H 29FN4O5[M+H]+: 545.48, measured value: 545.32.

[0667] Example Ctrl-1: 3-(1-oxo-4-((2-(1-neovalerylpiperidin-4-yl)oxazol-5-yl)methyl)amino)isoindol-2-yl)piperidin-2,6-dione

[0668]

[0669] Nalidomide (100 mg, 0.357 mmol), 4-(5-formyloxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (92 mg, 0.357 mmol), phenylsilane (44 μL, 0.357 mmol), and dibutyltin dichloride (108 mg, 0.357 mmol) were dissolved in 6 mL of tetrahydrofuran. The mixture was refluxed overnight. After the reaction was completed by TLC monitoring, the solution was concentrated under reduced pressure and subjected to column chromatography to give 90 mg of 4-(5-((2-(2,6-dioxadiazin-3-yl)-1-oxoisoquinoline-4-yl)amino)methyl)oxazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil, with a yield of 48%.

[0670] 4-(5-((2-(2,6-dioxadiazin-3-yl)-1-oxoisoquinoline-4-yl)amino)methyl)oxazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (90 mg, 0.17 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. After reacting for 0.5 hours, the mixture was concentrated under reduced pressure and dried under vacuum. The crude product was dissolved in 2 mL of N,N-dimethylformamide, and trimethylacetic acid (19 mg, 0.187 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (71 mg, 0.187 mmol) were added. Under stirring, N,N-diisopropylethylamine (296 μL, 1.7 mmol) was added. After reacting at room temperature for one hour, the reaction was quenched with water, extracted with ethyl acetate, separated, and the organic layer was washed several times with saturated sodium chloride water. The mixture was dried, filtered, concentrated, and purified by HPLC to obtain a white solid: 7 mg, yield 8%. 1¹H NMR (400MHz, DMSO) δ 11.01 (s, 1H), 7.28 (d, J = 7.7Hz, 1H), 6.98 (d, J = 10.2Hz, 2H), 6.88 (d, J = 8.0Hz, 1H), 6.21 (s, 1H), 5.11 (d, J = 8.3Hz, 1H), 4.40 (d, J = 5.3Hz, 2H), 4.29–4.08 (m, 4H), 3.15–2.86 (m, 5H), 2.68–2.57 (m, 2H), 2.37–2.21 (m, 1H), 2.10–1.89 (m, 4H), 1.52 (dd, J = 21.5, 10.8Hz, 2H), 1.18 (s, 9H). UPLC-MS (ESI) theoretical value is C 27 H 33 N5O5[M+H] + :508.59, measured value: 508.32.

[0671] Example Ctrl-2: N-((2-(4-chlorophenyl)oxazol-5-yl)methyl)-N-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoquinoline-4-yl)formamide

[0672]

[0673] 50 mg (0.11 mmol) of 4-((2-(4-chlorophenyl)oxazol-5-yl)methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione was dissolved in 1 mL of formic acid, and 300 μL of acetic anhydride was added. The reaction was carried out at 60 °C for 1 hour. After the reaction was completed by LC-Mass monitoring, the mixture was cooled to room temperature and purified by HPLC to give 14 mg of a yellow solid, with a yield of 26%. 1 ¹H NMR (400MHz, DMSO) δ 11.14 (s, 1H), 8.51 (s, 1H), 7.90 (dd, J = 16.7, 7.2Hz, 5H), 7.50 (d, J = 8.0Hz, 2H), 7.18 (s, 1H), 5.30–5.19 (m, 2H), 5.18–5.06 (m, 1H), 2.94–2.79 (m, 1H), 2.63 (d, J = 31.6Hz, 1H), 2.03–1.90 (m, 1H). UPLC-MS (ESI) theoretical value: C 24 H 17 ClN4O6[M+H] + :493.87, measured value: 493.59.

[0674] Example Ctrl-3: 4-((2-(4-chlorophenyl)oxazol-5-yl)methyl)(methyl)amino)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione

[0675]

[0676] Using intermediate 1-(2-(4-chlorophenyl)oxazol-5-yl)-N-methylmethylamine (100 mg, 0.45 mmol) as a starting material, 1-(2-(4-chlorophenyl)oxazol-5-yl)-N-methylmethylamine was dissolved in 5 mL of DMSO, and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (101 mg, 0.367 mmol) was added. N,N-diisopropylethylamine (182 μL, 0.367 mmol) was added with stirring, and the mixture was stirred overnight at 100 °C. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting product was purified by HPLC to obtain 130 mg of a yellow-green solid, with a yield of 74%. 1 ¹H NMR (400MHz, DMSO) δ 11.11 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.68 (t, J = 7.7Hz, 1H), 7.50 (d, J = 8.1Hz, 2H), 7.35 (t, J = 8.2Hz, 2H), 7.19 (s, 1H), 5.14 (dd, J = 12.2, 4.9Hz, 1H), 4.96 (q, J = 16.4Hz, 2H), 3.06 (s, 3H), 2.89 (t, J = 13.1Hz, 1H), 2.60 (d, J = 16.3Hz, 2H), 2.18–1.96 (m, 1H). UPLC-MS (ESI) theoretical value is C 24 H 19 ClN4O5[M+H] + :479.89, Measured value: 479.63.

[0677] Example Ctrl-4: 3-(4-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-1-oxoisoquinoline-2-yl)piperidine-2,6-dione

[0678]

[0679] 1-Azide-4-chlorobenzene and 3-(1-oxy-4-(prop-2-in-1-oxy)isoindol-2-yl)piperidin-2,6-dione were reacted via Click to give Example Ctrl-4. ¹H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.76 (s, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 7.29 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 5.13 (dd, J = 13). 3, 5.1 Hz, 1H), 4.52 (s, 2H), 4.29 (d, J = 17.2 Hz, 1H), 4.18 (d, J = 17.2 Hz, 1H), 2.99–2.88 (m, 1H), 2.67–2.58 (m, 1H), 2.30 (ddd, J = 26.5, 13.3, 4.4 Hz, 1H), 2.08–1.99 (m, 1H). The theoretical value of UPLC-MS (ESI) is C 22 H 19 ClN6O3[M+H] + :451.88, Measured value: 451.70.

[0680] II. Experimental Examples

[0681] This invention also tested the activity of the multisubstituted isoindoline compounds of the examples against three major hematologic malignancy cell lines: multiple myeloma (MM.1S), mantle cell lymphoma (Mino), and acute myeloid leukemia (MV-4-11). The cell proliferation inhibitory activity of these three representative cell lines was tested. Compounds 39, 40, and 41 in this invention are prodrug compounds obtained by hydrolyzing their ester bonds. Unless otherwise specified, all experimental materials required for the pharmacological experiments were commercially available.

[0682] 1. Effects of the compound on MM.1S cell proliferation

[0683] MM.1S cells were cultured and collected using 1640 micrograms of 10% fetal bovine serum. Cell concentrations were diluted according to a 7-day treatment time, and 180 μL of cell suspension was added to each well of a 96-well cell culture plate to achieve a cell count of 20,000. 20 μL of DMSO (final concentration 0.2%) was added to the control cell wells. The compound was serially diluted 5-fold from a 10 mM stock solution, with 20 μL added to each well (DMSO final concentration 0.2%). Cells were incubated at 37°C in a 5% CO2 incubator for 7 days. The reaction solution was prepared according to the MTS kit (Promega, G5430), and 20 μL was added to each well. Cells were incubated at 37°C in a 5% CO2 incubator for 3-4 hours. Absorbance at 490 nm was read using a microplate, with 690 nm absorbance as background. OD490-OD690 was used as the final raw data. The inhibition rate of the compound was calculated using the formula: Inhibition rate = (OD690 - OD490) / OD690. DMSO -OD 化合物 ) / (OD DMSO -O 空白 The proliferation inhibition IC50 of the compound was calculated using Graph PadPrism 5.0. The experiment was repeated three times, with three parallel experiments per experiment, and the mean and standard deviation were calculated.

[0684] The cell viability test results are shown in Table 1 below: A represents the cell viability IC50. 50 <15nM, B indicates cell viability at 15nM <IC 50 <30 nM, C indicates cell viability 30 nM <IC 50 <150 nM, D represents the cell viability IC50. 50 >150nM.

[0685] Table 1. Inhibitory activity of compounds on MM.1S cell proliferation

[0686]

[0687]

[0688] Based on the above cell growth inhibition activity test results, some of the compounds in this invention exhibit excellent inhibitory activity against the growth of multiple myeloma MM.1S cells. The activity of most compounds is superior to that of marketed drugs lenalidomide or pomalidomide, and comparable to that of the currently clinically investigated compound CC-220. Furthermore, the development of these structurally diverse compounds provides more alternative material bases and novel structures for obtaining drug molecules with higher activity and better pharmaceutical properties. Therefore, the compounds of this invention can be used for the prevention and treatment of CRBN (CRL4). CRBNDiseases associated with E3 ubiquitin ligase activity, such as multiple myeloma, or non-restrictive diseases including other underlying cancers, pain, neurological disorders, and immune system disorders.

[0689] 2. Inhibitory activity of the compound on Mino cell proliferation

[0690] Mino cells were cultured and collected using 1640 medium supplemented with 15% fetal bovine serum. Cell concentrations were diluted according to a 3-day treatment time, and 90 μL of cell suspension was added to each well of a 96-well cell plate to achieve a cell count of 8000 cells. 10 μL of DMSO (final concentration 0.2%) was added to the control cell wells. The compound was serially diluted 5-fold from a 10 mM stock solution, and 10 μL of this solution was added to each compound cell well (DMSO final concentration 0.2%). Cells were incubated at 37°C in a 5% CO2 incubator for 3 days. After preparing the reaction solution according to the MTS kit (Promega, G5430), 20 μL was added to each well and incubated at 37°C in a 5% CO2 incubator for 3–4 hours.

[0691] The absorbance at 490 nm was read using an ELISA plate, with the absorbance at 690 nm used as the background value. The final raw data was obtained from OD490 to OD690. The inhibition rate of the compound was calculated using the formula: Inhibition rate = (OD690 - OD490) / OD690. DMSO -OD 化合物 ) / (OD DMSO -O 空白 ()×100%. The proliferation inhibition IC50 of the compound. 50 The results were fitted using Graph Pad Prism 5.0. The experiment was repeated three times, with three parallel experiments used for each iteration to calculate the mean and standard deviation.

[0692] The cell viability test results are shown in Table 2 below: A represents the cell viability IC50. 50 <60 nM, B indicates cell viability 60 nM <IC 50 <120 nM, C represents the IC50 of cell viability. 50 >120nM.

[0693] Table 2. Inhibitory activity of compounds on Mino cell proliferation

[0694]

[0695]

[0696] Based on the cell growth inhibition activity test results of the compounds in the above embodiments, it was found that some of the compounds in this invention have excellent inhibitory activity against the growth of mantle cell lymphoma Mino cells. The activity of most of these compounds is superior to that of marketed drugs lenalidomide or pomalidomide, and most of the compounds in this invention are superior to the currently clinically investigated compound CC-220. Furthermore, the development of these structurally diverse compounds provides a selectable material basis and molecular source for obtaining drug molecules with higher activity and better pharmaceutical properties. Therefore, the compounds of this invention broaden the application scope of sulfadiazine drugs in the treatment of hematological malignancies, and can be used to expand to other indications of hematological malignancies, such as as active molecules for mantle cell lymphoma, and as preparation of drugs or diagnostic reagents for the prevention or treatment of this type of disease. Therefore, the compounds of this invention can serve as potent and novel CRBN modulators for the prevention, treatment, and regulation of CRBN (CRL4). CRBN Diseases associated with E3 ubiquitin ligase activity, such as multiple myeloma, mantle cell lymphoma, or non-restrictive diseases including other underlying oncological diseases, pain, neurological disorders, and immune system disorders.

[0697] 3. Inhibitory activity of the compound on the proliferation of MV-411 cells

[0698] MV-4-11 cells were cultured and collected using IMDM with 10% fetal bovine serum. Cell concentrations were diluted according to a 7-day treatment time, and 180 μL of cell suspension was added to each well of a 96-well cell culture plate to achieve a cell count of 2000 cells. 20 μL of DMSO (final concentration 0.2%) was added to the control cell wells. The compound was serially diluted 5-fold from a 10 mM stock solution, with 20 μL added to each well (DMSO final concentration 0.2%). Cells were incubated at 37°C in a 5% CO2 incubator for 7 days. The reaction solution was prepared according to the MTS kit (Promega, G5430), and 20 μL was added to each well. Cells were incubated at 37°C in a 5% CO2 incubator for 3-4 hours. The absorbance at 490 nm was read using a microplate, with the 690 nm absorbance as the background value. OD490-OD690 was used as the final raw data. The inhibition rate of the compound was calculated using the formula: Inhibition rate = (OD690 - OD490) / OD690. DMSO -OD 化合物 ) / (OD DMSO -O 空白 The proliferation inhibition IC50 of the compound was calculated using GraphPad Prism 5.0. The experiment was repeated three times, with three parallel experiments per experiment, and the mean and standard deviation were calculated.

[0699] The cell viability test results are shown in Table 3 below: A represents the cell viability IC50. 50 <1μM, B indicates cell viability 1μM≤IC 50≤20μM, C represents the cell viability IC50. 50 >20μM.

[0700] Table 3. Inhibitory activity of compounds on MV-4-11 cell proliferation

[0701]

[0702]

[0703] Based on the cell growth inhibitory activity test results of the compounds in the above-mentioned embodiments against the acute myeloid leukemia cell line (MV-4-11), it was found that some of the compounds in this invention exhibit very good inhibitory activity against MV-4-11 acute leukemia cells. The IC50 values ​​of some compounds... 50 At the nanomolar level, the compounds tested in the table show the best activity IC50. 50 It can reach <100 nM; however, positive compounds, whether the already marketed drugs lenalidomide or pomalidomide, or the currently clinically investigated compounds CC-220 or CC-122, show cytosolic inhibitory activity (IC50) on acute leukemia MV-4-11 cells. 50 All of these are greater than 20 μM. Therefore, the compounds in this invention, through the design and optimization of intramolecular hydrogen bond formation and substituents, have achieved unexpected results in acute myeloid leukemia cell line (MV-4-11) cells, exhibiting far superior activity in these cells compared to marketed drugs and drugs under clinical investigation.

[0704] 4. Pharmacokinetic experiments

[0705] Mouse pharmacokinetics experimental protocol

[0706] Female ICR mice, weighing 18-22g, were randomly divided into groups of four. The test compound was administered by gavage at a volume of 10 mL / kg, orally by oral administration of a solution prepared with DMSO / PEG-400 / water (5:30:65, v / v / v). Mice were fasted for 12 hours prior to the experiment but had free access to water. Food was introduced uniformly 2 hours after administration. The test compound (20 mg / kg) was administered orally to four mice. Blood samples of 50 μL (using EDTA-K2 nebulizer tubes) were collected from the orbital sinus at time points of 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 24 h. Plasma was collected after centrifugation at 12000 rpm for 2 min, separated, and frozen at -20°C for later blood drug concentration determination.

[0707] Pharmacokinetic tests revealed that compounds capable of forming intramolecular hydrogen bonds (C1 class), such as compounds 22, 37, 45, and 51 of the embodiments of this invention, exhibit C1 bonds. max (ng / mL)>2000, AUC last(h*ng / mL)>10000, and its related pharmacokinetic properties are significantly better than those of structurally comparable compounds but without intramolecular hydrogen bonds (Class B1 or Class B2); similar results are not limited to the examples mentioned above.

[0708] The compounds of this invention exhibit superior pharmacokinetics. Pharmacokinetic studies in mice have shown that the compounds of this invention, based on existing test results, are superior to structurally comparable compounds disclosed in the prior art that lack intramolecular hydrogen bonds. These examples are intended to illustrate the advantages of intramolecular hydrogen bonding in this invention and are not limited to other compounds exhibiting the same advantages.

[0709] discuss

[0710] During their research, the inventors of this invention unexpectedly discovered that the compound of formula I possesses excellent anti-cell proliferation activity and pharmacokinetic properties. Calculations and activity tests revealed that this is due to the substitution of the amino group at the 4-position of the pomalidomide core, which allows the hydrogen atom on the amino group to form a strong intramolecular hydrogen bond with the oxygen atom on the isoindoline ring (C1 type compounds, such as compounds 25 and 9, see...). Figure 1 The intramolecular hydrogen bonds have a certain restrictive effect on the molecular stereostructure, thus allowing the pomalidomide core and the five-membered heteroaromatic ring to form a dihedral angle with a certain angle through the alkylene group (e.g., Figure 1 (As shown). Therefore, the five-membered heteroaryl group and its attached substituents can bind well to the hydrophobic pocket of the target protein, resulting in a significant enhancement of the compound's cellular activity through hydrogen bonding. Furthermore, molecular activity tests revealed that compounds with the 4-position amino group lacking a hydrogen bond donor (hydrogen atom) (compounds D1-D2, with a methyl or formyl group introduced onto the NH group), or compounds where the five-membered heteroaryl ring is replaced by other groups such as a 6-membered aryl, 6-membered heteroaryl, or cyclohexyl group, showed poor activity (Table 4). Table 4 shows that compounds where the 4-position amino group can form a 6-membered intramolecular hydrogen bond with the oxygen atom on the isoindoline ring (Examples 9, 15, 25, etc.) exhibit significantly higher activity than compounds where the 4-position amino group cannot form a corresponding intramolecular hydrogen bond (Examples Ctrl-1-Ctrl-4, etc.). Similar examples are not limited to the examples in Table 4. Further in vivo metabolic experiments confirmed that C1-class compounds capable of forming intramolecular hydrogen bonds showed significantly improved drug metabolism properties in metabolic tests.

[0711]

[0712] The inventors analyzed the crystal structure (PDB ID: 4CI2, 5HXB, 5V3O) of the protein complex of lenalidomide, CC-885, CC-220, and CRBN. The side chains of both CC-220 and CC-885 molecules are connected by a groove, with the terminal fragments facing the adjacent hydrophobic pocket. F150 in the hydrophobic pocket is located next to the CC-220 and CC-885 fragments. By comparing the crystal structures of lenalidomide and CRBN, the position of F150 was found to have changed. This may be the reason why the fine-tuning of the CRBN protein conformation produces different degradation substrates. Crystal structure analysis suggests that the conformation of F150 is easily altered due to the relatively high degree of freedom of its β-loop, making it susceptible to external forces. Therefore, the CRL4 shown in Formula I of this application... CRBN E3 ubiquitin ligase molecular gel-like degraders, due to their specific dihedral structure, greatly enhance the affinity of the compounds in this application for CRBN, and may generate new degradation substrates, thereby significantly improving the therapeutic effect on tumors and their application in the treatment of new indications.

[0713] In addition, the inventors used molecular dynamics simulation to analyze the structural dynamics and binding sites of the model molecule and the E3 ubiquitin ligase interface. Combining molecular docking and pharmacophore-based strategies, they evaluated the binding mode and interactions of the compound at the active site of the E3 ubiquitin ligase using a scoring function, and performed computational simulations and optimizations in structural design to obtain a novel and specific small molecule regulator of CRL4CRBNE3 ubiquitin ligase.

[0714] Table 4. Comparison of the effects of intramolecular hydrogen bond formation on compound activity

[0715]

[0716]

[0717] As can be seen, the results of testing the compounds in the multiple myeloma cell line (MM 1S), mantle cell lymphoma cell line (Mino), and acute myeloid leukemia cell line (MV-4-11) show that some novel small molecule modulators exhibit better cell-inhibiting activity compared to marketed or clinically advanced lenalidomide, pomalidomide, and CC-220. Especially in the acute myeloid leukemia cell line (MV-4-11), lenalidomide, pomalidomide, and CC-220 showed poor activity, exhibiting micromolar levels of activity, while the IC50 values ​​of some of our designed compounds were significantly higher. 50 At the nanomolar level, the best IC50 activity of compounds in cell activity assays 50It can achieve a concentration of <100 nM; compared with compounds in the prior art, the most active compound can be more than 100 times more potent. Therefore, the compounds in this invention broaden the scope of application in the treatment of hematological malignancies and can serve as candidate drug molecules for the treatment of new indications for hematological malignancies.

[0718] In summary, the compounds of this invention broaden the application of amine drugs in the treatment of hematologic malignancies, allowing for the expansion to other indications related to hematologic tumors, such as as inhibitors of acute leukemia or as drugs for treating such diseases. Therefore, the compounds of this invention can serve as potent and novel CRBN modulators for the prevention, treatment, and regulation of CRBN (CRL4). CRBN Diseases associated with E3 ubiquitin ligase activity, such as multiple myeloma, mantle cell lymphoma, acute leukemia, or non-restrictive diseases including other underlying oncological diseases, pain, neurological disorders, and immune system disorders.

[0719] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: (Ⅰ) in, n is 0 or 1; X and Y are each independently selected from CH or N, and X and Y are not both CH at the same time; Z is selected from: O or S; Selected from: C6-C10 aryl, 5-10 heteroaryl, wherein the C6-C10 aryl, 5-10 heteroaryl is optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, having 1, 2 or 3 groups selected from nitrogen, oxygen The phenyl group is a C3-C8 heterocyclic alkyl group with a sulfur heteroatom, a C3-C8 cycloalkyl alkyl group, a hydroxyl-substituted C1-C6 alkoxy group, or a C1-C6 alkoxy group substituted with a C1-C6 alkoxy group; wherein the substituted or unsubstituted phenyl group is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy group; or It is a 4-10 membered heterocyclic group having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the 4-10 membered heterocyclic group is replaced by a group selected from the following: -C(O)-R1, -(CH2)m-R2; R1 is selected from: halogen-substituted or unsubstituted C1-C6 alkyl, C4-C12 cycloalkyl, C6-C10 aryl, 4-10 membered heterocyclic group having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, -CH2-(C4-C12 cycloalkyl), and said C4-C12 cycloalkyl, C6-C10 aryl, 4-10 membered heterocyclic group having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, -CH2-(C4-C12 cycloalkyl) is optionally substituted by one or more of the following groups: hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted or unsubstituted phenyl; R2 is a C6-C10 aryl group, and the C6-C10 aryl group is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy. m is 0 or 1; R3 is hydrogen or halogen; R4 can be hydrogen, deuterium, or fluorine.

2. A compound of formula (II) or a pharmaceutically acceptable salt thereof, characterized in that, It has the structure shown in Formula II. (II) Where n is 0 or 1; X and Y are each independently selected from CH or N, and X and Y are not both CH at the same time; Z is selected from: O or S; R3 is hydrogen or halogen; R4 is hydrogen, deuterium, or fluorine; A1 is a 4-6 membered heterocyclic group having one or two heteroatoms selected from nitrogen, oxygen, and sulfur; L stands for CO; A2 is selected from: C1-C6 alkyl, phenyl, C4-C10 cycloalkyl, 4-6 membered heterocyclic group having 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl; Ra1 and Ra2 are each independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic alkyloxy having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy; wherein the substituted or unsubstituted phenyl is optionally substituted by one or more groups selected from: hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; p and q are each independently 0, 1, 2, 3, 4 or 5.

3. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, Selected from: , , , , , .

4. The compound of claim 1, its pharmaceutically acceptable salt, or stereoisomer, characterized in that, The phenyl group is a phenyl group, and the phenyl group is optionally substituted with one or more of the following groups: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, C2-C6 alkenyl, C3-C8 heterocyclic alkyloxy having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, wherein the substituted or unsubstituted phenyl group is optionally substituted with one or more of the following groups: hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy.

5. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The compound has the structures shown in formulas (I-1)-(I-4): in, Selected from: , , , , , ; R3 is hydrogen or halogen; R4 is hydrogen, deuterium, or fluorine; R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Each is independently selected from: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, phenyl, vinyl, C3-C8 heterocyclic alkyloxy having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, C3-C8 cycloalkyloxy, hydroxyl-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

6. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The compound has the structure shown in formula (I-5) or (I-6): in, Selected from: , , , , , ; R1 is selected from: tert-butyl, cyclobutyl, cyclohexyl, phenyl, , Furthermore, the cyclobutyl, cyclohexyl, and phenyl groups are optionally substituted by one or more of the following groups: halogen, cyano, C1-C3 alkyl, trifluoromethyl, trifluoromethoxy, halogen-substituted or unsubstituted phenyl groups; R2 is a phenyl group, and the phenyl group is optionally substituted by one or more groups selected from the following: fluorine, cyano, trifluoromethoxy; R3 is hydrogen or halogen; R4 can be hydrogen, deuterium, or fluorine.

7. A compound of formula III, and a pharmaceutically acceptable salt thereof, characterized in that, It has the structure shown in Formula III. III in, R p It is CH2OCOC(CH3)3; R3 is hydrogen or halogen; R4 is hydrogen, deuterium, or fluorine; The definitions of X, Y, Z, A, and n are as described in claim 1.

8. The compound of claim 1 or 7, or its pharmaceutically acceptable salt, characterized in that, Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

9. A compound, and its pharmaceutically acceptable salt, characterized in that, The compound is one of the following compounds: 。 10. A method for preparing the compound according to any one of claims 1-9, characterized in that, The method is selected from one of the following methods: Synthesis Method 1: X and Y are each selected from CH or N, and X and Y cannot both be CH; Z is selected from O, S, or NH; The definitions of R3, R4, R5, R6, R7, R8, and R9 are the same as those in claim 5; Step 1-1: Compound 1A reacts with Compound 1B in the presence of phenylsilane and dichlorodibutyltin to give Compound 1C; or Compound 1A reacts with Compound 1B in the presence of acetic acid and sodium borohydride to give Compound 1C. Synthesis Method 2: X is N, Y is CH; Z is O; The definitions of R1, R3, and R4 are the same as those in claim 6; Step 2-1: Compound 2A reacts with 1,2-diiodoethane to give compound 2B; Step 2-2: Compound 2B and compound 2C undergo a coupling reaction to obtain compound 2D; Steps 2-3: Compound 2D is hydrogenated and reduced to obtain compound 2F; Steps 2-4: Compound 2F is reduced with sodium borohydride to obtain compound 2G; Steps 2-5: Compound 2G reacts with an oxidizing agent to give compound 2H; Steps 2-6: Compounds 2H and 1B react in the presence of phenylsilane and dibutyltin dichloro to give compound 2I; Steps 2-7: Compound 2I is reacted with hydrochloric acid to obtain compound 2J; Steps 2-8: Compound 2K and compound 2J react in the presence of HATU and N,N-diisopropylethylamine to give compound 2L; Synthesis Method 3: X is N, Y is CH; Z is O; The definitions of R2, R3, and R4 are the same as those in claim 6; Step 3-1: Compound 3A and compound 2J react in the presence of zinc chloride, triethylamine and sodium cyanoborohydride to give compound 3B; Synthesis Method 4: X is N, Y is CH; Z is O; The definition is the same as that in claim 7. Step 4-1: Compound 4A reacts with lithium aluminum hydride to give compound 4B; Step 4-2: Compound 4B reacts with tert-butyldiphenylchlorosilane to give compound 4C; Step 4-3: In the presence of boranetetrahydrofuran complex and n-butyllithium, compound 4C reacts with 4-formylmorpholine to give compound 4D; Step 4-4: Compound 4D is oxidized with Dess-Martin oxidant to obtain compound 4E; Steps 4-5: Compound 4E and In the presence of sodium borohydride acetate, compound 4F is obtained by reductive amination. Steps 4-6: In the presence of tetrabutylammonium fluoride in tetrahydrofuran solution, compound 4F is deprotected to give compound 4G; Steps 4-7: Compound 4G is oxidized with Dess-Martin oxidant to give compound 4H; Steps 4-8: In the presence of acetic acid and sodium borohydride, compound 4H reacts with compound 1B to give compound 4I; Synthesis Method 5: X and Y are each selected from CH or N, and X and Y cannot be CH at the same time; Z is selected from O, S, or NH; The definitions of R3, R4, Ra2, and q are the same as those in claim 2; Step 5-1: In the presence of a palladium catalyst, compound 5A and compound 5B undergo a Buchwald-Hartwig amination reaction to give compound 5C; Step 5-2: In the presence of acetic acid and sodium borohydride, compound 5C undergoes a reductive amination reaction with compound 1B to obtain compound 5D.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a therapeutically effective dose of any one of claims 1-9, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, further comprising one or more selected from PD-1 inhibitors, PDL-1 inhibitors, HDAC inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, BTK inhibitors, and erythrocyte growth hormone.

13. The pharmaceutical composition of claim 11, further comprising one or more selected from dexamethasone, rituximab, trastuzumab, pemetrexed, topotecan, doxorubicin, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofalabane injection, minocycline, elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, ubliximab, romidepsin, eltrombopag, and melphalan.

14. The compound of any one of claims 1-9, or its pharmaceutically acceptable salt, in the preparation of a compound for the prevention or treatment of CRL4. CRBN Use in medicines for diseases related to E3 ubiquitin ligases, wherein the CRL4 CRBN Diseases associated with E3 ubiquitin ligase are cancers.

15. The use as described in claim 14, characterized in that, The disease described is a solid tumor or a hematologic tumor.

16. The use as described in claim 14, characterized in that, The diseases described are selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, relapsed interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocyte leukemia, myeloid leukemia, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, malignant melanoma, glioblastoma, glioma, malignant glioma, refractory plasmacytoma, extraocular melanoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, or primary macroglobulinemia.

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