3,4-Dihydrophthalazine-1(2H)-one derivatives, methods for preparing them, and their use.

Abstract

The present invention relates to a 3,4-dihydrophthalazine-1(2H)-one compound represented by formula (I), pharmaceutically acceptable salts thereof, prodrugs, stable isotope derivatives, isomers, solvates, or polymorphs thereof, and pharmaceutical compositions comprising the above compound. Furthermore, the present invention also provides a method for preparing the compound represented by formula (I). The compound is used as a modulator of targeted ubiquitination, particularly for the treatment of diseases related to the CRBN protein. The compound is also used for the preparation of related proteolytic chimeric molecules (PROTACs) for CRL4 CRBN It can also be used as a ligand for E3 ubiquitin ligase. JPEG2026520709000104.jpg38149

Description

[Technical Field]

[0001] This application is based on the Chinese application No. 202310656044.9 (filed on June 5, 2023), and claims priority from the said Chinese application. The disclosures of the said Chinese application are incorporated in their entirety into this application.

[0002] [Technical field] This invention relates to 3,4-dihydrophthalazine-1(2H)-one compounds and their structural derivatives, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, methods for preparing them, and their use as pharmaceuticals. The compounds can be used as ubiquitination-targeting modulators, particularly for the treatment of diseases associated with the CRBN protein. [Background technology]

[0003] Thalidomide and its structural derivatives, lenalidomide and pomalidomide, are known as immunomodulators (IMiDs). Thalidomide was initially marketed in Germany as a sedative but was banned due to its potent teratogenic effects. Scientists later discovered that thalidomide could effectively alleviate symptoms in patients with leprosy-induced erythema nodosum and inhibit the expression of tumor necrosis factor during the treatment of leprosy. Thalidomide, lenalidomide, and pomalidomide were subsequently approved by the FDA for the treatment of patients with multiple myeloma. Multiple studies have confirmed that CRBN (cereblon) is a target for this class of immunomodulators.

[0004] CRBN is a "substrate acceptor" for E3 ubiquitin ligase. IMiD can activate E3 ubiquitin ligase after acting on CRBN, resulting in rapid ubiquitination of substrate proteins, which are then recognized and degraded by the proteasome. Multiple studies have shown that immunomodulators such as lenalidomide can activate CRBN. CRBNIt has been shown that immunomodulators exert their antitumor effects in multiple myeloma cell lines by regulating the function of E3 ubiquitin ligases. After acting on CRBNs, immunomodulators induce E3 ubiquitin ligases to recruit substrate proteins such as IKZF1 / IKZF3 and label them with ubiquitin, resulting in recognition and degradation of these proteins by the 26S proteasome. Degradation of IKZF1 and IKZF3 directly reduces the expression of transcription factors such as IRF4 and Myc, thus exerting a cytotoxic effect on myeloma cells. On the other hand, degradation of IKZF1 and IKZF3 increases IL-2 expression in T cells, thereby activating the T cell immune response, suppressing B cell function, achieving a tumor-killing effect, and inhibiting tumor growth.

[0005] Studies have indicated that different immunomodulators exhibit different substrate protein degradation characteristics after binding to the CRBN protein. For example, lenalidomide primarily achieves its therapeutic effect in treating multiple myeloma by selectively degrading IKZF1 and IKZF3; on the other hand, in treating myelodysplastic syndrome (del(5q)MDS), lenalidomide primarily achieves its therapeutic effect by degrading CK1α. Due to the progress of research and development and clinical trials of novel immunomodulators, the indications for thalidomide, lenalidomide, and pomalidomide are constantly expanding. For example, thalidomide is approved by the FDA for the treatment of erythema nodosum leprosy, lenalidomide is being used in clinical trials for the treatment of prostate cancer, and pomalidomide is being used in clinical trials for the treatment of myelofibrosis.

[0006] However, domid-type drugs have numerous side effects. Prescription information for lenalidomide explicitly states that the drug carries risks of myelosuppression, deep vein thrombosis, pulmonary embolism, and teratogenicity. During clinical trials, domid-type drugs exhibited serious hematological toxicity, resulting in the need for dose reduction in patient use. In other words, while lenalidomide possesses beneficial activity, its effectiveness is limited by the significant occurrence of side effects. Therefore, there is an urgent need in this field for novel and highly efficient CRBN modulators that optimize the performance of existing domid-type IMiDs while simultaneously addressing the serious problem of drug resistance.

[0007] [Contents of the invention] This invention describes a 3,4-dihydrophthalazine-1(2H)-one compound, a method for preparing it, and its use. This compound recruits endogenous proteins to E3 ubiquitin ligases for degradation, thereby generating diverse physiological activities related to substrate proteins through proteolysis, and thus effectively preventing, improving, and treating cancers such as multiple myeloma. The compound of this invention is used to prepare related proteolysis-inducing chimeric molecules (PROTACs) in CRL4. CRBN It is used as a ligand for E3 ubiquitin ligase.

[0008] A first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof: [ka] (In the formula, X1 is N or CH; n is 1 or 2; R1 is H, C 1~10 Linear or branched alkyl and C 3~10 Selected from the group consisting of cycloalkyl groups; S / D is either a single bond or a double bond; if S / D is a double bond, R1 does not exist; R2 and R3 are independently selected from the group consisting of H, D, halogens, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyls, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, substituted or unsubstituted heterocyclyls, -S-alkyls, -CN, -NO2, -N3, -CH(Ph)2, perfluoro-C1~C4 alkyls, perfluoro-C1~C4 alkoxys, -NR4R5, -OR4, -COR4, -CO2R4, -CONR4R5, -C(=NR4)NR5R6, -NR4COR5, -NR4CO2R5, -SO2R4, -NR4SO2NR5R6, and -NR4SO2R5; R4, R5, and R6 are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R4 and R5) and / or (R5 and R6) may each form a ring together with the atom they are linked to, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl).

[0009] In some embodiments, X1 is CH. In some embodiments, n is 2. In some embodiments, R1 is H and C 1~6 Selected from the group consisting of linear or branched alkyl groups. In some embodiments, R1 is H and C 1~4 Selected from the group consisting of linear or branched alkyl groups. In some embodiments, R1 is C 1~4 It is a linear or branched alkyl group. In some embodiments, R1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R1 is H. In some embodiments, R1 is CH3. In some embodiments, R2 is selected from the group consisting of H and halogens. In some embodiments, R2 is selected from the group consisting of H, F, Cl, Br, and I. In some embodiments, R2 is selected from the group consisting of H and F. In some embodiments, R2 is H. In some embodiments, S / D is a single bond.

[0010] In some embodiments, R3 is selected from the group consisting of H, D, halogens, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyls, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, substituted or unsubstituted heterocyclyls, -S-alkyls, -CN, -NO2, -N3, -CH(Ph)2, perfluoro-C1~C4 alkyls, perfluoro-C1~C4 alkoxys, -NR4R5, -OR4, -COR4, -CO2R4, -CONR4R5, -C(=NR4)NR5R6, -NR4COR5, -NR4CO2R5, -SO2R4, -NR4SO2NR5R6, and -NR4SO2R5; R4, R5, and R6 are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R4 and R5) and / or (R5 and R6) may each form a ring together with the atom they are linked to, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl.

[0011] In some embodiments, the substituents and chemical bonds of formula (I) are selected from the following: (a) X1 is CH and n is 2; (b) R1 is CH3; (c) R2 is H; (d) S / D is a single bond; (e) R3 is independently selected from the group consisting of H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-alkyl, -CN, -NO2, -N3, -CH(Ph)2, perfluoro-C1~C4 alkyl, perfluoro-C1~C4 alkoxy, -NR4R5, -OR4, -COR4, -CO2R4, -CONR4R5, -C(=NR4)NR5R6, -NR4COR5, -NR4CO2R5, -SO2R4, -NR4SO2NR5R6, and -NR4SO2R5; R4, R5, and R6 are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R4 and R5) and / or (R5 and R6) may each form a ring together with the atom they are linked to, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl.

[0012] In some embodiments, in formula (I), R3 is further selected from: H, D, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-R4, -CN, -NO2, perfluoro-C1-C4 alkyl, perfluoro-C1-C4 alkoxy, -NR4R5, -OR4, -COR4, -CO2R4, -CONR4R5, -C(=NR4)NR5R6, -NR4COR5, -NR4CO2R5, -SO2R4, -NR4SO2NR5R6, and -NR4SO2R5; R4, R5, and R6 are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; wherein, (R4 and R5) and / or (R5 and R6) may together with the atoms to which they are attached each form a ring, and said ring is optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl.

[0013] In some embodiments, R3 is selected from the group consisting of H, halogen, -OH, -S-R4, -CN, -NO2, and -NR4R5. In some embodiments, R3 is selected from the group consisting of H, halogen, -NO2, and -NR4R5. In some embodiments, R3 is -NR4R5. In some embodiments, R4 and R5 are each independently H, D, C 1~4 alkyl, or R4 and R5 together with the atoms to which they are attached form a ring optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl. In some embodiments, R4 and R5 are each independently H, D, C 1~4 alkyl. In some embodiments, R4 is H. In some embodiments, R5 is C 1~4 alkyl. In some embodiments, R5 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R5 is methyl.

[0014] In some embodiments, in formula (I), R3 is further selected from: H, D, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-R4, -CN, -NO2, perfluoro-C1-C4 alkyl, perfluoro-C1-C4 alkoxy, -NR4R5, -OR4, -COR4, -CO2R4, -CONR4R5, -C(=NR4)NR5R6, -NR4COR5, -NR4CO2R5, -SO2R4, -NR4SO2NR5R6, and -NR4SO2R5; R4, R5, and R6 are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R4 and R5) and / or (R5 and R6), together with the atom they are linked to, form formula (II) [ka] Each of them may form a ring as shown by . (In the formula, X2 is selected from the group consisting of NH or CH2 and O; Ring A is a 5-6 membered aromatic ring containing 0-3 heteroatoms selected from N, S, or O; R7 is selected from the group consisting of H, D, halogens, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl; R8 is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-alkyl, -CN, -NO2, -N3, -CH(ph)2, perfluoro-C1~C4 alkyl, perfluoro-C1~C4 alkoxy, -NR9R 10 , -OR9, -COR9, -CO2R9, -CONR9R10 -C(=NR9)NR9R 10 -NR9COR 10 -NR9CO2R 10 -SO2R9, -NR9SO2NR 10 R 11 , and -NR9SO2R 10 Selected from the group consisting of; R9, R 10 , and R 11 Each of these is independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R9 and R 10 ) and / or (R 10 and R 11 ) However, these atoms may each form a ring together with the atoms to which they are linked, and the above rings are optionally selected from the group consisting of substituted or unsubstituted cycloalkyls, saturated or unsaturated heterocyclyls, aryls, and heterocyclylaryls).

[0015] In some embodiments, the X2 end is the connecting portion of formula (II). In some embodiments, X2 is N. In some embodiments, ring A is a benzene ring. In some embodiments, R7 is selected from the group consisting of H, D, and halogens. In some embodiments, R7 is H.

[0016] In some embodiments, R8 is H, D, a substituted or unsubstituted 5- to 9-membered heterocycline ring and -NR9R 10 A group consisting of R9 and R is selected, where R9 and R 10 These are H, D, and C, respectively, independently. 1~4 Alkyl or R9 and R 10These, together with the atoms they link to, form a substituted or unsubstituted 5- to 9-membered cycloalkyl ring. In some embodiments, R8 is selected from the group consisting of substituted or unsubstituted 5- to 9-membered heterocyclyl rings. In some embodiments, the substituted 5- to 9-membered heterocyclyl ring consists of one or more R 12 It is a heterocyclyl ring of 5-9 members substituted with, where R 12 This is as defined in any embodiment. In some embodiments, the 5- to 9-membered heterocyclyl ring contains one, two, or three N atoms. In some embodiments, the 5- to 9-membered heterocyclyl ring is selected from the group consisting of morpholinyl and piperazinyl. In some embodiments, the 5- to 9-membered heterocyclyl ring is piperazinyl.

[0017] In some embodiments, R4 and R5, together with the atoms they are linked to, form formula (II) [ka] It forms a structural unit shown by (wherein R7, R8, X2 and ring A are as defined in any embodiment).

[0018] In some embodiments, R3 is H, halogen, -OH, -SH, -CN, -NO2, -NH2, -NH(C 1~4 Alkyl) and [ka] Selected from the group consisting of, and R7, R8, X2 and ring A are as defined in any embodiment.

[0019] In some embodiments, R3 is H, halogen, -NO2, -NH2, -NH(C3) and [ka] Selected from the group consisting of, and R7, R8, X2 and ring A are as defined in any embodiment.

[0020] In some embodiments, the ring represented by formula (II) is further selected from the following: Ring A is a benzene ring; R7 is H; X2 is NH; R8 is given by equation (III). [ka] The structure is shown by (In the formula, ring B is an N-substituted non-aromatic ring, which has the following structure: [ka] (Selected from the group consisting of any of the following).

[0021] R 12 is selected from the group consisting of H, D, halogen, -CN, -NO2, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl; where, if the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl is substituted, it is substituent R 13 It is optionally replaced by at least one of the following, where R 13 These are halogens, lower alkyls, lower alkoxys, cyanos, or nitros.

[0022] In some embodiments, the N atom of ring B is the linking site of formula (III). In some embodiments, ring B has the following structure: [ka] It is selected from the group consisting of any of the following.

[0023] In some embodiments, ring B is [ka] It is selected from the group consisting of the following.

[0024] In some embodiments, ring B is [ka] That is the case.

[0025] In some embodiments, R 12 H, D, halogen, -C(=O)-C 1~6 Selected from the group consisting of alkyl, phenyl, and 5-6 membered heteroaryl rings, where the phenyl and 5-6 membered heteroaryl rings are one or more R 13 It is replaced by an arbitrary selection, and here, R 13 is halogen, C 1~4 Selected from the group consisting of alkyl, cyano, and nitro.

[0026] In some embodiments, R 12 H, D, halogen, -C(=O)-C 1~4 Selected from the group consisting of alkyl and phenyl, where the phenyl has one, two, or three R groups. 13 It is replaced by an optional choice, and here, the above R 13 It is selected from the group consisting of F and cyano.

[0027] In some embodiments, R 12 It is -C(=O)OC(CH3)3, phenyl, [ka] Selected from the group consisting of the above R 13 It is selected from the group consisting of F and cyano.

[0028] In some embodiments, R 12 It is -C(=O)OC(CH3)3, phenyl, [ka] It is selected from the group consisting of the following.

[0029] In some embodiments, in formula (III), ring B is a piperazine ring substituted with a lower alkyl, alkenyl, alkynyl, halogen, nitro, etc., or formula (IV): [ka] This is a substituted piperazine represented by (wherein the formula, ring C is a 5-6 membered aromatic ring or aromatic heterocyclyl containing 0-3 heteroatoms selected from N, S, or O; R 14 This is selected from the group consisting of H, D, halogens, lower alkyls, lower alkoxys, cyanos, nitros, and hydroxyls; n = 0, 1, 2, 3, 4, or 5.

[0030] In some embodiments, in formula (III), ring B is formula (IV): [ka] This is a substituted piperazine represented by (In the formula, rings C, R 14 (where n is as defined in any embodiment of this application).

[0031] In some embodiments, the N atom of piperazine is the linking site of formula (IV). In some embodiments, in formula (III), ring B is a piperazine ring substituted with -C(=O)OC(CH3)3, or a substituted piperazine represented by formula (IV).

[0032] In some embodiments, structural units [ka] teeth, [ka] It is selected from the group consisting of the following. In some embodiments, ring C is phenyl.

[0033] In some embodiments, R 14 The element is selected from the group consisting of H, F, and cyano. In some embodiments, R 14 It is selected from the group consisting of F and cyano. In some embodiments, structural units [ka] Phenyle, [ka] It is selected from the group consisting of the following.

[0034] In some embodiments, structural units [ka] teeth, [ka] That is the case.

[0035] In some embodiments, the compound is of formula (I-1) [ka] The compound is shown as (R1, R2, and R3 are as defined in any embodiment.)

[0036] In some embodiments, structural units [ka] teeth, [ka] It is selected from the group consisting of the following.

[0037] In some embodiments, structural units [ka] teeth [ka] That is the case.

[0038] In some embodiments, structural units [ka] teeth [ka] That is the case.

[0039] In some embodiments, R3 is selected from the group consisting of H, halogen, -NO2, and -NR4R5, where R4 and R5 are as defined in any embodiment. In some embodiments, R3 is H, -NO2, -NH2, and -NH(C 1~4 Selected from the group consisting of alkyl groups. In some embodiments, R3 is selected from the group consisting of H, -NO2, -NH2, and -NH(CH3). In some embodiments, R3 is -NR4R5, where R4 and R5 are as defined in any embodiment. In some embodiments, R3 is selected from the group consisting of -NH2 and -NH(CH3). In some embodiments, R3 is -NO2.

[0040] In some embodiments, R3 is [ka] Herein, X2, ring A, R7, and R8 are as defined in any embodiment.

[0041] In some embodiments, R8 is H, D, a substituted or unsubstituted 5- to 9-membered heterocyclyl ring, and [ka] A group consisting of is selected, where rings B and R 12 This is as defined in any embodiment.

[0042] In some embodiments, the 5- to 9-membered heterocyclyl ring contains one, two, or three nitrogen atoms. In some embodiments, the 5- to 9-membered heterocyclyl ring is selected from the group consisting of morpholinyl and piperazinyl. In some embodiments, the 5- to 9-membered heterocyclyl ring is piperazinyl.

[0043] In some embodiments, the 5- to 9-membered heterocyclyl ring is composed of H, D, halogen, nitro, and C. 1~4 Alkyl, -C(=O)OC 1~4 Alkyl, and [ka] The rings C, R are optionally substituted with one, two, or three groups selected from the group consisting of the following: 14 And n are as defined in any embodiment.

[0044] In some embodiments, R 12 H, D, halogen, nitro, C 1~4 Alkyl, -C(=O)OC 1~4 Alkyl, and [ka] A group consisting of is selected, where ring C, R 14 And n are as defined in any embodiment.

[0045] In some embodiments, the compound is of formula (II-1) [ka] The compound is shown as (wherein R1, R2, R7, R8, X2, and ring A are as defined in any embodiment.)

[0046] In some embodiments, the compound is of formula (III-1) [ka] The compound is shown as (In the formula, R1, R2, R7, R 12 X2, ring A, and ring B are as defined in any embodiment.

[0047] In some embodiments, the compound is of formula (IV-1) [ka] The compound is shown as (In the formula, R1, ring C, R 14 , and n are as defined in any embodiment.

[0048] A second aspect of the present invention provides a pharmaceutical composition comprising the compound (for example, the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, and one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, and lanolin.

[0049] A third aspect of the present invention provides a compound comprising the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof, and at least one further drug, wherein the at least one further drug is a chemotherapeutic agent or an immunomodulator.

[0050] In some embodiments, the chemotherapeutic agent or immunomodulator is selected from the group consisting of immune checkpoint inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, antibiotics, alkylating agents, antibody inhibitors, hormones, immunomodulators, interferon-like activators, and mixed activators.

[0051] In some embodiments, the chemotherapeutic agent or immunomodulator is selected from the group consisting of dexamethasone, bortezomib, and tazemetostat. In some embodiments, the chemotherapeutic agent or immunomodulator is tazemetostat.

[0052] A fourth aspect of the present invention is CRL4 CRBN The present invention provides the use of the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition thereof, in the manufacture of a pharmaceutical for the treatment and / or prevention of diseases related to E3 ubiquitin ligase. The present invention also provides CRL4 CRBN The present invention relates to the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of diseases related to E3 ubiquitin ligase. CRBN The present invention relates to a method for treating and / or preventing diseases associated with E3 ubiquitin ligases, comprising administering an effective amount of the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition thereof, to an individual in need thereof.

[0053] In some embodiments, diseases include, but are not limited to, cancer, pain, neurological disorders, and immune system disorders. In some embodiments, the disease is a hematological malignancy. In some embodiments, the disease is myeloma. In some embodiments, the disease is multiple myeloma.

[0054] A fifth aspect of the present invention provides the use of the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or a pharmaceutical composition thereof, in the manufacture of a pharmacopoeia for the treatment and / or prevention of cancerous diseases. The present invention also relates to the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of cancerous diseases. The present invention further relates to a method for treating and / or preventing cancerous diseases, comprising administering an effective amount of the compound (e.g., the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or a pharmaceutical composition thereof, to an individual in need thereof.

[0055] In some embodiments, cancerous diseases include, but are not limited to, various types of leukemia, multiple myeloma, various malignant lymphomas, e.g., non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, erythema nodosum, autoimmune diseases, e.g., systemic lupus erythematosus, myelodysplastic syndrome, breast cancer, gastrointestinal cancer, various types of lung cancer, liver cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, ovarian cancer, various endocrine cancers, kidney cancer or ureteral cancer, and one or more CNS tumors. In some embodiments, lung cancer is non-small cell lung cancer. In some embodiments, endocrine diseases are selected from the group consisting of breast cancer, thyroid cancer, and gastric cancer.

[0056] In some embodiments, the cancerous disease is a hematological malignancy. In some embodiments, the cancerous disease is myeloma. In some embodiments, the cancerous disease is multiple myeloma.

[0057] A sixth aspect of the present invention provides compounds, or pharmaceutically acceptable salts thereof, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, or pharmaceutical compositions or formulations described herein, which can be administered via a suitable route. In some embodiments, suitable routes include oral, sublingual, rectal, parenteral, (intradermal, subcutaneous, intramuscular, intravenous, arterial) injection, pulmonary, nasal, lingual, buccal, skin, mucous membrane, conjunctival, topical administration, or administration via implant.

[0058] A seventh aspect of the present invention provides the use of the compound (for example, the compound represented by formula (I)), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof, in the production of a proteolytic chimeric molecule (PROTAC).

[0059] In some embodiments, the compound, or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates, or polymorphs, are used in the production of proteolytic chimeric molecules (PROTACs) for CRL4 CRBN It is used as a ligand for E3 ubiquitin ligase.

[0060] An eighth aspect of the present invention provides a synthetic method for preparing the compound (for example, the compound represented by formula (I)), the method which allows the compound to be synthesized from commercially available starting materials using known methods. In detailed practice, each step in the method may be extended or combined as necessary, and exemplary methods for preparing the compound include (but are not limited to) the processes described below.

[0061] In some embodiments, the compound of the present invention (for example, the compound represented by formula (I)) is synthesized according to the following route of scheme A: the step of reacting the compound represented by formula A1 with benzaldehyde and methylhydrazine to prepare A2; the step of cyclizing A2 under the catalysis of a Lewis acid to form A3; and the step of substituting A3 with 3-bromocycloglutarimide to produce the target product A4. [ka] (wherein R2 and R3 are as defined in the present invention).

[0062] In some embodiments, the Lewis acid is ZnCl2. In some embodiments, the synthesis path for scheme A is as follows: [ka] In some embodiments, the compounds of the present invention (e.g., the compounds represented by formula (I)) are synthesized according to the following route of scheme B: First, using 2-formylbenzoic acid B1 as a starting material, a condensation reaction with hydrazine hydrate under heating conditions is carried out to obtain phthalazinon B2; B2 is converted to dimethyl 2-bromoglutarate (B10 ) is subjected to a substitution reaction with to yield B3, followed by cyclization in the presence of a sodium amide as a basic catalyst to give B4 (where the key intermediate B 10 Using glutaric acid B7 as a raw material, thionyl acylation of chloride, liquid bromine substitution, and methanol esterification are sequentially performed to produce B8, B9, and B 10 This is induced via a one-pot process that brings about the following steps: in some embodiments, the step of reducing B4 to give B5; in some embodiments, the step of carrying out the reduction via zinc; in some embodiments, the step of methylating B5 to give B6; in some embodiments, the step of carrying out the methylation in the presence of formaldehyde and formic acid reagents.

[0063] [ka] In some embodiments, the compound of the present invention (for example, the compound represented by formula (I)) is synthesized according to the following route of scheme C: the step of synthesizing compound A4 according to scheme A; the step of substituting the unsaturated nitrogen-containing non-aromatic compound R with methyl 4-bromomethylbenzoate to give C5; the step of first completely reducing the methyl benzoate moiety of C5 to produce an alcohol (compound C6), then partially oxidizing C6 to produce an aldehyde C7; and finally, the step of carrying out a reductive amination reaction between C7 and the aromatic amino group of compound A4 to form an imine between them, thereby obtaining the target product. [ka] Here, R is the ring B defined by equation (III).

[0064] In some embodiments, the compounds of the present invention (e.g., the compounds represented by formula (I)) are synthesized according to the following route of scheme D: a Buchwald-Hartwig carbon-nitrogen coupling reaction between 1-tert-butyloxycarbonylpiperazine and a halogenated aromatic compound R under the conditions of Pd2(dba)3 as catalyst, X-Phos as ligand, and NaOtBu as base to produce compound D5; a deprotection of the Boc protecting group on the nitrogen of compound D5 to obtain D6; subsequent synthesis steps are consistent with the synthesis route of scheme C; a methyl 4-bromomethylbenzoate substitution, DIBAL reduction, and manganese dioxide oxidation are sequentially performed to obtain compounds D7, D8, and D9, respectively; and a reductive amination reaction between compound D9 and A4 to obtain the target compound. [ka]

[0065] Those skilled in the art can appropriately modify the process parameters of the compound represented by formula (I), as well as the methods for preparing the compound disclosed herein, pharmaceutical compositions, and therapeutic regimens, by referring to the contents of this application. Of particular importance, all similar substitution and modification forms will be obvious to those skilled in the art and are considered to be included in the present invention. While preferred examples have been given to the products, methods, and uses of the present invention, those skilled in the art will readily be able to modify, appropriately change, and combine the methods and uses described herein without departing from the content, spirit, and scope of the present invention in order to realize and apply the art of the present invention.

[0066] In some embodiments, the present invention provides compounds represented by formula (I), and pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates, polymorphs, and pharmaceutical compositions thereof, the compounds being provided, but not limited to, the following: [Table 1] JPEG2026520709000042.jpg208149JPEG2026520709000043.jpg206149JPEG2026520709000044.jpg110149

[0067] In this invention, unless otherwise intended by context, the terms, phrases, and symbols used below have the following meanings. If a compound name used in this invention differs from its chemical structural formula, the chemical structural formula shall prevail. The following abbreviations and terms have the following meanings throughout this specification.

[0068] The term "alkyl" refers to a hydrocarbon group selected from the group consisting of saturated linear and saturated branched hydroxycarbonyl groups. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0069] A lower alkyl group refers to an alkyl group having 1 to 8 carbon atoms, preferably 1 to 6, and more preferably 1 to 4 carbon atoms; a lower alkenyl or alkynyl group refers to an alkenyl or alkynyl group having 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0070] The term "alkenyl" refers to a hydrocarbon group selected from the group consisting of linear and branched hydroxycarbonyl groups, and contains at least one C=C double bond and 2 to 18 carbon atoms. Examples of alkenyl groups can be selected from the group consisting of vinyl (ethenyl or vinyl), propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0071] The term "alkynyl" refers to a hydrocarbon group selected from the group consisting of linear and branched hydroxycarbonyl groups, and contains at least one C≡C triple bond and 2 to 18 carbon atoms. Examples of alkynyl groups include ethynyl, propa-1-inyl, propa-2-inyl (propargyl), buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0072] The term "cycloalkyl" refers to a hydrocarbon group selected from the group consisting of saturated and partially unsaturated cycloalkyl groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, which can have 3 to 12 carbon atoms. For example, a cycloalkyl group can be a monocyclic group having 3 to 12 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopenta-1-en-1-yl, cyclopenta-2-en-1-yl, cyclopenta-3-en-1-yl, cyclohexyl, cyclohexa-1-en-1-yl, cyclohexa-2-en-1-yl, cyclohexa-3-en-1-yl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include bicyclic structures consisting of 7 to 12 ring atoms arranged in a ring system selected from the group consisting of [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or bridging bicyclic structures selected from the group consisting of bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but it may not be fully conjugated and may not be aromatic (as defined herein).

[0073] As used herein, the term “aryl” refers to a group selected from: five-membered and six-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic systems such as seven- to twelve-membered rings, where at least one ring is a carbocyclic ring and an aromatic ring, e.g., naphthalene, 1,2-dihydroindene, and 1,2,3,4-tetrahydroquinoline; and tricyclic systems, e.g., ten-membered and fifteen-membered rings, where at least one ring is a carbocyclic ring and an aromatic ring, e.g., fluorene.

[0074] For example, aryls are selected from the group consisting of five-membered and six-membered carbocyclic aromatic rings, in which case the carbocyclic aromatic ring is condensed onto a five-membered or seven-membered cycloalkyl or heterocyclic ring, each containing at least one heteroatom selected from the group consisting of N, O, and S, provided that when the carbocyclic aromatic ring is condensed onto a heterocyclic ring, the linkage site is on the carbocyclic aromatic ring; and when the carbocyclic aromatic ring is condensed onto a cycloalkyl ring, the linkage site may be on either the carbocyclic aromatic ring or the cycloalkyl ring. A divalent group formed from a substituted benzene derivative and having free valence on the ring atom is named a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon whose name ends in "-yl" by removing one hydrogen atom from a carbon atom with free valence is named by adding "-ene" to the name of the corresponding monovalent group; for example, a naphthyl group having two linkage sites is called a naphthylene group. However, the aryl group does not include heteroaryl groups or groups that overlap with heteroaryl groups, which are defined separately below. Therefore, when one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is a heteroaryl as defined herein, and not an aryl.

[0075] The term "halogen" refers to F, C1, Br, or I. The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom. The term "heteroaryl" refers to a group selected from the following: A 5- to 7-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being carbon; A bicyclic ring of 8 to 12 members containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being carbon, in which case at least one ring is an aromatic ring and at least one heteroatom is present in the aromatic ring; A tricyclic ring with 11 to 14 members containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being carbon, in which case at least one ring is an aromatic ring and at least one heteroatom is present in the aromatic ring.

[0076] For example, heteroaryls include a 5-7 membered heterocyclic aromatic ring fused to a 5-7 membered cycloalkyl ring. In this fused bicyclic heteroaryl ring system, only one ring contains at least one heteroatom, and the linking site may be on the heteroaromatic ring or the cycloalkyl ring.

[0077] If the total number of S atoms and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S atoms and O atoms in an aromatic heterocyclyl group does not exceed 1.

[0078] Examples of heteroaryl groups, but not limited to those listed above (numbered from preferred linking position 1), include pyridyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), synnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thiophenyl, triazinyl, benzothiophenyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, dihydroindolyl, phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl-5-yl), pyrazolopyridyl (e.g., 1H -Pyrazolo[3,4-b]pyridine-5-yl), benzoxazolyl (e.g., benzo[d]oxazole-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, Examples include 1-thia-3,4-diazolyl, flazanil, benzoflazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridyl, benzothiazolyl (e.g., benzo[d]thiazolyl-6-yl), indazolyl (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinolinil.

[0079] The terms “heterocyclic,” “heterocyclic,” or “heterocyclyl” refer to rings selected from the group consisting of four-membered to twelve-membered monocyclic, bicyclic, and tricyclic saturated or partially unsaturated rings containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. “Heterocyclic” also refers to five-membered, six-membered, and / or seven-membered cycloalkyl rings, carbocyclic aromatic rings, or five-membered to seven-membered heterocyclic rings fused with heteroaromatic rings, provided that the linking site is on the heterocyclic ring if the heterocyclic ring is fused with a carbocyclic aromatic ring or heteroaromatic ring; and if the heterocyclic is fused with a cycloalkyl ring, the linking site is on the cycloalkyl ring or heterocyclic ring.

[0080] A "heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from the group consisting of N, O, and S, provided that the linking site is on the heterocycle. The ring may be saturated or contain at least one double bond (i.e., partially unsaturated). The heterocycle may be substituted with an oxo group. The linking site may be a carbon atom or a heteroatom in the heterocycle. The heterocycle is not a heteroaryl as defined herein.

[0081] Examples of heterocycles, though not limited to these (numbered from preferred linking position 1), include 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxylanyl, azilidinyl, thyranyl, and aze. Thidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxothiepanyl, 1,4-oxazepanyl, 1,4- Dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-thiadinyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, Examples of substituted heterocycles include 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinol, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substitutive heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0082] As used herein, the term “fused ring” refers to a polycyclic system, such as a bicyclic or tricyclic system, in which two rings share only two ring atoms and one bond. Examples of fused rings include fused bicyclic alkyl rings, e.g., bicyclic rings composed of 7 to 12 ring atoms selected from the group consisting of the [4,4], [4,5], [5,5], [5,6], and [6,6] bicyclic ring systems described above; fused bicyclic aryl rings, e.g., the 7 to 12-membered bicyclic aryl ring systems described above; fused tricyclic aryl rings, e.g., the 10 to 15-membered tricyclic aryl ring systems described above; fused bicyclic heteroaryl rings, e.g., the 8 to 12-membered bicyclic heteroaryl rings described above; fused tricyclic heteroaryl rings, e.g., the 11 to 14-membered tricyclic heteroaryl rings described above; and the fused bicyclic or tricyclic heterocycles described above.

[0083] This compound may contain one chiral center and therefore may exist as an enantiomer. If it has two or more chiral centers, it may also exist as a diastereomer. Enantiomers and diastereomers are classified into a broader category with respect to stereoisomers. All of these possible stereoisomers include substantially pure, divided enantiomers, their racemic mixtures, and mixtures of diastereomers, including all stereoisomers of this compound and / or their pharmaceutically acceptable salts. Unless otherwise specified, a description of one isomer applies to all possible isomers. If isomeric components are not specified in detail, all possible isomers are included.

[0084] When a compound contains an alkene double bond, unless otherwise specified, such double bonds refer to both the E geometric isomer and the Z geometric isomer.

[0085] Some compounds may exist in tautomer form. For example, compounds containing a carbonyl-CH2C(O)- group (keto form) may undergo tautomerization to form a hydroxyl-CH=C(OH)- group (enol form). In the application of the present invention, both keto and enol forms, as well as mixtures thereof, are included.

[0086] The compounds represented by formulas (I), (I-1), (II), (II-1), (III), (III-1), (IV), and (IV-1) of the present invention may be in the form of their salts, generally in the form of salts formed with organic or inorganic bases or acids. Physiologically acceptable salts are preferred in the present invention. Physiologically acceptable salts of the compounds of the present invention can be salts of the substance of the present invention with inorganic acids, carboxylic acids, or sulfonic acids, and particularly preferably salts formed with, for example, the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, and tannic acid. Other acids, such as oxalic acid, which are pharmaceutically unacceptable on their own, can be used to prepare salts as intermediates, thereby obtaining the compounds of the present invention and their pharmaceutically acceptable salts.

[0087] Physiologically acceptable salts may be metal salts or ammonium salts of the compounds of the present invention having free carboxyl groups. Particularly preferred are sodium salts, potassium salts, magnesium salts or calcium salts, as well as ammonium salts of inorganic ammonia, or ammonium salts of organic amines such as ethylamine, diethylamine, triethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, N-methylglucosamine, procaine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, or ethylenediamine.

[0088] The compounds of the present invention can exist in tautomeristic forms, and the present invention includes such forms. The compounds of the present invention may also be their possible solvates.

[0089] The present invention also relates to a pharmaceutical product comprising at least one compound of the present invention, preferably one or more pharmaceutically acceptable excipients or carriers, and further to its use for the purposes described herein. Pharmaceutical carriers used herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, and lanolin. The active ingredient may have systemic and / or topical effects and can therefore be administered via appropriate routes such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical administration, or implantation.

[0090] The active ingredient may be administered in a form suitable for these routes of administration: Known dosage forms suitable for oral administration that allow the active ingredient to be delivered rapidly and / or in a modified form, such as tablets (uncoated or coated tablets, e.g., enteric-coated or film-coated tablets), capsules, sugar-coated tablets, granules, pills, powders, emulsions, suspensions, and aerosols.

[0091] Parenteral administration can either avoid the absorption phase (intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar administration) or may involve the absorption phase (intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal administration). Suitable forms for parenteral administration are preparations in the form of liquids, suspensions, emulsions, lyophilized formulations, and sterile powders for injection and infusion.

[0092] Forms suitable for alternative routes of administration include, for example, inhaled drugs (especially powder inhalers and sprays), nasal drops / liquids, sprays; tablets, capsules, or suppositories for lingual, sublingual, or buccal administration; preparations for ear and eye administration; vaginal capsules; aqueous suspensions (lotions, shaken mixtures); lipophilic suspensions; ointments, creams, lotions, pastes, powders, or implants such as stent molds.

[0093] The active ingredient can be converted into the described dosage form using methods known to the present day. This can be done using appropriate inert and non-toxic pharmaceutically acceptable excipients. Such excipients particularly include carriers (e.g., microcrystalline cellulose), solvents (e.g., liquid polyethylene glycol), emulsifiers (e.g., sodium lauryl sulfate), dispersants (e.g., polyvinylpyrrolidone), synthetic and natural biopolymers (e.g., proteins), stabilizers (e.g., antioxidants and ascorbic acid), colorants (e.g., inorganic dyes such as iron oxide), or flavorings and / or flavor masking agents. If necessary, the active ingredient may also be present in the form of microencapsulated capsules in one or more of the above carriers.

[0094] This application covers all possible crystalline forms or polymorphs of the compound, which may be a single polymorph or a mixture of two or more polymorphs in any proportion.

[0095] The compounds of this application may exist as solvates (e.g., hydrates), in which case the compounds of this application contain a solvent such as water, methanol, or ethanol as structural elements in the lattice of the compound. The amount of solvent may be stoichiometric or nonstoichiometric.

[0096] The term "prodrug" refers to a derivative of the compound of the present invention that can be obtained by hydrolysis, oxidation, or otherwise reaction under biological conditions (in vitro or in vivo) to yield the compound of the present invention. Prodrugs either become active only after undergoing such a reaction under biological conditions, or have no activity or low activity in their unreacted form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995), pp. 172-178, 949-982 (Manfred E. Wolff, ed., 5th edition).

[0097] The term "isotope derivative" refers to a compound in which one or more atoms are substituted by atoms having the same atomic number, but with an atomic mass or mass number different from the dominant atomic mass or mass number found in nature. Examples of isotopes of the compounds of the present invention that are suitable for inclusion include, but are not limited to, 2 H and 3 Hydrogen isotopes such as H; 11 C, 13 C and 14 Carbon isotopes such as C; 36 Chlorine isotopes such as Cl; 18 fluorine isotopes such as F; 123 I and 125 Iodine isotopes such as I; 13 N and 15 Nitrogen isotopes such as N;15 O, 17 O and 18 Oxygen isotopes such as O; and 35 Examples include sulfur isotopes such as 15S.

[0098] The term "effective dose" refers to a dose that can achieve the treatment and / or prevention of the disease or symptoms described in the present invention in a given subject.

[0099] The term "treatment" is intended to alleviate, reduce, improve, or eliminate the targeted condition or symptom. For example, a subject is considered "treated" if, after administration of the relevant drug, one or more indicators and symptoms show observable and / or detectable reduction or improvement. It should also be understood that treatment of the aforementioned condition or symptom includes not only complete cure but also the achievement of any biologically or medically significant outcome that does not result in complete cure.

[0100] The term “prevention” means avoiding, mitigating, preventing, or delaying the onset of a disease or disease-related symptom, in which case the disease or disease-related symptom was not present before administration of the drug. “Prevention” does not necessarily require complete prevention of the onset of the disease or disease-related symptom; for example, reducing the risk of a subject developing a particular disease or disease-related symptom after administration of the drug, or mitigating the severity of any subsequent related symptoms, may also be considered “prevention” of the onset or occurrence of the disease.

[0101] Beneficial effects: The compounds of the present invention exhibit excellent inhibitory effects against the proliferation of hematological tumor cells and can effectively inhibit the proliferation of drug-resistant cells, and also have excellent in vivo efficacy. [Brief explanation of the drawing]

[0102] [Figure 1] This figure shows the inhibitory effects of compounds I-4 and I-8 on human multiple myeloma RPMI-8226 xenograft tumors. [Figure 2] This figure shows the inhibitory effects of compounds I-4 and I-8 on human multiple myeloma NCI-H929 xenograft tumors. [Figure 3] This figure shows the inhibitory effects of compounds I-4 and I-8 in combination with dexamethasone on human multiple myeloma NCI-H929 xenograft tumors. [Figure 4] This figure shows the inhibitory effects of compound I-8 in combination with bortezomib and tazemettostat, respectively, on human multiple myeloma NCI-H929 xenograft tumors. Note: In the figure above, ** indicates p<0.01, and ns indicates no significant difference. Specific embodiments for carrying out the present invention

[0103] More detailed information regarding the preparation of compounds of general formula (I) is provided in the following examples, but these examples are merely illustrative of preferred embodiments of the present invention and are not intended to limit the scope of the present invention, but rather to illustrate it.

[0104] For all of the following examples, standard procedures and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (Celsius). The structure of the compounds was confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The melting points of the compounds were determined by an RY-1 melting point analyzer; the thermometer was uncalibrated. Units are °C. 1¹H NMR was determined by a JNM-ECA-600 NMR spectrometer (JEOL). Mass spectrometry was determined by an API 3000 (ESI) mass spectrometer. All solvents used in the reaction were not standardized unless otherwise specified. In the examples below, unless otherwise specified, % refers to mass percentage. Silica gel for column chromatography was manufactured at Qingdao Marine Chemical Plant (200-300 mesh); silica gel plates for thin-layer chromatography were pre-made silica gel plates for thin-layer chromatography manufactured by Yantai Chemical Industry Research Institute. The compounds of the present invention can be prepared using conventional methods in the art with appropriate reagents, raw materials and purification methods known to those skilled in the art.

[0105] Example 1: Synthesis of 3-(3-methyl-6-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-11) [ka] Synthesis of [1-1]methyl 2-(bromomethyl)-4-nitrobenzoate (compound <1-1>) 10 g (51.23 mmol) of methyl 2-methyl-4-nitrobenzoate was weighed and dissolved in 20 mL of dichloroethane. 420.4 mg (2.56 mmol) of AIBN was added, and the mixture was stirred until completely dissolved. The mixture was heated to 80°C, and a total of 10.94 g (61.48 mmol) of NBS was added in small increments. After 1 hour of reaction, TLC indicated that the reaction was complete. Heating was stopped, and the reaction solution was gradually cooled to 0°C. After 1 hour, a large amount of white crystals precipitated. The crystals were removed by filtration, the filtrate was concentrated, and silica gel column chromatography (eluent: V) was performed. 石油エーテル / V 酢酸エチル Separation was performed using (=100 / 1) to obtain 10.20 g of intermediate 1-1 as a colorless oily liquid in 72.65% yield. ESI-MS m / z: 274.04 [M+H] + .

[0106] [1-2] Synthesis of Methyl (E)-2-((2-benzylidene-1-methylhydrazinyl)methyl)-4-nitrobenzoate (Compound <1-2>) Weighed 1.89 g (13.14 mmol) of methylhydrazine sulfate and 1.39 g (13.14 mmol) of anhydrous sodium carbonate, suspended them in 20 mL of methanol, stirred, and heated to 60 °C. After 1 hour, 1.35 mL (13.14 mmol) of benzaldehyde and 3.00 g (10.95 mmol) of Compound 1-1 were added to the reaction system, and stirring was continued at 60 °C for 3 hours. After TLC monitoring indicated that the reaction was complete, the solid was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (eluent: V 石油エーテル / V 酢酸エチル = 15 / 1) to obtain 2.21 g of Compound 1-2 as an orange-yellow solid in a yield of 61.73%. ESI-MS m / z: 328.12 [M+H] + .

[0107] [1-3] Synthesis of 3-Methyl-6-nitro-3,4-dihydrophthalazin-1(2H)-one (Compound <1-3>) Weighed 1.17 g (3.57 mmol) of Compound 1-2, added it to 5 mL of a mixed solvent (V n-ブタノール / V 氷酢酸 = 1 / 1), stirred until Compound 1-2 was completely dissolved, then added 24.4 mg (0.18 mmol) of anhydrous zinc chloride, heated to 120 °C, and reacted for 6 hours. Heating and stirring were stopped, and the mixture was left overnight. A yellow solid precipitated, which was filtered. The obtained solid was washed with petroleum ether and dried to obtain Compound 1-3 (590 mg, yield 79.84%). ESI-HRMS m / z: 206.0560 [M-H] - .

[0108] [1-4] Synthesis of 3-(3-Methyl-6-nitro-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)piperidine-2,6-dione (Compound I-11) Compound 1-3 was weighed 500 mg (2.42 mmol), dissolved in 10 mL of anhydrous tetrahydrofuran, and stirred in an ice bath under nitrogen protection. 3.6 mL (3.60 mmol, 1 N in THF) of LiHMDS was added. After the addition was complete, the mixture was stirred in an ice bath for 30 minutes. Next, 695 mg (3.62 mmol) of 3-bromopiperidine-2,6-dione dissolved in 5 mL of anhydrous tetrahydrofuran was added. The mixture was then allowed to warm naturally to room temperature and reacted for 3 hours. When TLC detection indicated that the reaction had stopped, the reaction was quenched by adding saturated ammonium chloride solution. After layer separation, the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated for silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound I-11 was purified by (50 / 1) to obtain 20 mg as a white to pale yellow solid in a yield of 2.60%. ESI-MS m / z: 319.10 [M+H] + . 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.99 (s, 1H), 8.35 (dd, J = 8.3, 1.3 Hz, 1H), 8.26 (dd, J = 7.7, 1.3 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 5.19 (dd, J = 12.4, 4.9 Hz, 1H), 4.68 (d, J = 17.2 Hz, 1H), 4.50 (d, J = 17.1 Hz, 1H), 2.86 (ddd, J = 17.1, 13.7, 5.3 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H), 2.43 (dd, J = 13.2, 4.4 Hz, 1H), 2.14-2.10 (m, 1H).

[0109] Example 2: Synthesis of 3-(6-amino-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-10) [ka] [2-1] 20 mg (0.06 mmol) of Compound I-11 was weighed and added to 5 mL of methanol and stirred, but a part of the solid dissolved. Approximately 8.05 mg (0.13 mmol) of activated zinc powder was added, and subsequently, 300 μL of 3M HCl(aq.) was added dropwise with stirring and reacted overnight at room temperature. The next day, the solid had completely dissolved. TLC detection indicated that the reaction was complete. The zinc powder was removed by filtration, the filtrate was concentrated, and subjected to TLC separation to obtain 13 mg of Compound I-10 as a white solid in a yield of 71.78%. ESI-MS m / z: 289.13 [M+H] + . 1 1H-NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 8.4, 2.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 5.93 (s, 2H), 5.09 (dd, J = 12.5, 5.2 Hz, 1H), 4.25 (s, 1H), 3.82 (d, J = 12.2 Hz, 1H), 2.82 (ddd, J = 17.1, 13.7, 5.3 Hz, 1H), 2.58 - 2.53 (m, 1H), 2.50 (s, 3H), 2.39 (qd, J = 13.0, 4.3 Hz, 1H), 2.02 (dtd, J = 12.8, 5.2, 2.7 Hz, 1H).

[0110] Example 3: Synthesis of 3-(3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)piperidine-2,6-dione (Compound I-9) [[ID=1)2]]

Chem.

[0111] [3-2] Synthesis of 3-methyl-5-nitro-3,4-dihydrophthalazine-1(2H)-one (compound <3-2>) Weigh 17.0 g (52.00 mmol) of compound 3-1 and add it to the mixed solvent (V n-ブタノール / V 氷酢酸 Compound 3-1 was added to 50 mL of (1 / 1) solution and stirred until completely dissolved. 354 mg (2.60 mmol) of anhydrous zinc chloride was added, and the mixture was heated to 120°C and reacted for 6 hours. Heating and stirring were stopped, and the mixture was left overnight. A yellow solid precipitated, which was filtered. The obtained solid was washed with petroleum ether and dried to obtain compound 3-2 (5.90 g, yield 54.8%). ESI-HRMS m / z: 206.0560 [M+H] + .

[0112] [3-3] Synthesis of 3-(3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-9) 5.00 g (24.14 mmol) of compound 3-2 was weighed and dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture was stirred in an ice bath under nitrogen protection, and 3.6 mL (3.60 mmol, 1 N in THF) of LiHMDS was added. After the addition was complete, the mixture was stirred in an ice bath for 30 minutes. Next, 6.95 g (36.22 mmol) of 3-bromopiperidine-2,6-dione dissolved in 20 mL of anhydrous tetrahydrofuran was added. The mixture was then allowed to warm naturally to room temperature and reacted for 3 hours. After TLC detection indicated that the reaction had stopped, the reaction was quenched by adding saturated ammonium chloride solution. After layer separation, the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated for silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound I-9 was purified using a 50 / 1 (ESI-HRMS) assay to obtain 4.01 g of compound I-9 as a white to pale yellow solid in 52.10% yield. ESI-HRMS m / z: 318.3001 [M]+. 1 H-NMR (600 MHz, DMSO-d6) δppm: 11.00 (s, 1H), 8.36 (dd, J = 8.2, 1.3 Hz, 1H), 8.26 (dd, J = 7.7, 1.3 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 5.20 (dd, J = 12.8, 5.1 Hz, 1H), 4.68 (d, J = 17.2 Hz, 1H), 4.51 (d, J = 18.5 Hz, 1H), 2.86 (ddd, J = 17.2, 13.8, 5.4 Hz, 1H), 2.60 (t, J = 4.0 Hz, 1H), 2.57 (d, J = 3.7 Hz, 2H), 2.45 (d, J = 10.2 Hz, 1H), 2.43-2.38 (m, 1H), 2.12 (ddq, J = 10.5, 5.3, 2.6 Hz, 1H).

[0113] Example 4: Synthesis of 3-(5-amino-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-4) [Chemical formula] [4-1] 4.00 g (12.58 mmol) of compound I-9 was weighed and added to 40 mL of methanol, and stirred. A part of the solid dissolved. Approximately 133.86 mg (1.26 mmol) of 5% Pd-C was added, the reactor was purged with hydrogen gas, and then connected to a balloon filled with hydrogen. The reaction was allowed to proceed overnight at room temperature. The next day, the solid completely dissolved, and TLC detection indicated that the reaction was complete. The wet palladium-carbon catalyst was removed by filtration using diatomaceous earth and recovered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: V ジクロロメタン / V メタノール = 50 / 1 to 10 / 1) to obtain 1.21 g of product I-4 as a white solid in a yield of 33.34%. ESI-HRMS m / z: 289.1269 [M+H] + ; 1 1H-NMR (600 MHz, DMSO-d6) δ ppm: 10.90 (s, 1H), 7.13 - 7.06 (m, 2H), 6.86 (dd, J = 7.6, 1.5 Hz, 1H), 5.19 (s, 2H), 5.11 (dd, J = 12.7, 5.1 Hz, 1H), 4.18 (d, J = 16.2 Hz, 1H), 3.97 (d, J = 16.2 Hz, 1H), 2.83 (ddd, J = 17.1, 13.8, 5.3 Hz, 1H), 2.58 - 2.53 (m, 1H), 2.47 (s, 3H), 2.45 - 2.37 (m, 1H), 2.05 (dtd, J = 12.8, 5.2, 2.6 Hz, 1H).

[0114] Example 5: Synthesis of 3-(3-methyl-5-(methylamino)-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)piperidine-2,6-dione (Compound I-2) [Chemical formula] [5-1] 300 mg (1.04 mmol) of compound I-4 and 100 mg (1.61 mmol) of paraformaldehyde were weighed and placed in a 25 mL neck flask, and 10 mL of water was added. The reaction flask was placed in a mixer, and formic acid (0.32 g, 7 mmol) was added while stirring. The mixture was then heated to 70°C and reacted for 6 hours. TLC indicated that the reaction was complete. The reaction flask was cooled to room temperature and then filtered by suction. The resulting solids were washed with 10 mL of water, 10 mL of dichloromethane, and 10 mL of tetrahydrofuran, respectively. After vacuum drying, the crude product was subjected to silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound I-2 was purified using ESI-HRMS (50 / 1~10 / 1) to obtain 180 mg of compound I-2 as a white solid in a yield of 57.32%. ESI-HRMS m / z: 303.1455 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.90 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.12 (dd, J = 7.6, 1.1 Hz, 1H), 6.76 (dd, J = 8.2, 1.1 Hz, 1H), 5.42 (d, J = 5.0 Hz, 1H), 5.11 (dd, J = 12.7, 5.1 Hz, 1H), 4.19 (d, J = 16.2 Hz, 1H), 3.98 (d, J = 16.2 Hz, 1H), 2.83 (ddd, J = 17.1, 13.8, 5.3 Hz, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.60-2.54 (m, 1H), 2.46 (s, 3H), 2.42 (dd, J = 13.3, 4.4 Hz, 1H), 2.06 (dtd, J = 12.8, 5.2, 2.6 Hz, 1H).

[0115] Example 6: Synthesis of 3-(1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (compound YJ-1a) [ka] [6-1] Synthesis of dimethyl-2-bromoglutarate (compound <6-1>) Glutaric acid (2.64 g, 20 mmol) was weighed and placed in a 50 mL two-necked round-bottom flask, and 30 mL of dichloromethane was added. The reaction flask was placed in a mixer and stirred at room temperature until a suspension was formed. Then, thionyl chloride (7.13 g, 60 mmol) was slowly added. The mixture was then heated under reflux and reacted for 10 hours. The flask was cooled to room temperature, and the solvent and unreacted thionyl chloride were evaporated to obtain a golden-colored liquid. The golden-colored liquid was transferred to a 100 mL three-necked round-bottom flask equipped with a thermometer and a serpentine condenser. The temperature was raised to 80°C, and liquid bromine (3.20 g, 20.05 mmol) was added dropwise through a dropping funnel. After the first drop of bromine was added, the reaction mixture turned red. After the red color disappeared, the second drop of bromine was added. After the bromine had been completely added over 6 hours, the reaction was continued at 80°C for 12 hours. After the reaction was complete, the flask was cooled to room temperature. Next, 50 mL of methanol was added to a 100 mL necked flask, and the flask was placed in an ice bath and stirred for 10 minutes. Then, the reaction mixture was slowly added dropwise to the methanol. After the dropwise addition was complete, the reaction flask was left at room temperature and stirred for 3 hours. Next, the solvent was evaporated using a rotary evaporator to obtain 5.22 g of red liquid. The red liquid was washed three times with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated sodium thiosulfate solution, and then once with 30 mL of saturated saline solution. Next, the washed red liquid was subjected to vacuum distillation, and the fraction at 80-85°C was collected to obtain 3.63 g of 6-1 as a pale yellow liquid in 76.1% yield. 1 H-NMR (600 MHz, CDCl3) δppm: 4.39 (dd, J = 8.5, 5.8 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 2.59-2.46 (m, 2H), 2.44-2.34 (m, 2H). ESI-MS m / z: 240.99 [M+H] + .

[0116] [6-2] Synthesis of phthalazine-1-(2H)-one (compound <6-2>) 7.50 g of 2-formylbenzoic acid (50 mmol) was weighed and placed in a 200 mL round-bottom flask, and 50 mL of n-butanol was added. The reaction flask was placed in a mixer and stirred at room temperature until a suspension was formed. Then, 3.53 g of 85% hydrazine hydrate (60 mmol) was slowly added. The temperature was raised to 100 °C and the reaction was allowed to proceed for 2 hours, after which the reaction mixture was allowed to cool to room temperature. The mixture was filtered by suction. The solid was washed with dichloromethane, then with water, and dried to obtain 5.85 g of 6-2 as white needle-shaped crystals in 80.5% yield. 1 H-NMR (600 MHz, DMSO-d6) δppm: 12.66 (s, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.24 (dq, J = 7.8, 0.9 Hz, 1H), 7.97-7.91 (m, 2H), 7.86 (dp, J = 8.5, 4.3 Hz, 1H); ESI-MS m / z: 147.06 [M+H] + .

[0117] [6-3] Synthesis of dimethyl 2-(1-oxophthalazine-2(1H)-yl)glutarate (compound <6-3>) 6-2 (0.44 g, 3 mmol) and potassium carbonate (0.46 g, 3.3 mmol) were weighed and placed in a 50 mL two-necked round-bottom flask. 10 mL of DMF was added, and the flask was placed in a mixer. 6-1 (0.87 g, 3.6 mmol) was added while rapidly stirring, and the reaction temperature was then raised to 80°C. After 18 hours of reaction, TLC indicated that the reaction was complete. After allowing the reaction flask to cool to room temperature, the reaction mixture was added dropwise to 20 mL of cold water and extracted three times with 30 mL of ethyl acetate. The organic layers were combined and dehydrated with anhydrous sodium sulfate. Silica gel was then added and thoroughly mixed. The mixture was then subjected to column chromatography (eluent: V 石油エーテル / V 酢酸エチル The solution was subjected to (15 / 1) and 0.78 g of 6-3 was obtained as a colorless, transparent liquid in a yield of 86.2%. 1H-NMR (400 MHz, CDCl3) δppm: 8.43 (dd, J = 7.8, 1.4 Hz, 1H), 8.22 (s, 1H), 7.89-7.76 (m, 2H), 7.73 (dd, J = 7.9, 1.3 Hz, 1H), 5.74 (dd, J = ESI-MS m / z: 305.11 [M+H] + .

[0118] [6-4] Synthesis of 3-(1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (compound YJ-1a) Sodium amide (0.12 g, 3 mmol) was weighed and placed in a 50 mL two-neck round-bottom flask. Nitrogen protection was applied through a three-way valve. 10 mL of ultra-dried tetrahydrofuran was added via syringe, and the reaction flask was then placed in a -30°C cooling bath. After cooling for 20 minutes, 6-3 (0.60 g, 2 mmol) was dissolved in 10 mL of ultra-dried tetrahydrofuran and slowly added dropwise to the reaction flask via syringe over 10 minutes. After reacting in the cooling bath for 6 hours, 5 mL of saturated ammonium chloride solution was slowly added, and the reaction flask was left at room temperature with stirring continued for 30 minutes. The mixture was filtered by suction. The solids were washed with 40 mL of water, 30 mL of dichloromethane, and 30 mL of tetrahydrofuran, respectively, and then dried to obtain 0.28 g of YJ-1a as a white solid in 56.5% yield. 1H-NMR (400 MHz, DMSO-d6) δppm: 11.07 (s, 1H), 8.52-8.48 (m, 1H), 8.28 (dt, J = 7.9, 1.0 Hz, 1H), 7.99 (dd, J = 3.7, 1.1 Hz, 2H), 7.91 (ddd, J = 8.3, 4.9, 3.6 Hz, 1H), 5.83 (dd, J = 12.3, 5.4 Hz, 1H), 2.94 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.67-2.52 (m, 2H), 2.19-2.08 (m, 1H). ESI-MS m / z: 258.09 [M+H] + .

[0119] Example 7: Synthesis of 3-(1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound YJ-2a) [ka] [7-1] Compound YJ-1a (0.39 g, 1.5 mmol) and zinc powder (0.16 g, 2.5 mmol) were weighed and placed in a 50 mL round-bottom flask. 10 mL of water was added, and the reaction flask was placed in an ice bath. After 10 minutes, 2 mL of 3 mol / L hydrochloric acid was slowly added dropwise to the reaction flask through a dropping funnel, and the addition was completed over 10 minutes. The reaction was maintained in the ice bath for 3 hours, then the mixture was heated to room temperature and stirred for 30 minutes. The mixture was filtered by suction. The solid was washed with water and vacuum dried. The obtained solid was then mixed with the solvent (V ジクロロメタン / V メタノール The mixture was slurryed to 20 mL (1 / 1). After 30 minutes, the mixture was filtered by suction, and the filtrate was evaporated to dryness to obtain 0.14 g of compound YJ-2a as a white solid in a yield of 37.6%. 1H-NMR (400 MHz, DMSO-d6) δppm: 10.93 (s, 1H), 7.89 (dd, J = 7.7, 1.4 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.42 (td, J = 7.6, 1.3 Hz, 1H), 7.31-7.25 (m, 1H), 5.84 (t, J = 8.2 Hz, 1H), 5.36 (dd, J = 12.4, 5.3 Hz, 1H), 4.13-3.92 (m, 2H), 2.85 (ddd, J = 17.2, 13.8, 5.4 Hz, 1H), 2.62-2.52 (m, 1H), 2.38-2.23 (m, 1H), 1.93 (dtd, J = 13.1, 5.4, 2.6 Hz, 1H). ESI-MS m / z: 260.11 [M+H] + .

[0120] Example 8: Synthesis of 3-(3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound YJ-3a) [ka] [8-1] Compound YJ-2a (0.30 g, 1 mmol) and paraformaldehyde (0.05 g, 1.5 mmol) were weighed and placed in a 25 mL neck flask, and 10 mL of water was added. The reaction flask was placed in a mixer, and formic acid (0.32 g, 7 mmol) was added while stirring. The temperature was then raised to 70°C and the reaction was allowed to proceed for 6 hours. TLC indicated that the reaction was complete. The reaction flask was cooled to room temperature, and the mixture was filtered by suction. The obtained solids were washed with 10 mL of water, 10 mL of dichloromethane, and 10 mL of tetrahydrofuran, respectively. The solids were vacuum-dried to obtain 0.25 g of compound YJ-3a as a white solid in 93.3% yield. 1H-NMR (400 MHz, DMSO-d6) δppm: 10.96 (s, 1H), 7.77 (td, J = 5.5, 2.6 Hz, 1H), 7.57 (td, J = 7.6, 1.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 4.96 (s, 2H), 4.63-4.18 (m, 3H), 3.60 (s, 2H), 2.78 (t, J = 15.7 Hz, 1H), 2.26-1.32 (m, 2H). ESI-MS m / z: 272.10 [M+H] + .

[0121] Example 9: Synthesis of 3-(1-oxophthalazine-2(1H)-yl)pyrrolidine-2,5-dione (compound YJ-1b) [ka] Synthesis of [9-1]dimethyl 2-bromosuccinate (compound <9-1>) 1.97 g of 2-bromosuccinic acid (10 mmol) was weighed and placed in a 50 mL round-bottom flask. 20 mL of methanol was then added, and the mixture was stirred until the 2-bromosuccinic acid was completely dissolved. The reaction flask was placed in a mixer, and 3 drops of concentrated sulfuric acid were added dropwise while stirring at room temperature. The reaction temperature was then raised and reflux was performed. After 16 hours of reflux and reaction, the reaction flask was cooled to room temperature, and the solvent was evaporated to dryness using a rotary evaporator. 30 mL of ethyl acetate was added to the remaining liquid, which was then transferred to a separatory funnel and washed three times with 30 mL of saturated sodium bicarbonate, followed by one wash with saturated brine. The organic layer was dehydrated with anhydrous sodium sulfate, and then evaporated to dryness using a rotary evaporator to obtain 2.05 g of 9-1 as a colorless, transparent liquid in 91.2% yield. 1 H-NMR (600 MHz, CDCl3) δppm: 4.59 (dd, J = 8.8, 6.2 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.32-2.97 (m, 2H). ESI-MS m / z: 226.98 [M+H] + .

[0122] [9-2] Synthesis of phthalazine-1-(2H)-one (compound <9-2>) 7.50 g of 2-formylbenzoic acid (50 mmol) was weighed and placed in a 200 mL round-bottom flask, and 50 mL of n-butanol was added. The reaction flask was placed in a mixer and the mixture was stirred at room temperature until a suspension was formed. Then, 3.53 g of 85% hydrazine hydrate (60 mmol) was slowly added. The temperature was raised to 100 °C and the reaction was allowed to proceed for 2 hours, after which the reaction mixture was allowed to stand and cool to room temperature. The mixture was filtered by suction. The solid was washed with dichloromethane, then with water, and dried to obtain 5.85 g of 9-2 as white needle-shaped crystals in 80.5% yield. 1 H-NMR (600 MHz, DMSO-d6) δppm: 12.66 (s, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.24 (dq, J = 7.8, 0.9 Hz, 1H), 7.97-7.91 (m, 2H), 7.86 (dp, J = 8.5, 4.3 Hz, 1H); ESI-MS m / z: 147.06 [M+H] + .

[0123] Synthesis of [9-3]dimethyl 2-(1-oxophthalazine-2(1H)-yl) succinate (compound <9-3>) 9-2 (0.44 g, 3 mmol) and potassium carbonate (0.46 g, 3.3 mmol) were weighed and placed in a 50 mL two-necked round-bottom flask, and 10 mL of DMF was added. The reaction flask was placed in a mixer. 9-1 (0.81 g, 3.6 mmol) was added rapidly while stirring, and then heated to 80°C. After reacting for 24 hours, TLC indicated that the reaction was complete. The reaction flask was left at room temperature, and the reaction solution was added dropwise to 20 mL of cold water. The mixture was extracted three times with 30 mL of ethyl acetate. The organic layers were combined, dehydrated with anhydrous sodium sulfate, then silica gel was added, and the mixture was stirred well. Column chromatography (eluent: V) was performed. 石油エーテル / V 酢酸エチル The solution was subjected to (15 / 1) and 0.77 g of 9-3 was obtained as a colorless, transparent liquid in 88% yield. 1H-NMR (400 MHz, CDCl3) δ ppm: 8.44 (dd, J = 7.7, 1.5 Hz, 1H), 8.19 (s, 1H), 7.88 - 7.69 (m, 3H), 6.08 (dd, J = 8.1, 6.0 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H). 3.45 - 3.08 (m, 2H). ESI-MS m / z: 291.18 [M+H] + .

[0124] [9 - 4] Synthesis of 3-(1-oxophthalazin-2(1H)-yl)pyrrolidine-2,5-dione (Compound YJ-1b) Sodium amide (0.12 g, 3 mmol) was weighed and placed in a 50 mL two-neck round-bottom flask under nitrogen protection. 10 mL of ultra-dry tetrahydrofuran was added, and then the reaction flask was placed in a cooling bath at -30 °C. After cooling for 20 minutes, 9-3 (0.58 g, 2 mmol) was dissolved in 10 mL of ultra-dry tetrahydrofuran, and using a syringe, it was slowly added dropwise to the reaction flask over 10 minutes. After reacting in the cooling bath for 6 hours, 5 mL of saturated ammonium chloride solution was slowly added. The reaction flask was left at room temperature and stirring was continued for 30 minutes. The mixture was suction filtered. The obtained solid was washed with water, dichloromethane, and tetrahydrofuran respectively to obtain 0.24 g of Compound YJ-1b as a white solid in a yield of 50.2%. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 11.57 (s, 1H), 8.52 (s, 1H), 8.26 (dd, J = 8.0, 1.0 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.92 (dq, J = 8.3, 4.3 Hz, 1H), 5.78 (s, 1H), 3.12 (dd, J = 17.8, 9.5 Hz, 1H), 2.90 (dd, J = 17.8, 5.2 Hz, 1H). ESI-MS m / z: 244.08 [M+H] + .

[0125] Example 10: Synthesis of 3-(1-oxo-3,4-dihydrophthalazine-2(1H)-yl)pyrrolidine-2,5-dione (compound YJ-2b) [ka] [10-1] Compound YJ-1b (0.36 g, 1.5 mmol) and zinc powder (0.16 g, 2.5 mmol) were weighed and placed in a 50 mL round-bottom flask, and 10 mL of water was added. The reaction flask was placed in an ice bath. After 10 minutes, 3 mL of 3 mol / L hydrochloric acid was slowly added dropwise to the reaction flask through a dropping funnel, and the addition was completed over 10 minutes. The reaction was maintained in the ice bath for 3 hours, and then the mixture was heated to room temperature and stirred for 30 minutes. The mixture was filtered by suction. The resulting solid was washed with water and vacuum dried. The resulting solid was then mixed with a solvent (V ジクロロメタン / V メタノール The mixture was slurryed to 20 mL (1 / 1). After 30 minutes, the mixture was filtered by suction, and the filtrate was evaporated to dryness to obtain 0.19 g of compound YJ-2b as a white solid in a yield of 35.1%. 1 H-NMR (400 MHz, DMSO-d6) δppm: 11.42 (s, 1H), 7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.54 (td, J = 7.5, 1.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 6.12 (dd, J = 9.4, 7.1 Hz, 1H), 5.49 (dd, J = 9.3, 5.1 Hz, 1H), 4.12-3.94 (m, 2H), 2.94 (dd, J = 17.8, 9.2 Hz, 1H), 2.71 (dd, J = 17.8, 5.1 Hz, 1H). ESI-MS m / z: 246.09 [M+H] + .

[0126] Example 11: Synthesis of 3-(7-fluoro-3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-13) [ka] Synthesis of [11-1]methyl(E)-2-((2-benzylidene-1-methylhydrazineyl)methyl)-5-fluoro-3-nitrobenzoate (compound <11-1>) 217.7 mg (2.05 mmol) of sodium carbonate and 295.5 mg (2.05 mmol) of methylhydrazine sulfate were weighed and suspended in 10 mL of methanol. The mixture was heated to 60°C and reacted for 1 hour. 209 μL (2.05 mmol) of benzaldehyde and 500 mg of methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate were added, and the reaction was continued for 5 hours. After TLC detection indicated completion of the reaction, the solid was removed by filtration. The residue was purified by silica gel column chromatography to obtain 11-1,460 mg as an orange-yellow solid in a yield of 77.80%. ESI-MS m / z: 346.09 [M+H] +

[0127] [11-2] Synthesis of 7-fluoro-3-methyl-5-nitro-3,4-dihydrophthalazine-1(2H)-one (compound <11-2>) 11-1 460 mg (1.33 mmol) was weighed and dissolved in a mixed solvent of 3 mL of n-butanol and 3 mL of glacial acetic acid. 10 mg (0.07 mmol) of anhydrous zinc chloride was added. The mixture was heated to 120°C and reacted for 3 hours. Once TLC indicated the completion of the reaction, the solution was cooled to room temperature and purified by silica gel column chromatography to obtain 11-2 210 mg as a yellow solid in 70.12% yield. ESI-MS m / z: 224.05 [MH] -

[0128] [11-3] Synthesis of 3-(7-fluoro-3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-13) 11-2 210 mg was weighed and dissolved in 5 mL of anhydrous tetrahydrofuran. The mixture was pre-cooled to -20°C under nitrogen protection. 1.2 mL of LiHMDS (1.2 mmol, 1 M in THF) was added to the reaction system. After stirring at -20°C for 30 minutes, 358.1 mg (1.87 mmol) of 3-bromopiperidine-2,6-dione dissolved in 5 mL of anhydrous tetrahydrofuran was added. The mixture was then reacted overnight at room temperature. After TLC detection indicated completion of the reaction, the reaction was quenched with water. After layer separation, the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain compound I-13 70 mg as a white solid in 22.39% yield. 1 H-NMR (600 MHz, DMSO-d6) δppm: 11.01 (s, 1H), 8.31 (dd, J = 8.5, 2.8 Hz, 1H), 8.06 (dd, J = 8.0, 2.8 Hz, 1H), 5.19 (dd, J = 12.8, 5.0 Hz, 1H), 4.64 (d, J = 17.1 Hz, 1H), 4.49 (d, J = 17.1 Hz, 1H), 2.86 (ddd, J = 17.0, 13.7, 5.4 Hz, 1H), 2.58 (dt, J = 18.4, 4.7 Hz, 2H), 2.46-2.37 (m, 1H), 2.15-2.09 (m, 1H); ESI-MS m / z: 337.10 [M+H] + .

[0129] Example 12: Synthesis of 3-(5-amino-7-fluoro-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-12) [ka] [12-1] 50 mg (0.15 mmol) of compound I-13 was weighed into a round-bottom flask, and 20 mg (0.30 mmol) of activated zinc powder and 5 mL of methanol were added. Then, 2 mL of 3 M hydrochloric acid aqueous solution was slowly added dropwise to the reaction solution. After the dropwise addition was complete, the mixture was stirred for 1 hour. When TLC detection indicated that the reaction was complete, excess zinc powder was removed by filtration, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 20 mg of compound I-12 as a white solid in yield 43.57%. 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.91 (s, 1H), 6.74 (dd, J = 8.8, 2.6 Hz, 1H), 6.63 (dd, J = 11.5, 2.6 Hz, 1H), 5.56 (s, 2H), 5.10 (dd, J = 12.9, 5.1 Hz, 1H), 4.14 (d, J = 16.1 Hz, 1H), 3.95 (d, J = 16.2 Hz, 1H), 2.87-2.79 (m, 1H), 2.57 (t, J = 3.7 Hz, 1H), 2.47 (s, 3H), 2.41 (qd, J = 13.0, 4.2 Hz, 1H), 2.10-2.01 (m, 1H); ESI-MS m / z: 307.12 [M+H] +

[0130] Example 13: Synthesis of tert-butyl 4-(4-(((2-(2,6-dioxopiperidine-3-yl)-3-methyl-1-oxo-1,2,3,4-tetrahydrophthalazine-5-yl)amino)methyl)benzyl)piperazine-1-carboxylate (Compound I-5) [ka] Synthesis of [13-1]methyl(E)-2-((2-benzylidene-1-methylhydrazineyl)methyl)-3-nitrobenzoate (compound <13-1>) 10.50 g (72.84 mmol) of methylhydrazine sulfate and 11.60 g (109.26 mmol) of anhydrous sodium carbonate were weighed, suspended in 200 mL of methanol, stirred, and heated to 60°C. After 1 hour, 7.29 mL (72.84 mmol) of benzaldehyde and 20.00 g (72.84 mmol) of methyl 2-bromomethyl-3-nitrobenzoate were added to the reaction system, and the mixture was stirred at 60°C for a further 3 hours. After TLC detection indicated that the reaction of methyl 2-bromomethyl-3-nitrobenzoate was complete, solid matter was removed by filtration. The filtrate was concentrated and subjected to silica gel column chromatography (eluent: V 石油エーテル / V 酢酸エチル The compound 13-1 was purified by (15 / 1) to obtain 17.0 g of compound 13-1 as an orange-yellow solid in 71.1% yield. ESI-MS m / z: 328.12 [M+H] + .

[0131] [13-2] Synthesis of 3-methyl-5-nitro-3,4-dihydrophthalazine-1(2H)-one (compound <13-2>) Weigh 17.0 g (52.00 mmol) of compound 13-1 and mix with the solvent (V n-ブタノール / V 氷酢酸 Compound 13-1 was added to 50 mL of solution and stirred until completely dissolved. 354 mg (2.60 mmol) of anhydrous zinc chloride was added. The mixture was heated to 120°C and reacted for 6 hours. Heating and stirring were stopped, and the mixture was left overnight. A yellow solid precipitated, which was filtered. The obtained solid was washed with petroleum ether and dried to obtain compound 13-2 (5.90 g, yield 54.8%). ESI-HRMS m / z: 206.0560 [M+H] + .

[0132] [13-3] Synthesis of 3-(3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound <13-3>) Compound 13-2 was weighed at 5.00 g (24.14 mmol) and dissolved in 50 mL of anhydrous tetrahydrofuran under nitrogen protection. The mixture was stirred in an ice bath and 36 mL (36.00 mmol, 1 N in THF) of LiHMDS was added. After the addition was complete, the mixture was stirred in an ice bath for 30 minutes. Next, 6.95 g (36.22 mmol) of 3-bromopiperidine-2,6-dione dissolved in 20 mL of anhydrous tetrahydrofuran was added. The mixture was allowed to warm naturally to room temperature and reacted for 3 hours. After TLC detection indicated that the reaction had stopped, the reaction was quenched by adding saturated ammonium chloride solution. After layer separation, the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound 13-3 was purified using a 50 / 1 (ESI-HRMS) assay to obtain 4.01 g of compound 13-3 as a white to pale yellow solid in 52.10% yield. ESI-HRMS m / z: 318.3001 [M]+. 1 H-NMR (600 MHz, DMSO-d6) δppm: 11.00 (s, 1H), 8.36 (dd, J = 8.2, 1.3 Hz, 1H), 8.26 (dd, J = 7.7, 1.3 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 5.20 (dd, J = 12.8, 5.1 Hz, 1H), 4.68 (d, J = 17.2 Hz, 1H), 4.51 (d, J = 18.5 Hz, 1H), 2.86 (ddd, J = 17.2, 13.8, 5.4 Hz, 1H), 2.60 (t, J = 4.0 Hz, 1H), 2.57 (d, J = 3.7 Hz, 2H), 2.45 (d, J = 10.2 Hz, 1H), 2.43-2.38 (m, 1H), 2.12 (ddq, J = 10.5, 5.3, 2.6 Hz, 1H).

[0133] [13-4] Synthesis of 3-(5-amino-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound <13-4>) Compound 13-3 was weighed at 4.00 g (12.58 mmol) and added to 40 mL of methanol. The mixture was stirred, and some of the solids dissolved. Approximately 133.86 mg (1.26 mmol) of 5% Pd-C was added. The reactor was then purged with hydrogen gas and connected to a hydrogen-filled balloon. The reaction was allowed to proceed overnight at room temperature. The next day, the solids were completely dissolved. TLC detection indicated that the reaction was complete. The wet palladium-carbon catalyst was removed and recovered by filtration using diatomaceous earth. The filtrate was concentrated and subjected to silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound 13-4 was purified using ESI-HRMS (50 / 1~10 / 1) to obtain 1.21 g of compound 13-4 as a white solid in 33.34% yield. ESI-HRMS m / z: 289.1269 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.90 (s, 1H), 7.13-7.06 (m, 2H), 6.86 (dd, J = 7.6, 1.5 Hz, 1H), 5.19 (s, 2H), 5.11 (dd, J = 12.7, 5.1 Hz, 1H), 4.18 (d, J = 16.2 Hz, 1H), 3.97 (d, J = 16.2 Hz, 1H), 2.83 (ddd, J = 17.1, 13.8, 5.3 Hz, 1H), 2.58-2.53 (m, 1H), 2.47 (s, 3H), 2.45-2.37 (m, 1H), 2.05 (dtd, J = 12.8, 5.2, 2.6 Hz, 1H).

[0134] Synthesis of [13-5]tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (compound <13-5>) 1.00 g (4.37 mmol) of methyl 4-bromomethylbenzoate was dissolved in 20 mL of ethyl acetate. 1.21 g (8.74 mmol) of potassium carbonate and 0.81 g (4.37 mmol) of 1-tert-butyloxycarbonylpiperazine were added, and the mixture was heated to 60°C and reacted for 1 hour. TLC detection indicated completion of the reaction, and a large amount of white solid was produced. The solid was removed by filtration, and the filtrate was concentrated to obtain a colorless oily liquid, which was compound 13-5 and could be used directly in the next step without further purification. ESI-HRMS m / z: 335.1965 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 7.97-7.91 (m, 2H), 7.50-7.43 (m, 2H), 3.86 (s, 3H), 3.55 (s, 2H), 3.37-3.29 (m, 4H), 2.32 (t, J = 5.1 Hz, 4H), 1.40 (s, 9H).

[0135] Synthesis of [13-6]tert-butyl 4-(4-(hydroxymethyl)benzyl)piperazine-1-carboxylate (compound <13-6>) Compound 13-5 (4.37 mmol) obtained in the previous step was added to a 100 mL three-necked flask, and 20 mL of anhydrous tetrahydrofuran was added to dissolve it in compound 13-5. The flask was purged with nitrogen, and a nitrogen-filled balloon was connected. The reaction flask was pre-cooled to -78°C, and then 10.9 mL of DIBAL-H (10.91 mmol, 1 M in THF) was slowly added. After the addition was complete, the reaction was carried out at -78°C. After 6 hours, TLC detection indicated that the reaction was complete. The reaction was quenched by carefully adding H2O. The reaction solution released heat and solidified into a gel. The reaction flask was brought to room temperature, and sufficient saturated potassium sodium tartrate solution was added until the gel dissolved, and then the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 13-6 as a colorless oily liquid, which could be used directly in the next reaction. ESI-MS m / z: 307.20 [M+H]+ ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 7.27 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.14 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 4.2 Hz, 2H), 3.30 (t, J = 5.1 Hz, 4H), 2.29 (t, J = 5.1 Hz, 4H), 1.39 (s, 9H).

[0136] Synthesis of [13-7] tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (compound <13-7>) The oily compound 13-6 (4.37 mmol) obtained in the previous step was dissolved in 20 mL of dichloromethane, and 3.81 g (43.70 mmol) of activated manganese dioxide powder was added. The mixture was heated under reflux for 2 hours with stirring. TLC detection indicated that the reaction was complete. Solid manganese dioxide was removed by filtration using diatomaceous earth. The filtrate was concentrated and subjected to silica gel column chromatography (eluent: V 石油エーテル / V 酢酸エチル Separation was performed using ESI-HRMS (=10 / 1) to obtain 300 mg of compound 13-7 as a colorless oily liquid. In this case, the overall yield of the three-step reaction was 22.56%. ESI-HRMS m / z: 305.1861 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 9.99 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 3.58 (s, 2H).3.35-3.28 (m, 4H), 2.32 (t, J = 5.0 Hz, 4H), 1.39 (s, 9H).

[0137] Synthesis of [13-8] tert-butyl 4-(4-(((2-(2,6-dioxopiperidine-3-yl)-3-methyl-1-oxo-1,2,3,4-tetrahydrophthalazine-5-yl)amino)methyl)benzyl)piperazine-1-carboxylate (compound I-5) Compound 13-4 (181.63 mg, 0.63 mmol) and compound 13-7 (287.5 mg, 0.95 mmol) were weighed and placed in a 100 mL round-bottom flask. 10 mL of anhydrous methanol was added, and the mixture was stirred until some of the solids dissolved. 0.5 mL of glacial acetic acid was added dropwise as a catalyst, and the mixture was heated to 50°C and reacted overnight. The next day, the solids in the reaction flask were completely dissolved. Heating was stopped, and the mixture was cooled to room temperature. Then, 79.18 mg (1.26 mmol) of sodium borohydride cyanohydride was added. After stirring the mixture for 8 hours, TLC detection indicated that the reaction was complete. The reaction solution was concentrated, and 20 mL of saturated sodium bicarbonate solution was added to the residue. Foam was released, and solids were formed. The mixture was then extracted with dichloromethane (3 × 10 mL). The organic layers were combined and dehydrated with anhydrous sodium sulfate. After filtration, the filtrate was concentrated and analyzed by silica gel column chromatography (elution: V ジクロロメタン / V メタノール Separation was performed using ESI-HRMS (50 / 1~10 / 1) to obtain 70 mg of compound I-5 as a white solid in 19.30% yield. ESI-HRMS m / z: 577.3134 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.91 (s, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 8.1 Hz, 3H), 7.15-7.08 (m, 2H), 6.69 (dd, J = 7.5, 1.9 Hz, 1H), 6.04 (t, J = 5.9 Hz, 1H), 5.13 (dd, J = 12.8, 5.3 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H), 4.30 (d, J = 16.3 Hz, 1H), 4.12 (d, J = 16.3 Hz, 1H), 3.44 (s, 2H), 3.30 (s, 4H), 2.91-2.79 (m, 1H), 2.61 (s, 1H), 2.47-2.42 (m, 1H), 2.30 (s, 5H), 2.12-2.04 (m, 1H), 1.40 (d, J = 1.6 Hz, 9H). 13C-NMR (151 MHz, DMSO-d6) δppm: 173.34, 171.65, 163.58, 154.25, 145.39, 139.06, 133.65, 129.44, 128.18, 128.04, 127.52, 127.29, 126.83, 121.10, 114.99, 114.72, 79.22, 63.19, 62.14, 58.01, 55.38, 52.78, 51.40, 46.67, 44.34, 31.39, 28.52 (3C), 28.40, 22.62.

[0138] Example 14: Synthesis of 3-(3-methyl-5-((4-(morpholinomethyl)benzyl)amino)-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-1) The synthesis method was as described in Example 13. Product I-1 was a white solid (130 mg, yield 33.10%). ESI-HRMS m / z: 478.2449 [M+H] + ; 1H-NMR (600 MHz, DMSO-d6) δppm: 10.92 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.13-7.07 (m, 2H), 6.67 (dd, J = 7.9, 1.5 Hz, 1H), 6.04 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 13.0, 5.0 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 4.28 (d, J = 16.2 Hz, 1H), 4.10 (d, J = 16.2 Hz, 1H), 3.55 (t, J = 4.6 Hz, 4H), 3.41 (s, 2H), 2.84 (ddd, J = 17.1, 13.8, 5.4 Hz, 1H), 2.57 (dd, J = 16.9, 3.7 Hz, 1H), 2.49 (s, 3H), 2.43 (dd, J = 13.3, 4.4 Hz, 1H), 2.32 (s, 4H), 2.07 (dtd, J = 12.7, 5.2, 2.6 Hz, 1H). 13 C-NMR (151 MHz, DMSO-d6) δppm: 173.35, 171.66, 163.59, 145.38, 139.00, 136.62, 129.42 (2C), 128.18, 128.04, 127.26 (2C), 121.10, 114.99, 114.73, 66.64, 62.66, 58.01, 55.38, 53.63 (2C), 51.40, 46.68, 44.34, 31.39, 22.62.

[0139] Example 15: Synthesis of 3-(3-methyl-1-oxo-5-((4-((4-phenylpiperazine-1-yl)methyl)benzyl)amino)-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (Compound I-3) The synthesis method was as described in Example 13. Product I-3 was a white solid (90 mg, yield 40.65%). ESI-HRMS m / z: 553.2922 [M+H] + ; 1H-NMR (600 MHz, DMSO-d6) δppm: 10.92 (s, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 8.7, 7.2 Hz, 2H). 7.14-7.08 (m, 2H), 6.92-6.88 (m, 2H), 6.78-6.74 (m, 1H), 6.68 (dd, J = 8.0, 1.4 Hz, 1H), 6.05 (t, J = 6.0 Hz, 1H), 5.13 (dd, J = 12.7, 5.0 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H), 4.29 (d, J = 16.3 Hz, 1H), 4.14-4.09 (m, 1H), 3.48 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.11 (t, J = 5.0 Hz, 4H), 2.84 (ddd, J = 17.0, 13.7, 5.3 Hz, 1H), 2.57 (dd, J = 16.7, 3.5 Hz, 1H), 2.53-2.52 (m, 1H), 2.47 (s, 3H), 2.46-2.39 (m, 1H), 2.07 (dqd, J = 12.6, 5.0, 2.7 Hz, 1H), 1.24 (s, 2H). 13 C-NMR (151 MHz, DMSO-d6) δppm: 173.35, 171.66, 163.59, 151.49, 145.40, 139.01, 136.89, 129.44, 129.36 (2C), 128.19, 128.06, 127.30 (2C), 126.85, 121.11, 119.23, 115.83 (2C), 114.99, 114.74, 62.27, 58.02, 53.01 (2C), 51.41, 48.64 (2C), 46.70, 44.35, 31.39, 22.62, 22.57.

[0140] Example 16: Synthesis of 3-(5-((4-(4-(4-Fluorophenyl)piperazin-1-yl)methyl)benzyl)amino)-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (Compound I-6) [ka] Synthesis of [16-1]methyl(E)-2-((2-benzylidene-1-methylhydrazineyl)methyl)-3-nitrobenzoate (compound <16-1>) 10.50 g (72.84 mmol) of methylhydrazine sulfate and 11.60 g (109.26 mmol) of anhydrous sodium carbonate were weighed and suspended in 200 mL of methanol. The mixture was stirred and heated to 60°C. After 1 hour, 7.29 mL (72.84 mmol) of benzaldehyde and 20.00 g (72.84 mmol) of methyl 2-bromomethyl-3-nitrobenzoate were added to the reaction system, and the mixture was stirred at 60°C for a further 3 hours. After TLC detection indicated that the reaction of methyl 2-bromomethyl-3-nitrobenzoate was complete, solid matter was removed by filtration. The filtrate was concentrated and subjected to silica gel column chromatography (eluent: V 石油エーテル / V 酢酸エチル The compound 16-1 was purified by (15 / 1) to obtain 17.0 g of compound 16-1 as an orange-yellow solid in 71.1% yield. ESI-MS m / z: 328.12 [M+H] + .

[0141] Synthesis of [16-2]3-methyl-5-nitro-3,4-dihydrophthalazine-1(2H)-one (compound <16-2>): Weigh 17.0 g (52.00 mmol) of compound 16-1 and add it to the mixed solvent (V n-ブタノール / V 氷酢酸Compound 16-1 was added to 50 mL of solution and stirred until completely dissolved. 354 mg (2.60 mmol) of anhydrous zinc chloride was added. The mixture was heated to 120°C and reacted for 6 hours. Heating and stirring were stopped, and the mixture was left overnight. A yellow solid precipitated, which was filtered. The obtained solid was washed with petroleum ether and dried to obtain compound 16-2 (5.90 g, yield 54.8%). ESI-HRMS m / z: 206.0560 [M+H] + .

[0142] [16-3] Synthesis of 3-(3-methyl-5-nitro-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound <16-3>) Compound 16-2 was weighed at 5.00 g (24.14 mmol) and dissolved in 50 mL of anhydrous tetrahydrofuran under nitrogen protection. The mixture was stirred in an ice bath and 36 mL (36.00 mmol, 1 N in THF) of LiHMDS was added. After the addition was complete, the mixture was stirred in an ice bath for 30 minutes. Next, 6.95 g (36.22 mmol) of 3-bromopiperidine-2,6-dione dissolved in 20 mL of anhydrous tetrahydrofuran was added. The mixture was allowed to warm naturally to room temperature and reacted for 3 hours. After TLC detection indicated that the reaction had stopped, the reaction was quenched by adding saturated ammonium chloride solution. After layer separation, the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound 16-3 was purified by (=50 / 1) to obtain 4.01 g as a white to pale yellow solid in a yield of 52.10%. ESI-HRMS m / z: 318.3001 [M]+. 1H-NMR (600 MHz, DMSO-d6) δppm: 11.00 (s, 1H), 8.36 (dd, J = 8.2, 1.3 Hz, 1H), 8.26 (dd, J = 7.7, 1.3 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 5.20 (dd, J = 12.8, 5.1 Hz, 1H), 4.68 (d, J = 17.2 Hz, 1H), 4.51 (d, J = 18.5 Hz, 1H), 2.86 (ddd, J = 17.2, 13.8, 5.4 Hz, 1H), 2.60 (t, J = 4.0 Hz, 1H), 2.57 (d, J = 3.7 Hz, 2H), 2.45 (d, J = 10.2 Hz, 1H), 2.43-2.38 (m, 1H), 2.12 (ddq, J = 10.5, 5.3, 2.6 Hz, 1H).

[0143] [16-4] Synthesis of 3-(5-amino-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound <16-4>) Compound 16-3 was weighed at 4.00 g (12.58 mmol) and added to 40 mL of methanol, and stirred until some of the solids dissolved. Approximately 133.86 mg (1.26 mmol) of 5% Pd-C was added. The reactor was then purged with hydrogen gas and connected to a hydrogen-filled balloon. The reaction was allowed to proceed overnight at room temperature. The next day, the solids were completely dissolved. TLC detection indicated that the reaction was complete. The wet palladium-carbon catalyst was removed and recovered by filtration using diatomaceous earth. The filtrate was concentrated and subjected to silica gel column chromatography (eluent: V ジクロロメタン / V メタノール The compound 16-4 was purified using ESI-HRMS (50 / 1~10 / 1) to obtain 1.21 g of compound 16-4 as a white solid in 33.34% yield. ESI-HRMS m / z: 289.1269 [M+H] + ; 1H-NMR (600 MHz, DMSO-d6) δppm: 10.90 (s, 1H), 7.13-7.06 (m, 2H), 6.86 (dd, J = 7.6, 1.5 Hz, 1H), 5.19 (s, 2H), 5.11 (dd, J = 12.7, 5.1 Hz, 1H), 4.18 (d, J = 16.2 Hz, 1H), 3.97 (d, J = 16.2 Hz, 1H), 2.83 (ddd, J = 17.1, 13.8, 5.3 Hz, 1H), 2.58-2.53 (m, 1H), 2.47 (s, 3H), 2.45-2.37 (m, 1H), 2.05 (dtd, J = 12.8, 5.2, 2.6 Hz, 1H).

[0144] Synthesis of [16-5]tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (compound <16-5>) 2.00 g (11.43 mmol) of p-bromofluorobenzene, 3.14 g (13.71 mmol) of 1-tert-butyloxycarbonylpiperazine, 30.52 g (0.57 mmol) of Pd2 (dba), and 0.82 g (1.72 mmol) of X-Phos were weighed and placed in a three-necked flask under nitrogen protection. 20 mL of anhydrous dioxane and NaO were added. t 17.2 mL of Bu (1N in THF) was added, and the mixture was heated to 80°C and reacted for 2 hours. TLC detection indicated that the reaction was complete. Heating was stopped, and the mixture was filtered through diatomaceous earth. The filtrate was washed with water. After layer separation, the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: V 石油エーテル / V 酢酸エチル Separation was performed using ESI-MS (=20 / 1) to obtain 2.8 g of intermediate 16-5 as a yellow oily liquid in 87.50% yield. ESI-MS m / z: 281.17 [M+H] + ; 1H-NMR (600 MHz, DMSO-d6) δppm: 7.05 (dd, J = 9.8, 7.9 Hz, 2H), 6.98-6.92 (m, 2H), 3.46 (t, J = 5.1 Hz, 4H), 3.05-2.98 (m, 4H), 1.42 (s, 9H).

[0145] [16-6] Synthesis of 1-(4-fluorophenyl)piperazine (compound <16-6>) 2.80 g (9.99 mmol) of compound 16-5 was weighed and dissolved in 10 mL of dichloromethane. 10 mL of trifluoroacetic acid was added, and the mixture was stirred and allowed to react at room temperature for 1 hour. TLC detection indicated completion of the reaction. The reaction solution was evaporated to dryness, the residue was washed with saturated sodium bicarbonate, and extracted with dichloromethane (2 × 10 mL). The organic layers were combined and dehydrated with anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to obtain 1.93 g of crude product 16-6 in yield 107.34%. This crude product 16-6 was used directly in the next reaction without purification. ESI-MS m / z: 181.12 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 7.06-7.01 (m, 2H), 6.94-6.89 (m, 2H), 2.98 (s, 1H), 2.97 (d, J = 5.2 Hz, 4H), 2.84 (dd, J = 6.2, 3.8 Hz, 4H).

[0146] [16-7] Synthesis of 3-(5-((4-(4-(4-(4-fluorophenyl)piperazine-1-yl)methyl)benzyl)amino)-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-6) The process for synthesizing compound I-6 from intermediate 16-6 was the same as the process for synthesizing I-5 from the starting material 1-tert-butyloxycarbonylpiperazine in Example 13. Product I-6 was a white solid (110 mg, yield 30.21%). ESI-HRMS m / z: 571.2827 [M+H] + ;1 H-NMR (600 MHz, CDCl3)δppm: 8.18 (s, 1H), 7.47 (dd, J = 7.8, 1.1 Hz, 1H), 7.36 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.9 Hz, 1H), 6.98-6.93 (m, 2H), 6.89-6.84 (m, 3H), 5.23 (dd, J = 12.4, 5.0 Hz, 1H), 4.35 (s, 3H), 3.91-3.82 (m, 1H), 3.60 (s, 2H), 3.14 (t, J = 4.9 Hz, 4H), 2.90-2.82 (m, 1H), 2.71 (ddd, J = 17.2, 13.6, 5.1 Hz, 2H), 2.63 (d, J = 16.8 Hz, 8H), 2.20 (dtd, J = 12.9, 4.9, 2.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO-d6) δppm: 173.35, 171.66, 163.59, 157.21-155.65, 148.40, 145.40, 139.00, 136.88, 129.44 (2C), 128.19, 128.06, 127.30 (2C), 121.11, 117.57, 117.52, 115.76, 115.62, 115.00, 114.74, 62.22, 58.01, 52.99 (2C), 51.40, 49.43 (2C), 46.70, 44.34, 31.39, 22.62.

[0147] Example 17: Synthesis of 3-(5-((4-(4-(4-cyanophenyl)piperazine-1-yl)methyl)benzyl)amino)-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (compound I-7) The synthesis method was the same as in Example 16, except that p-bromofluorobenzene in [16-5] was replaced with 4-bromobenzonitrile. The resulting product I-7 was a white solid (80 mg, yield 26.09%). ESI-HRMS m / z: 578.2874 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6) δppm: 10.94 (s, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H). 7.29 (d, J = 7.9 Hz, 2H), 7.16-7.08 (m, 2H), 7.04-6.96 (m, 2H), 6.70 (dd, J = 7.0, 2.4 Hz, 1H), 6.07 (t, J = 6.0 Hz, 1H), 5.15 (dd, J = 12.6, 5.1 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.31 (d, J = 16.2 Hz, 1H), 4.13 (d, J = 16.4 Hz, 1H), 3.51 (s, 2H), 3.32 (s, 4H), 2.91-2.79 (m, 1H), 2.61 (t, J = 13 C-NMR (151 MHz, DMSO-d6) δppm: 173.34, 171.66, 163.60, 153.59, 151.35, 149.70, 145.40, 133.77, 129.63, 129.38, 128.20, 128.05, 127.55, 127.34, 121.13, 120.54, 119.34, 116.40, 115.88, 115.01, 114.73, 114.51, 58.02, 55.38, 51.43, 46.70, 44.34, 40.42, 40.28, 40.14, 40.00, 39.86, 39.72, 39.58, 34.19, 31.40, 29.50, 24.99, 22.63, 14.43.

[0148] Example 18: Synthesis of 3-(5-((4-(4-(3-fluoro-4-cyanophenyl)piperazine-1-yl)methyl)benzyl)amino)-3-methyl-1-oxo-3,4-dihydrophthalazine-2(1H)-yl)piperidine-2,6-dione (Compound I-8) The synthesis method was the same as in Example 16, except that p-bromofluorobenzene in [16-5] was replaced with 2-fluoro-4-bromobenzonitrile. The resulting product I-8 was a white solid (130 mg, yield 32.55%). ESI-HRMS m / z: 596.2780 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δppm: 10.92 (s, 1H), 7.58 (t, J = 8.5 Hz, 1H), 7.32 (d, J = 7.9 Hz). Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 7.14-7.08 (m, 2H), 6.92 (dd, J = 14.2, 2.4 Hz, 1H), 6.83 (dd, J = 9.0, 2.4 Hz, 1H), 6.68 (dd, J = 7.7, 1.6 Hz, 1H), 6.05 (t, J = 6.0 Hz, 1H), 5.13 (dd, J = 12.7, 5.1 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H), 4.29 (d, J = 16.2 Hz, 1H), 4.11 (d, J = 16.3 Hz, 1H), 3.48 (s, 2H), 3.36 (t, J = 5.0 Hz, 4H), 2.84 (ddd, J = 17.0, 13.8, 5.3 Hz, 1H), 2.57 (dt, J = 17.1, 3.7 Hz, 1H), 2.44 (t, J = 5.4 Hz, 5H), 2.07 (dtd, J = 12.8, 5.2, 2.6 Hz, 1H). 13C-NMR (151 MHz, DMSO-d6) δppm: 173.35, 171.66, 165.53-163.88, 163.59, 155.67, 155.60, 145.38, 139.12, 134.42, 134.40, 129.46, 128.19, 128.04, 127.32, 121.11, 115.89, 115.00, 114.74, 110.54, 100.69, 100.53, 86.48, 86.38, 61.99, 58.02, 55.38, 52.42, 51.40, 46.72, 46.69, 44.35, 31.39, 22.62.

[0149] Example 19: Evaluation of the activity of a compound on the proliferation of hematological tumor cells The cell model used in this example was human hematological tumor cells, which included NCI-H929, RPMI-8226, MV-4-11, U937, and WSU-DLCL-2. Several compounds of the present invention were selected, and their inhibitory activity against the proliferation of each of the NCI-H929, RPMI-8226, MV-4-11, U937, and WSU-DLCL-2 cells was determined.

[0150] 1. Experimental materials and equipment 1.1 Experimental materials and equipment [Table 2]

[0151] 2. Experimental Procedure (1) Preparation of the solution 1) Selected compounds were dissolved in DMSO to prepare a 10 mM stock solution. Compounds to be used within 3 months needed to be stored in a desiccator at room temperature; others could be stored at -20°C for long-term storage. 2) The stock solution and the positive reference compound, pomalidomide, were diluted with DMSO. The initial concentration was 10 μM. In experiments with NCI-H929 cells and RPMI-8226 cells, a 3-fold serial dilution was performed at 11 concentration points, starting with a minimum concentration of 0.00047 μM. The resulting solutions were shaken in a shaker for 5 minutes.

[0152] (2) Drug application to cells 1) NCI-H929, RPMI-8226, MV-4-11, U937, and WSU-DLCL-2 cells in the logarithmic growth phase were inoculated into 96-well plates at a rate of 20,000 to 30,000 cells per well, and the plates were pre-cultured in an incubator (at 37°C and 5% CO2) for 24 hours. 2) The culture medium in the plate was replaced, and the corresponding concentration of the compound and the positive control were added to the plate in 50 μl volumes. 3) The plates were incubated in an incubator for 144 hours, then 15 μl of CCK-8 solution was added to each well, and the plates were incubated in the incubator for a further 1–4 hours. 4) The absorbance at 450 nm was measured using a microplate reader.

[0153] (3) Data processing 1) Calculation of % inhibition: %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100. 2) IC of compounds 50 Calculation of values ​​and plotting of dose-response curves: I C 50 The values ​​were calculated by fitting the logarithm of the % inhibition and compound concentration to a nonlinear regression (dose-response - variable gradient) using GraPhPad 6.0. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) X: Logarithm of inhibitor concentration; Y: % inhibition.

[0154] 3. Experimental Results After calculating the % inhibition, the dose-response curve was plotted with the logarithm of the test compound concentration on the x-axis and the mean cell viability on the y-axis, and IC was calculated. 50 The values ​​were obtained through fitting. Table 1 shows the test results for the aforementioned compounds and the positive reference compound pomalidomide against NCI-H929, RPMI-8226, MV-4-11, U937, and WSU-DLCL-2 cells. The experimental results indicate that all compounds, including pomalidomide, exhibited good inhibitory effects on the proliferation of NCI-H929, RPMI-8226, MV-4-11, U937, and WSU-DLCL-2 cells. In particular, compounds I-5, I-6, I-7, and I-8 showed significantly better inhibitory effects on these cells than the control drug pomalidomide. [Table 3]

[0155] Example 20: In vivo activity of compounds against human multiple myeloma RPMI-8226 transplanted tumors In this example, the human multiple myeloma (RPMI-8226) cell line was used as a cell model. The inhibitory effect of the compound on tumor growth in NOD / SCID mice transplanted with RPMI-8226 tumor cells was determined. The evaluation method and results are described below.

[0156] 1. Experimental materials and equipment 1.1 Experimental consumables for biological activity evaluation [Table 4]

[0157] 2. Establishment of a tumor model Human multiple myeloma (RPMI-8226) cells were routinely cultured in RPMI1640 containing 10% fetal bovine serum in a 5% CO2 incubator at 37°C. After three passages in vitro, the cells were digested and harvested once they reached over 80% confluence and the required confluence rate. After washing with PBS, the cells were counted, and the cell concentration was adjusted to approximately 5 × 10⁶. 7 The cells were adjusted to 1 / mL. Then, the cells were placed in a 4 mL centrifuge tube on ice for later use. Female NOD / SCID mice aged 4-5 weeks were selected and RPMI-8226 cells were ectopically inoculated subcutaneously. The mice were held in a lateral position, the forelimb axillae were disinfected with 75% alcohol, and 100 μL of cell suspension was subcutaneously injected into the axilla using a 1 mL syringe (1.5 × 10⁻¹⁴). 7 (Individual cells / mouse / 100 μL).

[0158] 3. Grouping and administration of animals The tumor is 90-150 mm in size. 3 Once they had grown to a certain size, the animals were randomly divided into groups of 8 and administered according to the following different administration methods: Model control group: The same amount of the medium (DMSO:0.5% sodium carboxymethylcellulose:distilled water = 1:1:8) was administered daily by force-feeding. Test group: Compound I-4 solution and compound I-8 solution were administered daily by force-feeding at a dose of 10 mg / kg (mouse body weight); Positive control group: Pomalidomide solution was administered daily by force-feeding at a dose of 10 mg / kg (mouse body weight). The administration route was oral forced feeding, administered once daily for 12 consecutive days. The first day of administration was defined as day 1 of the experiment. Changes in the tumor volume of mice were measured and recorded every two days. Tumor volume was measured using calipers, specifically measuring the longest diameter (a) and shortest diameter (b) of the tumor, and the tumor volume was calculated as: Tumor Volume V (mm²). 3The tumor weight was calculated using the formula a × b^2 / 2. After the experiment, the mice were dissected and the tumor weight was measured. The data was entered using GraPhPad Prism 6 software and statistically analyzed. The data was expressed as mean ± SEM (standard error of the mean), and one-way ANOVA was used. P ≤ 0.05 was considered statistically significant.

[0159] 4. Experimental Results As shown in Figures 1A and 1B and Table 2, Figure 1A shows the changes in mouse tumor volume on days 0, 2, 4, 6, 8, 10, and 12, and Figure B shows the tumors excised from each group after the experiment. The experimental results show that compounds I-4 and I-8 (10 mg / kg, QD) significantly inhibit the growth of RPMI-8226-grafted tumors. At the same dose, I-4 and I-8 show better inhibitory effects on tumor growth than the positive control drug pomalidomide. As shown in Figure 1C, no significant changes in mouse body weight occurred in any group during the experiment, and no obvious toxic side effects were observed. [Table 5]

[0160] Example 21: In vivo antitumor activity of a compound against human multiple myeloma NCI-H929 transplanted tumors. In this example, the human multiple myeloma NCI-H929 cell line was used as a cell model. The inhibitory effect of the compound on tumor growth in NOD / SCID mice transplanted from NCI-H929 tumor cells was determined. The evaluation method and results are described below.

[0161] 1. Experimental materials and equipment 1.1 Experimental consumables for biological activity evaluation [Table 6]

[0162] 2. Establishment of a tumor model Human multiple myeloma (NCI-H929) cells were routinely cultured in RPMI1640 containing 10% fetal bovine serum in a 5% CO2 incubator at 37°C. After three passages in vitro, the cells were digested and harvested once they reached over 80% confluence and the required confluence rate. After washing with PBS, the cells were counted, and the cell concentration was adjusted to approximately 5 × 10⁶. 7 The cells were adjusted to 1 / mL. Then, the cells were placed in a 4 mL centrifuge tube on ice for later use. Female NOD / SCID mice aged 4-5 weeks were selected and ectopically subcutaneously inoculated with NCI-H929 cells. The mice were held in a lateral position, the forelimb axillae were disinfected with 75% alcohol, and 100 μL of cell suspension was subcutaneously injected into the axilla using a 1 mL syringe (1.5 × 10⁻¹⁴). 7 (Individual cells / mouse / 100 μL).

[0163] 3. Grouping and administration of animals The tumor is 90-150 mm in size. 3 After growing to maturity, the animals were randomly divided into groups of 8 and administered according to the following different administration methods: Model control group: The same amount of the medium (DMSO:0.5% sodium carboxymethylcellulose:distilled water = 1:1:8) was administered daily by force-feeding; Control group 1: Pomalidomide solution was administered daily at a dose of 10 mg / kg (mouse body weight) via force-feeding; Control group 2: CC-220 solution was administered daily at a dose of 3 mg / kg (mouse body weight) via force-feeding; Control group 3: CC-220 solution was administered daily at a dose of 10 mg / kg (mouse body weight) via force-feeding; Experimental compound group 4: Compound I-4 solution was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Experimental compound group 5: Compounds I-4 were administered daily by force-feeding at a dose of 10 mg / kg (mouse body weight); Experimental compound group 6: Compounds I-8 were administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Experimental compound group 7: Compounds I-8 were administered daily by force-feeding at a dose of 10 mg / kg (mouse body weight). The administration route was oral forced feeding, administered once daily for 10 consecutive days. The first day of administration was defined as day 1 of the experiment. Changes in the tumor volume of mice were measured and recorded every two days. Tumor volume was measured using calipers, specifically measuring the longest diameter (a) and shortest diameter (b) of the tumor, and the tumor volume was expressed as tumor volume V (mm²). 3 The tumor weight was calculated using the formula a × b^2 / 2. After the experiment, the mice were dissected and the tumor weight was measured. The data was entered using GraPhPad Prism 6 software and statistically analyzed. The data was expressed as mean ± SEM (standard error of the mean), and one-way ANOVA was used. P ≤ 0.05 was considered statistically significant.

[0164] 4. Experimental Results As shown in Figure 2A and Table 3, the experimental results indicate that compounds I-4 and I-8 (3 mg / kg and 10 mg / kg, QD) significantly inhibited the growth of NCI-H929 transplanted tumors. At the same dose, I-4 and I-8 (10 mg / kg, QD) showed significantly better inhibitory effects on tumor growth than the control drug pomalidomide (Pom, 10 mg / kg, QD). At the same dose, I-8 (3 mg / kg, QD) was more effective than the control drug CC-220 (3 mg / kg, QD). As shown in Figure 2B, during the experiment, the CC-220 (10 mg / kg, QD) group showed a tendency toward weight loss, while the other groups did not show a significant tendency toward weight loss, and no obvious toxic side effects were observed. [Table 7]

[0165] Example 22: In vivo activity of compounds combined with dexamethasone against human multiple myeloma NCI-H929 transplanted tumors. In this example, the human multiple myeloma NCI-H929 cell line was selected as a cell model, and the inhibitory effects of the compound alone, dexamethasone alone, and combinations thereof on tumor growth in NOD / SCID mice transplanted from NCI-H929 tumor cells were determined. The evaluation methods and results are described below.

[0166] 1. Experimental materials and equipment 1.1 Experimental consumables for biological activity evaluation [Table 8]

[0167] 2. Establishment of a tumor model Human multiple myeloma (NCI-H929) cells were routinely cultured in RPMI1640 containing 10% fetal bovine serum in a 5% CO2 incubator at 37°C. After three passages in vitro, the cells were digested and harvested once they reached over 80% confluence and the required confluence rate. After washing with PBS, the cells were counted, and the cell concentration was adjusted to approximately 5 × 10⁶. 7 The cells were adjusted to 1 / mL. Then, the cells were placed in a 4 mL centrifuge tube on ice for later use. Female NOD / SCID mice aged 4-5 weeks were selected and ectopically subcutaneously inoculated with NCI-H929 cells. The mice were held in a lateral position, the forelimb axillae were disinfected with 75% alcohol, and 100 μL of cell suspension was subcutaneously injected into the axilla using a 1 mL syringe (1.5 × 10⁻¹⁴). 7 (Individual cells / mouse / 100 μL).

[0168] 3. Grouping and administration of animals The tumor is 90-150 mm in size. 3 After growing to maturity, the animals were randomly divided into groups of 8 and administered according to the following different administration methods: Model control group: The same amount of the medium (DMSO:0.5% sodium carboxymethylcellulose:distilled water = 1:1:8) was administered daily by force-feeding; Test group 1: Dexamethasone (Dex) solution was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Test group 2: The I-4 solution was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Test group 3: I-8 solution was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Test group 4: Dexamethasone was administered daily at 3 mg / kg (mouse body weight) and I-4 solution at 3 mg / kg (mouse body weight) via force-feeding; Test group 5: Dexamethasone was administered daily at a dose of 3 mg / kg (mouse body weight) and I-8 solution at a dose of 3 mg / kg (mouse body weight) via force-feeding. The administration route was oral forced feeding, administered once daily for 10 consecutive days. The first day of administration was defined as day 1 of the experiment. Changes in the tumor volume of mice were measured and recorded every two days. Tumor volume was measured using calipers, specifically measuring the longest diameter (a) and shortest diameter (b) of the tumor, and the tumor volume was defined as tumor volume V (mm²). 3 The tumor weight was calculated using the formula a × b^2 / 2. After the experiment, the mice were dissected and the tumor weight was measured. The data was entered using GraPhPad Prism 6 software and statistically analyzed. The data was expressed as mean ± SEM (standard error of the mean), and one-way ANOVA was used. P ≤ 0.05 was considered statistically significant.

[0169] 4. Experimental Results As shown in Figure 3, Table 4-1, and Table 4-2, the experimental results indicate that compounds I-4 and I-8 (3 mg / kg, QD) alone effectively inhibit the growth of NCI-H929 transplanted tumors, while dexamethasone (3 mg / kg, QD) exhibits weaker tumor inhibitory activity. The combination of I-4 (3 mg / kg, QD) and dexamethasone (3 mg / kg, QD) significantly inhibits the growth of NCI-H929 transplanted tumors. Simultaneously, the inhibitory effects of I-4 (3 mg / kg, QD) and I-8 (3 mg / kg, QD) in combination with dexamethasone (3 mg / kg, QD) are significantly superior to those of monotherapy, demonstrating a significant synergistic effect. [Table 9] [Table 10]

[0170] Example 23: In vivo activity of compound combination therapy for human multiple myeloma NCI-H929 transplanted tumors In this example, the human multiple myeloma NCI-H929 cell line was selected as a cell model, and the inhibitory effects of the compounds bortezomib (Bort) and tazemetostat (Taze), both as monotherapy and in combination, on tumor growth in NOD / SCID mice transplanted from NCI-H929 tumor cells were determined. The evaluation methods and results are described below.

[0171] 1. Experimental materials and equipment 1.1 Experimental consumables for biological activity evaluation [Table 11]

[0172] 2. Establishment of a tumor model Human multiple myeloma (NCI-H929) cells were routinely cultured in RPMI1640 containing 10% fetal bovine serum in a 5% CO2 incubator at 37°C. After three passages in vitro, the cells were digested and harvested once they reached over 80% confluence and the required confluence rate. After washing with PBS, the cells were counted, and the cell concentration was adjusted to approximately 5 × 10⁶. 7 The cells were adjusted to 1 / mL. Then, the cells were placed in a 4 mL centrifuge tube on ice for later use. Female NOD / SCID mice aged 4-5 weeks were selected and ectopically subcutaneously inoculated with NCI-H929 cells. The mice were held in a lateral position, the forelimb axillae were disinfected with 75% alcohol, and 100 μL of cell suspension was subcutaneously injected into the axilla using a 1 mL syringe (1.5 × 10⁻¹⁴). 7 (Individual cells / mouse / 100 μL).

[0173] 3. Grouping and administration of animals The tumor is 90-150 mm in size. 3 After growing to maturity, the animals were randomly divided into groups of 8 and administered according to the following different administration methods: Model control group: The same amount of the medium (DMSO:0.5% sodium carboxymethylcellulose:distilled water = 1:1:8) was administered daily by force-feeding; Test group 1: I-8 solution was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight); Test group 2: Bortezomib (Bort) solution was administered twice a week by force-feeding at a dose of 1 mg / kg (mouse body weight); Test group 3: Tazemetostat solution was administered daily by force-feeding at a dose of 100 mg / kg (mouse body weight); Test group 4: I-8 was administered daily by force-feeding at 3 mg / kg (mouse body weight), and bortezomib (Bort) solution was administered twice a week by force-feeding at 1 mg / kg (mouse body weight); Test group 5: I-8 was administered daily by force-feeding at a dose of 3 mg / kg (mouse body weight), and tazemettostat (Taze) solution was administered daily by force-feeding at a dose of 100 mg / kg (mouse body weight). The administration route was oral forced feeding, administered once daily for 10 consecutive days. The first day of administration was defined as day 1 of the experiment. Changes in the tumor volume of mice were measured and recorded every two days. Tumor volume was measured using calipers, specifically measuring the longest diameter (a) and shortest diameter (b) of the tumor, and the tumor volume was defined as tumor volume V (mm²). 3 The tumor weight was calculated using the formula a × b^2 / 2. After the experiment, the mice were dissected and the tumor weight was measured. The data was entered using GraPhPad Prism 6 software and statistically analyzed. The data was expressed as mean ± SEM (standard error of the mean), and one-way ANOVA was used. P ≤ 0.05 was considered statistically significant.

[0174] 4. Experimental Results As shown in Figure 4, Table 5-1, and Table 5-2, Figure 4A shows the changes in tumor volume of mice on days 0, 2, 4, 6, 8, 10, and 12; Figure 4B shows the tumors dissected from each group after the experiment; and Figure 4C shows the mass of the tumors dissected from each group. The experimental results indicate that compound I-8 (3 mg / kg, QD) alone effectively inhibits the growth of NCI-H929 transplanted tumors, while bortezomib (Bort, 1 mg / kg, BIW) alone and tazemetostat (Taze, 100 mg / kg, QD) alone show weaker tumor inhibitory activity. The combination of I-8 (3 mg / kg, QD) and bortezomib (1 mg / kg, BIW) significantly induced regression of NCI-H929 transplanted tumors, and the combination of I-8 (3 mg / kg, QD) and tazemetostat (100 mg / kg, QD) significantly inhibited the growth of NCI-H929 transplanted tumors. Furthermore, the inhibitory effect of the combination therapy was significantly superior to that of monotherapy, demonstrating a significant synergistic effect. [Table 12] [Table 13]

[0175] Example 24: Evaluation of compound activity against lenalidomide resistance and pomalidomide resistance In this example, lenalidomide-resistant human multiple myeloma cells, including NCI-H929 (NCI-H929-lenalidomide-R) and RPMI-8226 (RPMI-8226-lenalidomide-R), and pomalidomide-resistant human multiple myeloma cells, including NCI-H929 (NCI-H929-pomalidomide-R) and RPMI-8226 (RPMI-8226-pomalidomide-R), were selected as cell models, and the inhibitory activity of compound I-8 of the present invention against the proliferation of resistant cells was determined.

[0176] 1. Experimental materials and equipment 1.1 Experimental materials and equipment [Table 14]

[0177] 2. Experimental Procedure (1) Preparation of the solution 1) A 10 mM stock solution was prepared by dissolving I-8 in DMSO. Compounds to be used within 3 months needed to be stored in a desiccator at room temperature; others could be stored at -20°C for long-term storage. 2) The I-8 stock solution and the reference compounds lenalidomide and pomalidomide were all diluted with DMSO. Their initial concentrations were 10 μM. In experiments with lenalidomide-resistant human multiple myeloma cells (NCI-H929 (NCI-H929-lenalidomide-R) and RPMI-8226 (RPMI-8226-lenalidomide-R)) and pomalidomide-resistant human multiple myeloma cells (NCI-H929 (NCI-H929-pomalidomide-R) and RPMI-8226 (RPMI-8226-pomalidomide-R)), a minimum concentration of 0.00047 μM was used, and 11 concentration points were used for 3-fold serial dilution. The resulting solutions were shaken in a shaker for 5 minutes.

[0178] (2) Drug application to cells 1) NCI-H929-lenalidomide-R, RPMI-8226-lenalidomide-R, NCI-H929-pomalidomide-R, and RPMI-8226-pomalidomide-R cells in the logarithmic growth phase were inoculated into 96-well plates at a rate of 20,000 to 30,000 cells per well, and the plates were pre-cultured in an incubator (at 37°C and 5% CO2) for 24 hours. 2) The culture medium in the plate was replaced, and the corresponding concentration of the compound and the positive control were added to the plate in 50 μl volumes. 3) The plates were incubated in an incubator for 144 hours, then 15 μl of CCK-8 solution was added to each well, and the plates were incubated in the incubator for a further 1–4 hours. 4) The absorbance at 450 nm was measured using a microplate reader.

[0179] (3) Data processing 1) Calculation of % inhibition: %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100. 2) IC of compounds 50 Calculation of values ​​and plotting of dose-response curves: I C 50 The values ​​were calculated by fitting the logarithm of the % inhibition and compound concentration to a nonlinear regression (dose-response - variable gradient) using GraPhPad 6.0. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) X: Logarithm of inhibitor concentration; Y: % inhibition.

[0180] 3. Experimental Results After calculating the % inhibition, the dose-response curve was plotted with the logarithm of the test compound concentration on the x-axis and the mean cell viability on the y-axis, and IC was calculated. 50 The values ​​were obtained through fitting. Table 6 shows the I-8 test results for cells treated with NCI-H929-lenalidomide-R, RPMI-8226-lenalidomide-R, NCI-H929-pomalidomide-R, and RPMI-8226-pomalidomide-R. The experimental results indicate that the IC (inducible conjugate) of pomalidomide and lenalidomide in these cells is... 50 The values ​​exceed 100 μM, indicating that I-8 has a good inhibitory effect on these cells. [Table 15]

[0181] The above description relates only to preferred embodiments of the present invention and is not intended to limit the invention. Those skilled in the art should note that various improvements and modifications can be made without departing from the technical principles of the present invention, and that these improvements and modifications should also be considered to be within the scope of the protection of the present invention.

Claims

1. Compounds represented by formula (I), or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates, or polymorphs thereof: 【Chemistry 1】 (In the formula, X １ is N or CH; n is 1 or 2; R １ However, H, C １～１０ Linear or branched alkyl and C ３～１０ Selected from the group consisting of cycloalkyl groups; S / D is either a single bond or a double bond, and if S / D is a double bond, R １ It does not exist; R ２ and R ３ are each independently selected from the group consisting of H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-alkyl, -CN, -NO ２ , -N ３ , -CH(Ph) ２ , perfluoro-C １ ~C ４ alkyl, perfluoro-C １ ~C ４ alkoxy, -NR ４ R ５ , -OR ４ , -COR ４ , -CO ２ R ４ , -CONR s ４ R ５ , -C(=NR ４ )NR ５ R ６ , -NR ４ COR ５ , -NR ４ CO ２ R ５ , -SO ２ R ４ , -NR ４ SO ２ NR ５ R ６ , and -NR ４ SO ２ R ５ ; and are each independently selected from the group consisting of R ４ , R ５ and R ６ Each of these is independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R ４ and R ５ ) and / or (R ５ and R ６ ) may each form a ring together with the atoms to which they are linked, and the ring is optionally selected from the group consisting of substituted or unsubstituted cycloalkyls, saturated or unsaturated heterocyclyls, aryls, and heterocyclylaryls).

2. The following features: (a) X １ The condition is that CH and n is 2; (b) R １ However, H and C １～６ Linear or branched alkyl groups, preferably H and C １～４ Linear or branched alkyl groups, preferably C １～４ Linear or branched alkyl groups, preferably CH ３ Being selected from a group consisting of; (c) R ２ However, the selection is made from the group consisting of H and halogens, preferably H and F, preferably H; (d) S / D is a single bond; (e) R ３ However, H, D, halogens, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyls, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, substituted or unsubstituted heterocyclyls, -S-alkyls, -CN, -NO ２ , -N ３ , -CH(Ph) ２ , perfluoro-C １ ~C ４ Alkyl, perfluoro-C １ ~C ４ Alkoxy, -NR ４ R ５ , -OR ４ , -COR ４ , -CO ２ R ４ , -CONR ４ R ５ , -C(=NR ４ ) NR ５ R ６ , -NR ４ COR ５ , -NR ４ CO ２ R ５ , -SO ２ R ４ , -NR ４ SO ２ NR ５ R ６ , and -NR ４ SO ２ R ５ Selected from the group consisting of; R ４ , R ５ and R ６ are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; wherein, (R ４ and R ５ ) and / or (R ５ and R ６ ) may together with the atoms to which they are attached each form a ring, said ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl A compound according to claim 1, having one or more of the above, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof.

3. R ３ is selected from the group consisting of H, D, halogen, substituted or unsubstituted C １ ~C ４ alkyl, substituted or unsubstituted C ２ ~C ６ alkenyl, substituted or unsubstituted C ２ ~C ６ alkynyl, substituted or unsubstituted C ３ ~C ８ cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-R ４ , -CN, -NO ２ , perfluoro-C １ ~C ４ alkyl, perfluoro-C １ ~C ４ alkoxy, -NR ４ R ５ , -OR ４ , -COR ４ , -CO ２ R ４ , -CONR ４ R ５ , -C(=NR ４ )NR ５ R ６ , -NR ４ COR ５ , -NR ４ CO ２ R ５ , -SO ２ R ４ , -NR ４ SO ２ NR ５ R ６ , and -NR ４ SO ２ R ５ ; R ４ , R ５ and R ６ Each of these is independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R ４ and R ５ ) and / or (R ５ and R ６ ) however, together with the atoms to which they are linked, each may form a ring, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyls, saturated or unsaturated heterocyclyls, aryls, and heterocyclylaryls; Preferably, R ３ However, H stands for halogen, -OH, -S-R ４ -CN, -NO ２ , and -NR ４ R ５ Preferably H, halogen, -NO ２ , and -NR ４ R ５ A group consisting of R is selected, where R ４ and R ５ H, D, and C are each independent of each other. １～４ It is alkyl, or R ４ and R ５ These atoms, together with the linked atoms, form a ring, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyls, saturated or unsaturated heterocyclyls, aryls, and heterocyclylaryls. The compound described in claim 2, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof.

4. R ３ However, H, D, halogen, substituted or unsubstituted C １ ~C ４ Alkyl, substituted, or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ６ Alkynyl, substituted or unsubstituted C ３ ~C ８ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-R ４ -CN, -NO ２ , perfluoro-C １ ~C ４ Alkyl, perfluoro-C １ ~C ４ Alkoxy, -NR ４ R ５ , -OR ４ , -COR ４ , -CO ２ R ４ , -CONR ４ R ５ , -C(=NR ４ ) NR ５ R ６ , -NR ４ COR ５ , -NR ４ CO ２ R ５ , -SO ２ R ４ , -NR ４ SO ２ NR ５ R ６ , and -NR ４ SO ２ R ５ Selected from the group consisting of; R ４ , R ５ and R ６ Each of these is independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R ４ and R ５ ) and / or (R ５ and R ６ ) together with the atoms to which they are bonded, form equation (II) 【Chemistry 2】 Each of them may form a ring, [In the formula, X ２ However, NH or CH ２ Selected from the group consisting of and O, preferably X ２ is N; Ring A is a 5-6 membered aromatic ring containing 0-3 heteroatoms N, S, or O, preferably a benzene ring; R ７ The group consists of H, D, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl, preferably R ７ However, it is selected from the group consisting of H, D, and halogens; R ８ However, H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -S-alkyl, -CN, -NO ２ , -N ３ , -CH(Ph) ２ , perfluoro-C １ ~C ４ Alkyl, perfluoro-C １ ~C ４ Alkoxy, -NR ９ R １０ , -OR ９ , -COR ９ , -CO ２ R ９ , -CONR ９ R １０ , -C(=NR ９ ) NR ９ R １０ , -NR ９ COR １０ , -NR ９ CO ２ R １０ , -SO ２ R ９ , -NR ９ SO ２ NR １０ R １１ , and -NR ９ SO ２ R １０ Selected from the group consisting of; R ９ , R １０ , and R １１ However, each is independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl; where (R ９ and R １０ ) and / or (R １０ and R １１ ) however, together with the atoms to which they are linked, each may form a ring, the ring being optionally selected from the group consisting of substituted or unsubstituted cycloalkyls, saturated or unsaturated heterocyclyls, aryls, and heterocyclylaryls; Preferably, R ８ However, H, D, substituted or unsubstituted 5- to 9-membered heterocyclyl rings and -NR ９ R １０ Selected from the group consisting of R ９ and R １０ However, H, D and C are independent of each other. １～４ It is alkyl, or R ９ and R １０ However, together with the linked atoms, they form a substituted or unsubstituted 5- to 9-membered cycloalkyl ring; preferably, the 5- to 9-membered heterocyclyl ring contains one, two, or three N atoms; preferably, the 5- to 9-membered heterocyclyl ring is selected from the group consisting of morpholino and piperazine. Preferably, R ３ However, H, halogen, -OH, -SH, -CN, -NO ２ , -NH ２ ,-NH(C １～４ Alkyl) and 【Transformation 3】 Preferably, H, halogen, -NO ２ , -NH ２ ,-NH(CH ３ ) and 【Chemistry 4】 Selected from the group consisting of, and R ７ , R ８ , X ２ And ring A is as defined in this claim, The ring represented by formula (II) is as follows: (In the formula, ring A is a benzene ring; R ７ H is; X ２ is NH; R ８ Equation (III) 【Transformation 5】 The structure is shown by; Here, ring B is an N-substituted non-aromatic ring, and its structure is as follows: 【Transformation 6】 Selected from a group consisting of any of the following: Preferably, ring B is 【Transformation 7】 Preferably, 【Transformation 8】 Selected from the group consisting of; R １２ However, H, D, halogen, -CN, -NO ２ Selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heterocyclylaryl; where, if the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heterocyclylaryl is substituted, it is substituent R １３ It is optionally replaced by at least one of the following, R １３ These are halogens, lower alkyls, lower alkoxys, cyanos, or nitros; Preferably, R １２ However, H, D, halogen, -C (=O)-C １～６ Selected from the group consisting of alkyl, phenyl, and 5-6 membered heteroaryl rings, where the phenyl and 5-6 membered heteroaryl rings are one or more R １３ It is optionally replaced, and here, R １３ is halogen, C １～４ Selected from the group consisting of alkyl, cyano, and nitro; Preferably, R １２ However, H, D, halogen, -C (=O)-C １～４ Selected from the group consisting of alkyl and phenyl, where the phenyl has one, two, or three R groups. １３ It is optionally replaced, and here, R １３ It is selected from the group consisting of F and cyano; Preferably, R １２ is -C(=O)OC(CH ３ ) ３ phenyl, 【Chemistry 9】 A group consisting of R is selected, where R １３ It is selected from the group consisting of F and cyano; In formula (III), ring B is preferably a piperazine ring substituted with a lower alkyl, alkenyl, alkynyl, halogen, nitro, or the like, or formula (IV) 【Chemistry 10】 It is a substituted piperazine represented by; Here, ring C is a 5-6 membered aromatic ring or aromatic heterocyclyl containing 0-3 heteroatoms N, S, or O; R １４ However, it is selected from the group consisting of H, D, halogens, lower alkyls, lower alkoxys, cyanos, nitros, and hydroxyls; n = 0, 1, 2, 3, 4, or 5; Preferably, in formula (III), ring B is -C(=O)OC(CH ３ ) ３ A piperazine ring substituted with, or a substituted piperazine represented by formula (IV); Preferably, structural units 【Chemistry 11】 but, 【Chemistry 12】 Selected from the group consisting of; Preferably, the C ring is phenyl; Preferably, R １４ However, it is selected from the group consisting of H, F, and cyano, preferably F and cyano; Preferably, structural units 【Chemistry 13】 However, phenyl, 【Chemistry 14】 (Selected from the group consisting of) More preferably selected from, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph.

5. Equation (I-1) 【Chemistry 15】 It is a compound represented by, R １ , R ２ , and R ３ However, as defined in any one of claims 1 to 4; Preferably, structural units 【Chemistry 16】 but, 【Chemistry 17】 Selected from the group consisting of, Preferably, structural units [Chemistry 18] but, 【Chemistry 19】 And; Preferably, R ３ However, H, halogen, -NO ２ , and -NR ４ R ５ A group consisting of R is selected, where R ４ and R ５ This is defined in any one of claims 1 to 4; Preferably, R ３ However, H, -NO ２ , -NH ２ , and -NH(C １～４ Selected from the group consisting of alkyl; Preferably, R ３ However, H, -NO ２ , -NH ２ , and -NH(CH ３ Selected from the group consisting of; Preferably, R ３ ga-NR ４ R ５ And here R ４ and R ５ This is defined in any one of claims 1 to 4; Preferably, R ３ ga-NH ２ and -NH(CH ３ Selected from the group consisting of; Preferably, R ３ NO ２ And; Preferably, R ３ but 【Chemistry 20】 And here X ２ , ring A, R ７ and R ８ This is defined in any one of claims 1 to 4; Preferably, R ８ However, H, D, substituted or unsubstituted 5- to 9-membered heterocyclyl rings, and 【Chemistry 21】 Selected from the group consisting of rings B and R １２ This is defined in any one of claims 1 to 4; Preferably, the 5- to 9-membered heterocyclyl ring contains one, two, or three N atoms; preferably, the 5- to 9-membered heterocyclyl ring is selected from the group consisting of morpholino and piperazine; Preferably, the 5- to 9-membered heterocyclyl ring is H, D, halogen, nitro, C １～４ Alkyl, -C(=O)OC １～４ Alkyl, and 【Chemistry 22】 The rings C, R are optionally substituted with one, two, or three groups selected from the group consisting of the above, where C, R １４ and n are as defined in any one of claims 1 to 4; Preferably, R １２ However, H, D, halogen, nitro, C １～４ Alkyl, -C(=O)OC １～４ Alkyl and 【Chemistry 23】 It is substituted with a group selected from the group consisting of, where the ring C, R １４ and n are as defined in any one of claims 1 to 4; Preferably, formula (II-1) 【Chemistry 24】 It is a compound represented by (In the formula, R １ , R ２ , R ７ , R ８ , X ２ , and ring A is as defined in any one of claims 1 to 4 or as defined in this claim); Preferably, formula (III-1) 【Chemistry 25】 It is a compound represented by (In the formula, R １ , R ２ , R ７ , R １２ , X ２ (where ring A and ring B are as defined in any one of claims 1 to 4, or as defined in this claim); Preferably, formula (IV-1) 【Chemistry 26】 The compound is shown as (In the formula, R １ , ring C, R １４ , and n is as defined in any one of claims 1 to 4, or as defined in this claim), A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof. 【Request Item 6】 【Chemistry 27】 A compound according to any one of claims 1 to 5, selected from the group consisting of the above, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof.

7. A method for preparing the compound according to any one of claims 1 to 6, Synthesis scheme A: Chemical formula A １ The compound shown is reacted with benzaldehyde and methylhydrazine to form A ２ Steps to prepare a Lewis acid (e.g., ZnCl) ２ A under the catalyst of ) ２ By cyclizing A ３ Steps to form; A ３ Substitute with 3-bromocycloglutarimide to produce target product A ４ The step of generating (in the formula, R ２ and R ３ (as defined in any one of claims 1 to 6); 【Chemistry 28】 Or, Synthesis scheme B: First, 2-formylbenzoate B １ Using as a starting material, a condensation reaction with hydrazine hydrate is carried out under heating conditions to produce phthalazinon B ２ Step B to obtain; ２ Dimethyl 2-bromoglutarate (B １０ ) is subjected to a substitution reaction with B ３ The step of giving; then, under the basic catalysis of sodium amide, B ３ Perform cycloaddition to B ４ The step of giving (where the key intermediate B) １０ Glutaric acid B ７ Using as the starting material, thionyl acylation of chloride, liquid bromine substitution, and methanol esterification are carried out sequentially to produce B ８ , B ９ , and B １０ (This is induced through a one-pot process that brings about the following); B ４ By reducing (for example, by zinc reduction) B ５ Step B ５ Methylate (for example, using formaldehyde and formic acid reagents) B ６ The step of giving; 【Chemistry 29】 Or, Synthesis scheme C: Compound A according to scheme A ４ Steps to synthesize: Substitute the unsaturated nitrogen-containing non-aromatic ring compound R with methyl 4-bromomethylbenzoate and C ５ Steps that bring about this; first, C ５ The methylbenzoate portion is completely reduced to an alcohol (compound C) ６ ) generates, and then C ６ Partially oxidized to aldehyde C ７ Steps to generate C ７ and the aforementioned compound A ４ The step of carrying out a reductive amination reaction with the aromatic amino group to form an imine between them, thereby obtaining the target product (wherein R is ring B as defined in formula (III)); 【Transformation 30】 Or, Synthesis scheme D: Pd as catalyst ２ (dba) ３ Under conditions of X-Phos as ligand and NaOtBu as base, a Buchwald-Hartwig carbon-nitrogen coupling reaction was carried out between 1-tert-butyloxycarbonylpiperazine and halogenated aromatic ring compound R to form compound D. ５ Steps to generate compound D ５ Deprotect the Boc protecting group on N and D ６ The steps to obtain compound D; the subsequent synthesis steps are consistent with the synthesis route of scheme C; methyl 4-bromomethylbenzoate substitution, DIBAL reduction, and manganese dioxide oxidation are carried out sequentially to obtain compound D, respectively. ７ , D ８ and D ９ Steps to obtain compound D ９ and A ４ A step of performing a reduction-amination reaction between the two to obtain the target compound; 【Chemistry 31】 A method that includes this.

8. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, and one or more pharmaceutically acceptable carriers or excipients, Preferably, the pharmaceutically acceptable carrier or excipient includes ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, and lanolin. Pharmaceutical composition.

9. A combination formulation comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, and at least one further drug, wherein the at least one further drug is a chemotherapeutic agent or immunomodulator (e.g., a combination of immune checkpoint inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, antibiotics, alkylating agents, antibody inhibitors, hormones, immunomodulators, interferon-like agents, or agonists), preferably selected from the group consisting of dexamethasone, bortezomib, and tazemetostat. Compounding agent.

10. CRL4 ＣＲＢＮ Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or the pharmaceutical composition according to claim 8, or the formulation according to claim 9, in the manufacture of a pharmaceutical for the treatment and / or prevention of diseases related to E3 ubiquitin ligase, wherein the disease includes cancer, pain, neurological disorders and immune system disorders.

11. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition according to claim 8, or a compound according to claim 9, in the manufacture of a pharmaceutical for the treatment and / or prevention of cancerous diseases, wherein the cancerous disease is various types of leukemia, multiple myeloma, various malignant lymphomas, such as non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle One or more of the following are included: lupus cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, erythema nodosum, autoimmune diseases such as systemic lupus erythematosus, myelodysplastic syndrome, breast cancer, gastrointestinal cancer, various types of lung cancer (e.g., non-small cell lung cancer), liver cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, ovarian cancer, various endocrine cancers (e.g., breast cancer, thyroid cancer, stomach cancer), kidney cancer or ureteral cancer, and CNS tumors, preferably multiple myeloma. use.

12. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition according to claim 8, or a compound according to claim 9, which can be administered via an appropriate route, for example, orally, sublingually, rectally, parenterally, by injection (intradermal, subcutaneous, intramuscular, intravenous, arterial), pulmonary, nasally, lingual, buccal, skin, mucous membrane, conjunctiva, local administration, or via implant.

13. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof, in the production of a proteolytic chimeric molecule (PROTAC), Preferably, the compound, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate, or polymorph thereof, is used in the production of proteolytic chimeric molecules (PROTACs) with respect to CRL4 ＣＲＢＮ Used as a ligand for E3 ubiquitin ligase, use.

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