Isobenzindolinone compounds and their uses

Abstract

This application belongs to the medical field.The present disclosure provides an isoindolinone compound as shown in structural formula (I) or its pharmaceutically acceptable salt, and its use in treating proliferative diseases.It further provides a pharmaceutical composition comprising said compound or its salt, and a pharmaceutically acceptable carrier. JPEG2024521966000318.jpg43114

Description

Technical Field

[0001] This application belongs to the medical field. The present invention provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and their use in the treatment of proliferative diseases. The present invention further provides a pharmaceutical composition comprising the compound or a salt thereof described herein, and a pharmaceutically acceptable carrier.

Background Art

[0002] Casein kinase 1α (CK1α), encoded by the gene CSNK1A1, is a serine / threonine protein kinase that is ubiquitously expressed within the CK1 kinase family. CK1α is involved in the regulation of various physiological and pathological processes of cells and regulates the orderly progression of claims through various signaling pathways (Jiang et al., Cell common signal (2018) 16:23). For example, CK1α is an important regulator of the Wnt / β-catenin pathway, directly phosphorylates the Ser45 site of β-catenin, and degrades it through the proteasome (Liu et al., Cell (2002) 108:837-847). CK1α also regulates the stability of the tumor suppressor p53 protein by regulating the activity of the MDM2 / MDMX E3 ligase complex (Huart et al., J Biol Chem (2009) 284:32384-94; Wu et al., Mol Cell Biol (2012) 32:4821-4832). CK1α has been reported to be overexpressed in various human cancers, but the exact role of CK1α in the development of various tumors has not been clearly elucidated (Richter et al., BMC cancer (2018) 18:140). According to the Cancer Dependency Map (DepMap) scheme, inactivation of CK1α by regularly spaced clustered short palindromic repeat (CRISPR) / cas9-mediated gene knockdown or short hairpin RNA (shRNA)-mediated gene knockdown indicates that it may significantly reduce the proliferation and / or survival of many cancer cell lines across various cancer types (Tsherniak et al., Cell (2017) 170:564-576; Behan et al., Nature (2019) 568:511-516). Furthermore, inhibition of CK1α using shRNA gene knockdown or D4476 (a CK1α kinase inhibitor) can effectively inhibit the development of mouse MLL-AF9 leukemia, but has less effect on normal hematopoietic stem cells (HSPCs) (Jaras et al., J Exp medical, 2014, 211(4):605-612). Collectively, these data suggest that CK1α is a potential therapeutic target for hematological malignancies and solid tumor indications. CK1α is a novel and known substrate of lenalidomide, which has been approved by the FDA as a drug for multiple myeloma and low-risk myelodysplastic syndrome with 5q deletion (del(5q) MDS) in humans. (Kronke et al., Nature (2015) 523:183-188). Lenalidomide as a molecular collagen degrader mobilizes CK1α by changing the selectivity of the CUL4 / DDB1 / CRBN / RBX 1 E3 ligase complex, causing its polyubiquitination and proteasomal degradation. However, in addition to CK1α, lenalidomide induces the degradation of many other novel substrates, including Ikaros, Aiolos, ZFP91, and SALL4 (Kronke et al., Science (2014) 343(6168):301-305; Lu et al., Science (2014) 343(6168):305-309; Matyskiela et al., Nat Chem Biol (2018) 14(10):981-987; An et al., Nat Commun (2017) 8:15398). So far, CK1α-selective molecular glue degraders for the treatment of cancer and other human diseases have not yet been successfully developed.

[0003] GSPT1, also known as eukaryotic release factor 3a (eRF3a), is an important translation termination factor that binds to and activates eRF1 and mediates the recognition of stop codons and the release of translated ribosomal nascent proteins (Zhouravleva et al., EMBO J (1995) 14(16):4065-4072). It has been reported that some CRBN-based molecular glue degraders, including CC-885 and CC-90009, may degrade GSPT1 and exert antitumor effects in acute myeloid leukemia (AML) (Matyskiela et al., Nature (2016) 535:252-257; Surka et al., Blood (2021) 137(5):661-677). However, the degradation of GSPT1 by CC-90009 causes severe off-target toxicities such as hypocalcemia, hypotension, and antibilirubinemia in AML patients (Uy et al., Blood (2019) 134(Supplement_1):232). Therefore, when developing the next generation of CK1α-selective molecular glue degraders, it is necessary to avoid off-target degradation of GSPT1 and make them highly tolerable and low-toxic therapeutic agents. Furthermore, since the known classes of Cereblon-based molecular glue degraders cannot clearly predict GSPT1 activity by their chemical structures, it is necessary to carefully analyze and monitor the degradation activity of GSPT1 during development.

Summary of the Invention

[0004] A first embodiment of the present invention relates to a compound as shown in structural formula (I):

Chemical

[0005] Another embodiment of the present invention relates to a compound as shown in structural formula (II):

Chemical

[0006] Another embodiment of the present invention relates to a compound as shown in structural formula (III):

Chemical formula

[0007] Another embodiment of the present invention relates to a compound as shown in structural formula (IV):

Chemical formula

[0008] Another embodiment of the present invention relates to a compound as shown in structural formula (V):

Chemical formula

[0009] Another embodiment of the present invention relates to a compound as shown in structural formula (VI):

Chemical formula

[0010] Another embodiment of the present invention relates to a compound as shown in structural formula (VII):

Chemical formula

[0011] Another embodiment of the present invention relates to a compound as shown in structural formula (VIII): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0012] Another embodiment of the present invention is a compound as shown in structural formula (IX): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0013] Another embodiment of the present invention is a compound as shown in structural formula (X): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0014] Another embodiment of the present invention is a compound as shown in structural formula (XI): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0015] Another embodiment of the present invention is a compound as shown in structural formula (XII): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0016] Another embodiment of the present invention is a compound as shown in structural formula (XIII): [Chemical formula] with respect to the compound or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present disclosure.

[0017] Another embodiment of the present invention is a compound as shown in structural formula (XIV):

Chemical formula

[0018] Another embodiment of the present invention is a compound as shown in structural formula (XV):

Chemical formula

[0019] Another embodiment of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and a compound described in the present disclosure or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is used, for example, to treat a proliferative disease in a subject.

[0020] Mode for Carrying Out the Invention The present invention relates to a compound as shown in the following structural formula or a pharmaceutically acceptable salt thereof. The variables in the following structural formula will be described in the next paragraph. It should be understood that the present invention includes all combinations of substituent variables (e.g., R a , R b , R 1 , R 2 , R 3 , etc.) as defined in the present disclosure. The compound or a salt thereof described in the present disclosure can be used for the treatment of proliferative diseases. The first embodiment of the present invention is a compound as shown in structural formula (I):

Chemical formula

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0021] In the 11th aspect of the first embodiment, the structural formula (I) is

Chem.

Chem.

Chem.

[0022] In the 14th aspect of the first embodiment, the compound represented by the structural formula (I) is the compound represented by the following formula, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein, n is 0, 1, 2 or 3, m is 0, 1, 2 or 3, each R a is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl group, cyano group, methoxy group, ethyl group, trifluoromethoxy group, [Chemical formula] trifluoromethyl group and ethoxy group. each R b is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl group, cyano group, methoxy group, ethyl group, trifluoromethoxy group, [Chemical formula] It is selected from the group consisting of a trifluoromethyl group and an ethoxy group.

[0023] In the 15th aspect of the first embodiment, the compound represented by the structural formula (I) is a compound represented by the following formula,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0024] The second embodiment of the present invention is a compound of structural formula (II) [Chemical formula] or a pharmaceutically acceptable salt thereof, provided that [Chemical formula] the total number of heteroatoms contained in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0025] The third embodiment of the present invention is a compound of structural formula (III) [Chemical formula] or a pharmaceutically acceptable salt thereof, provided that [Chemical formula] the total number of heteroatoms contained in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0026] The fourth embodiment of the present invention is a compound of structural formula (IV) [Chemical formula] or a pharmaceutically acceptable salt thereof, provided that [Chemical formula] the total number of heteroatoms contained in the moiety is 3 or less, [Chemical formula] the total number of heteroatoms contained in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0027] The fifth embodiment of the present invention is a compound of structural formula (V) [Chemical formula] or a pharmaceutically acceptable salt thereof, provided that

Chem.

Chem.

[0028] The sixth embodiment of the present invention is a compound of structural formula (VI)

Chem.

Chem.

Chem.

[0029] The seventh embodiment of the present invention is a compound of structural formula (VII)

Chem.

Chem.

[0030] The eighth embodiment of the present invention is a compound of structural formula (VIII)

Chemical formula

Chemical formula

[0031] The ninth embodiment of the present invention is a compound of structural formula (IX)

Chemical formula

Chemical formula

Chemical formula

[0032] The tenth embodiment of the present invention is a compound of structural formula (X)

Chemical formula

Chemical formula

Chemical formula

[0033] The eleventh embodiment of the present invention is a compound of structural formula (XI)

Chemical formula

Chemical formula

Chemical formula

[0034] The twelfth embodiment of the present invention is a compound of structural formula (XII)

Chemical formula

Chemical formula

[0035] In the first aspect of the twelfth embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 15 or R 16 are each independently hydrogen, fluorine, chlorine, bromine, methyl group, cyano group, methoxy group, ethyl group, trifluoromethoxy group,

Chemical formula

[0036] The 13th embodiment of the present invention is a compound of structural formula (XIII)

Chemical formula

Chemical formula

[0037] In the first aspect of the 13th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, a methyl group, a cyano group, a methoxy group, an ethyl group, a trifluoromethoxy group,

Chemical formula

[0038] The 14th embodiment of the present invention is a compound of structural formula (XIV)

Chemical formula

Chemical formula

[0039] In the first aspect of the 14th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl group, cyano group, methoxy group, ethyl group, trifluoromethoxy group,

Chemical formula

[0040] The 15th embodiment of the present invention is a compound of structural formula (XV)

Chemical formula

Chemical formula

[0041] In the first aspect of the 15th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 17 or R 18 is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl group, cyano group, methoxy group, ethyl group, trifluoromethoxy group,

Chemical formula

[0042] The present invention also relates to the following compounds.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0043] Also included are pharmaceutically acceptable salts of the compounds of the present invention. For example, acid salts of the compounds of the present invention containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid to form a pharmaceutically acceptable anionic salt. Examples of anionic salts include edetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, triglyceride, carbonate, chloride, citrate, hydrochloride, edetate, edisylic acid salt, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, rentilate, methanesulfonate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salt. Salts of the compounds of the present invention containing a carboxylic acid or other acidic functional group can be prepared by reaction with a suitable base. Such pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable cationic bases including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts, and ammonium salts, and physiologically acceptable organic bases such as, for example, trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)amine, tris(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylethylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids (e.g., lysine and arginine). The present invention also includes various isomers and mixtures thereof. Some compounds of the present invention can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers that cannot be superimposed by mirror images, most commonly because they contain one carbon atom asymmetrically substituted as a chiral center. The term "enantiomer" refers to one of the molecules that are mirror images of each other and cannot be superimposed. Diastereomers are stereoisomers that are not mirror images of each other, most commonly because they contain two or more carbon atoms asymmetrically substituted. "R" and "S" represent the arrangement of substituents surrounding one or more chiral carbon atoms. When the chiral center is not defined as R or S, either a pure enantiomer or a mixture of two configurations exists. The compounds of the present invention can be synthesized by isomer-specific synthesis or isolated as individual isomers from a mixture of isomers. The disclosed compounds can have one or more stereocenters, and each stereocenter can independently exist in an R or S configuration. The compound itself can be separated into individual stereoisomers and is enantiomerically / diastereomerically pure, but when the absolute stereochemistry of the stereocenter is not determined, the stereochemical configuration can be labeled with (*) at the designated center. In one embodiment, the compounds described in the present invention are either optically active or racemic. It should be understood that the compounds described in this disclosure include racemates, optically active forms, positional isomers, and stereoisomeric forms, or combinations thereof, having the therapeutically effective properties described in this disclosure. As a non-limiting example, optically active isomers can be prepared by any suitable means, including the division of ceramic bodies using recrystallization techniques, synthesis from starting materials of optically active substances, chiral synthesis, or chromatographic separation using chiral stationary phases. In one embodiment, a mixture of one or more isomers is utilized as the compounds described in this disclosure. In another embodiment, the compounds described in this disclosure contain one or more chiral centers. These compounds can be prepared by any method, including stereoselective synthesis, enantioselective synthesis, or separation of enantiomer or diastereomer mixtures. The separation of compounds and their isomers can be achieved by any method, including, as non-limiting examples, chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography. When the absolute configuration R or S of a compound cannot be determined, it can be determined by the retention time of chromatographic separation under specific chromatographic conditions measured by a chromatographic column, eluent, etc. In a specific embodiment, an asterisk (*) is used to represent a chiral atom. In some embodiments, the asterisk "*" is used to indicate that the chiral atom is basically in a single configuration, but its absolute stereochemical nature is uncertain (i.e., even when the bond is specifically depicted stereochemically). The chiral atom can be a chiral carbon atom, a chiral nitrogen atom, or a chiral phosphorus atom. The term "basically" refers to a variation range of 5%, 2%, 1%, or even 0.1% from a reference value. The term "single configuration" can be a single R configuration or a single S configuration.

[0044] The term "alkyl group" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains from 1 to about 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains from 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C 1 -C 2, C 1 -C 3 or C 1 -C 6 That is. The specified ranges used in this specification represent alkyl groups having each value within the range as independent classes. For example, the C 1 -C 6 The term "alkyl group" means a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and each of these alkyl groups is described as an independent class. For example, the C 1 -C 4 The term "alkyl group" means a straight-chain or branched-chain alkyl group having 1, 2, 3, or 4 carbon atoms, and each of these alkyl groups is described as an independent class. C 0 -C n When an alkyl group is used in combination with another group such as, for example, (C 3 -C 7 cycloalkyl group)C 0 -C 4 alkyl group or -C 0 -C 4 alkyl group (C 3 -C 7 cycloalkyl group), etc., the said group (here a cycloalkyl group) is directly bonded by a single covalent bond (C 0 alkyl group), or is bonded here by an alkyl group chain (here having 1, 2, 3, or 4 carbon atoms). The alkyl group is -O-C 0 -C 4 alkyl (C 3 -C 7It can also be bonded via other groups such as heteroatoms such as (cycloalkyl). Examples of the alkyl group include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, n-butyl group, n-pentyl group, isopentyl group, t-pentyl group, neopentyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group and 2,3-dimethylbutyl group. In one embodiment, the alkyl group is optionally substituted as described herein.

[0045] "Alkenyl group" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable sites on the chain. Non-limiting examples include C 2 -C 8 alkenyl group (e.g., C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 ), C 2 -C 6 alkenyl group and C 2 -C 4 alkenyl group. The specified ranges used herein represent, as independent classes, alkenyl groups having each value of said range, e.g., an alkenyl group such as the alkyl group moiety described herein. Examples of the alkenyl group include, but are not limited to, vinyl group, propenyl group, butadienyl group (including 1,2-butadienyl group and 1,3-butadienyl group). In one example, the alkenyl group is optionally substituted as described herein.

[0046] "Alkynyl group" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable site on the chain. For example, C 2 -C 8 alkynyl group (e.g., C 2 , C 3 , C 4 , C 5 , C6 , C 7 , C 8 ) or C 2 -C 6 is an alkynyl group. The specified ranges used in this specification represent, as independent classes, alkynyl groups having each value within said range, for example, alkynyl groups such as the alkyl group moieties described herein. Examples of alkynyl groups include, but are not limited to, ethynyl group, propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group and 5-hexynyl group. In one embodiment, the alkynyl group is optionally substituted as described herein.

[0047] "Alkoxy group" is an alkyl group as defined above, consisting of a specified number of carbon atoms covalently bonded via an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, 2-butoxy group, t-butoxy group, n-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group and 3-methylpentyloxy group. Similarly, "alkylthio group" or "thioalkyl group" is an alkyl group as defined above, having a specified number of carbon atoms covalently bonded via a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described herein.

[0048] "Alkenyloxy group" is an alkenyl group as defined above, consisting of a specified number of carbon atoms covalently bonded to a group substituted via an oxygen bridge (-O-).

[0049] "Alkynyloxy group" is an alkynyl group as defined above, consisting of a specified number of carbon atoms covalently bonded to a group substituted via an oxygen bridge (-O-).

[0050] "Calcanyl" is an alkyl group as defined above, consisting of a specified number of carbon atoms, covalently bonded via a carbonyl group (C=O) bridge. The carbon number includes the carbonyl group carbon, i.e., C 2 Alkanes are CH 3 (C=O)-group. In one embodiment, the calcanyl is optionally substituted as described herein.

[0051] "Alkyl ester" is an alkyl group as defined above, consisting of a specified number of carbon atoms, covalently bonded via an ester bond. The ester bond may be in either direction, for example, a group of alkyl groups having the formula -O(C=O), or a group of alkyl groups having the formula -(C=O)O.

[0052] "Cycloalkyl group" refers to a saturated or partially unsaturated cycloalkyl group having a monocyclic or polycyclic structure, including fused rings, bridged rings, and spiro ring systems. The term "cycloalkyl group" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, C 3 -8 cycloalkyl group has 3 to 8 ring carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 ring carbon atoms). Examples of cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, and partially unsaturated groups such as cyclopentenyl group and cyclohexenyl group.

[0053] "Amide" or "carboxamide" is -C(O)NR c R d where R c and R d are each independently hydrogen, an alkyl group such as, for example, a C 1 -C 6 alkyl group, an alkenyl group such as, for example, a C 2 -C 6 alkenyl group, an alkenyl group such as, for example, a C 2 -C 6An alkynyl group such as an alkynyl group, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 4 alkyl (C 3 -C 7 heterocycloalkyl), -C 0 -C 4 alkyl (aryl) and -C 0 -C 4 alkyl (heteroaryl), or R c and R d together with the nitrogen to which they are attached can form a C 3 -C 7 heterocyclic ring. In one embodiment, R c and R d groups are each independently optionally substituted as described herein.

[0054] "Carbocyclic", "carbocyclic group", "carbocyclic ring" or "cycloalkyl group" are saturated or partially unsaturated (i.e., non-aromatic) groups containing all carbon ring atoms. A carbocyclic group typically contains one ring of 3 to 7 carbon atoms or two fused rings each containing 3, 4, 5, 6 or 7 carbon atoms. A cycloalkyl group substituent may be a side chain on a substituted nitrogen or carbon atom, or may have a cycloalkyl group attached as a spiro group to a substituted carbon atom having two substituents. Examples of carbocyclic rings include rings of cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl groups. In one embodiment, the carbocyclic ring is optionally substituted as described herein. In one embodiment, the cycloalkyl group is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, the cycloalkyl group is a saturated group containing all carbon ring atoms.

[0055] "Haloalkyl group" refers to a branched or straight-chain alkyl group substituted by one or more halogen atoms up to the maximum number of halogen atoms allowed. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl group, monofluoromethyl group, difluoromethyl group, 2-fluoroethyl group, and pentafluoroethyl group.

[0056] "Haloalkoxy group" refers to a haloalkyl group as defined herein, bonded through an oxygen bridge (the oxygen of the alcohol radical).

[0057] "Thioalkyl group" refers to a branched or straight-chain alkyl group substituted by one or more sulfur atoms up to the maximum number of sulfur atoms allowed.

[0058] "Halogenated" or "halogen" is independently any one of fluoro, chloro, bromo, and iodo.

[0059] "Aryl group" refers to an aromatic ring or an aromatic group containing only carbon within the ring. In one embodiment, the aryl group contains, as ring members, 1 to 3 separate or fused rings, 6 to 18 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms) and does not contain heteroatoms. The aryl group can be further substituted with carbon atoms, non-carbon atoms, or groups. The substitution can include fusion to a 5- to 7-membered saturated ring group, which can optionally contain 1 or 2 heteroatoms independently selected from N, O, and S, for example, to form a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl group, naphthyl groups such as 1-naphthyl group and 2-naphthyl group, fluorenyl group, and anthracenyl group. In one embodiment, the aryl group is a side chain. An example of a side chain ring is a phenyl group substituted by a phenyl group. In one embodiment, the aryl group is optionally substituted as described herein.

[0060] As used herein, the terms "heterocyclyl group" and "heterocycle / heterocyclic ring" refer to monocyclic or bicyclic radicals having 4, 5, 6, 7, 8, 9 or 10 ring atoms, which are saturated or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within a non-aromatic ring), where at least one ring atom is a heteroatom arbitrarily selected from N, O and S, and the remaining ring atoms are C, where one or more ring atoms are optionally and independently substituted by one or more of the above substituents. In one embodiment, the only heteroatom is oxygen. The heterocycle can be a monocyclic ring having 4 to 7 ring members (selecting 1 to 4 heteroatoms from N, O and S and 2 to 6 carbon atoms), or a ring having 6 to 10 ring members (selecting 1 to 6 heteroatoms from N, O and S and 4 to 9 carbon atoms), for example: bicyclic [4,5], [5,5], [5,6] or [6,6] systems. In one embodiment, the only heteroatom is sulfur. The heterocycle is described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, 9; "Chemistry of Heterocyclic Compounds, a Series of Monographs" (John Wiley & Sons, New York, 1950 - present), particularly Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82:5566.Examples of heterocyclic rings include, but are not limited to, pyridylalkyl groups, dihydrofuryl groups, tetrahydrothienethyl groups, tetrahydropyranyl groups, dihydropyridyl groups, tetrahydrothiopyranyl groups, piperidino, piperidonyl, morpholino, thiomorpholinyl groups, thioxanthenyl groups, piperazinyl groups, monopiperazinyl groups, azetidinyl groups, oxetanyl groups, thietanyl groups, homopiperidinyl groups, oxepanyl groups, thietanyl groups, azoxanyl groups, diazyl, thiazyl, 2-pyridyl groups, 3-pyridyl groups, indolyl groups, 2H-pyranyl groups, 4H-pyranyl groups, dioxyl, 1,3-dioxyl, pyrazolinyl groups, dithianyl groups, dilipoic acid, dihydropyranyl groups, dihydrothienyl groups, dihydrofuryl groups, dihydroisoquinolyl groups, tetrahydroisoquinolyl groups, imidazolopyrazolidinyl groups, imidazolyl groups, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolyl groups, quinolyl groups, N-pyridylurea and pyrrolopyrimidine. Spiro groups are also included within the scope of this definition. Here, examples of heterocyclyl groups in which a carbon atom on the ring is substituted by an oxo (=O) moiety at the 1- or 2-position are pyrimidinone and 1,1-dioxo-thiomorpholinyl groups. The heterocyclyl groups described herein are optionally and independently substituted by one or more substituents described herein.

[0061] As described above, a "heterocyclic oxy group" is a monocyclic or bicyclic heterocyclic group connected to the substituted group via oxygen, -O-, and a linker.

[0062] "Heteroaryl group" can be a stable monocyclic aromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring. The aromatic ring can contain 1 to 3 heteroatoms selected from N, O, and S, or in some embodiments 1 to 2 heteroatoms, and the remaining ring atoms are carbon. The 5- to 18-membered heteroaryl groups described herein can contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, a bicyclic heteroaryl group is a 9- to 10-membered heteroaryl group, i.e., a group containing 9 or 10 ring atoms, where one 5- to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group does not exceed 2. In another embodiment, the total number of S and O atoms in the aromatic heterocyclic ring is 1 or less.Examples of the heteroaryl group include a pyridyl group (e.g., including a 2-pyridyl group, 2-hydroxypyridyl group, 3-pyridyl group, 3-hydroxypyridyl group, 4-pyridyl group, 4-hydroxypyridyl group), imidazolyl group, imidazopyridyl group, pyrimidinyl group (e.g., including a 4-hydroxypyridyl group), pyrazolyl group, triazolyl group, pyrazinyl group, tetrazolyl group, furyl group, thienyl group, isoxazolyl group, thiazolyl group, oxadiazolyl group, oxazolyl group, isothiazolyl group, pyrrolyl group, quinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, indolyl group, benzimidazolyl group, benzofuranyl group, cinnoline, indazolyl group, indolizinyl group, phthalazinyl group, pyrazinyl group, triazinyl group, isoindolyl group, pteridinyl group, purinyl group, oxazolopyridazine, triazolyl group, thiadiazolyl group, thiadiazolyl group, furazanyl group, benzofurazanyl group, benzothienyl group, benzothiazolyl group, benzoxazolyl group, quinazolinyl group, quinoxalinyl group, naphthyridinyl group, tetrahydrofuryl group and furopyridinyl group, but are not limited thereto. The heteroaryl group can be independently substituted, optionally, by one or more substituents described herein.

[0063] The "aromatic heterocyclic oxy group" is a heteroaryl group connected to the substituted group via oxygen, -O-, and a linker.

[0064] The "heterocycloalkyl group" is a saturated cyclic group. For example, it can have 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, and the remaining ring atoms are carbon atoms. In a representative embodiment, the heteroatom is nitrogen. The monocyclic heterocycloalkyl group usually has 3 to about 8 ring atoms or 4 to 6 ring atoms. Examples of the heterocycloalkyl group include a morpholinyl group, piperazinyl group, piperidinyl group, and pyrrolinyl group.

[0065] The term "mono- or dialkylamine" refers to a secondary or tertiary alkylamine group, where the alkyl group is independently selected from alkyl groups as defined herein. The attachment site of the alkylamine group is on the nitrogen. Examples of monoalkylamino and dialkylamino groups include ethylamine, dimethanamine, and methylpropylamino groups.

[0066] As used herein, the term "substituted" refers to the replacement of any one or more hydrogens on a specified atom or group by a moiety selected from the specified groups, provided that the positive valence of the specified atom is not exceeded.

[0067] When a single stereocenter is designated as "*R" or "*S", this means that even if it is essentially in a single stereoconfiguration, the absolute stereochemical nature of this stereocenter is uncertain (i.e., even if the bonds are specifically drawn stereochemically). In other words, "*R" may be in the absolute R configuration or the absolute S configuration. Similarly, "*S" may be in the absolute R configuration or the absolute S configuration. "*R" or "*S" is randomly assigned to these molecules. A stereocenter labeled "*R" can have the same or a different single stereoconfiguration as another stereocenter labeled "*S". A stereocenter labeled "*R" can have the same or a different single stereoconfiguration as another stereocenter labeled "*R". A stereocenter labeled "*S" can be in the same or a different single stereoconfiguration as another stereocenter labeled "*S". For example, compound 5

Chem.

Chem.

Chem.

[0068] When the “*R” or “*S” of the first stereocenter appears simultaneously within the same molecule as a second stereocenter designated as “(R)” or “(S)” (referred to as the absolute stereochemistry of the second stereocenter), the absolute stereochemistry of the first stereocenter designated as “*R” or “*S” is uncertain (i.e., even if the bond is specifically depicted stereochemically), even if the first stereocenter is essentially in a single stereoconfiguration. For example, compound 82

Chem.

Chem.

[0069] The compounds or salts thereof described herein can be used for the treatment of proliferative diseases. The present invention provides the use of the compounds or pharmaceutically acceptable salts thereof described herein in the preparation of a medicament for treating proliferative diseases. The present invention further provides the use of the compounds or pharmaceutically acceptable salts thereof described herein in the preparation of proliferative diseases. The present invention further provides a method for treating a proliferative disease, which comprises administering to a subject in need of a therapeutically effective amount of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0070] The applicants have discovered that the compounds or salts thereof described herein can effectively degrade CK1α. Therefore, the compounds or salts thereof described herein can be used for the treatment of proliferative diseases. Furthermore, the applicants have also discovered that the compounds or salts thereof described herein degrade CK1α without simultaneously inhibiting / degrading GSPT1. In other words, the compounds or salts thereof described herein can selectively degrade CK1α, and since the effects on other proteins / kinases are reduced or not at all, the toxic side effects are reduced or not at all compared to previous CK1α degrading agents / inhibitors.

[0071] The terms "proliferative disease" or "cell proliferative disease" refer to diseases associated with some degree of abnormal cell proliferation, whether malignant or benign. In some embodiments, the proliferative disease is cancer. In some aspects, the cancer is a solid tumor. In some aspects, such cancer is a hematological malignancy. The terms "proliferative disease", "cell proliferative disease", "cancer", "cancerous" and "tumor" are not mutually exclusive as described herein.

[0072] "Cancer" includes cancer cells and / or benign or pre-cancerous cells. Examples of cancer include breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, stomach cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, lymphoid organ cancer, and leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia) included in hematological malignancies, lymphoma (small lymphocytic lymphoma (SLL)), Hodgkin lymphoma (nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted or non-lymphocyte-depleted, and nodular lymphocyte-predominant Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (e.g., Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, plasma cell tumors (plasma cell myeloma, plasmacytoma, monoclonal gammopathy, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), nodular marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphoblastic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell proliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), anaplastic large cell lymphoma, multiple myeloma (plasma cell myeloma or Kahler disease), but are not limited to these.

[0073] The present invention further provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition described herein can be tablets, capsules, granules, syrups, suspensions, solutions, dispersants, sustained-release preparations for oral or parenteral administration, intravenous injection preparations, subcutaneous injection preparations, inhalation preparations, transdermal preparations, rectal or vaginal suppositories.

[0074] The pharmaceutically acceptable carriers described in this specification refer to pharmaceutically acceptable carriers well-known to those skilled in the art. The pharmaceutically acceptable carriers of the present invention include, but are not limited to, fillers, wetting agents, adhesives, disintegrants, lubricants, adhesives, lubricants, fragrances, surfactants, preservatives, etc. Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, etc. Wetting agents and adhesives include, but are not limited to, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, sucrose, polyvinylpyrrolidone, etc. Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium cellulose, low-substituted hydroxypropyl cellulose, etc. Lubricants include, but are not limited to, magnesium stearate, tall oil, talc powder, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, etc. Adhesives include, but are not limited to, gum arabic, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, glucose, dextrin, glucose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, syrup, and yellow gum. Colloids include, but are not limited to, colloidal silica, powdered cellulose, magnesium trisilicate, silica, and talc powder. Fragrances include, but are not limited to, aspartame, stevia, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizic acid, etc. Surfactants include, but are not limited to, Tween-80, poloxamer. Preservatives include, but are not limited to, parabens, sodium benzoate, potassium sorbate, etc.

[0075] Based on this disclosure, methods for preparing various pharmaceutical compositions containing various active ingredients are known or obvious to those skilled in the art as described in REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., Mack Publishing Company, 19th Edition (1995). Methods for preparing pharmaceutical compositions include incorporating appropriate pharmaceutical excipients, carriers, diluents, etc. The pharmaceutical compositions described herein are prepared by known methods including conventional methods of mixing, dissolving or lyophilizing.

[0076] In the pharmaceutical compositions described herein, the content of the active ingredient can be from about 0.01% to about 99% by weight of a given unit dosage form. In such therapeutic pharmaceutical compositions, the content of the active ingredient can reach an effective dosage level.

[0077] The tablets, capsules and the like described herein can include binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or flavors such as mint flavor, wintergreen or cherry flavor. When the unit dosage form is a capsule, in addition to the above types of materials, it can further include a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials can function as coatings or otherwise modify the physical form of the solid unit dosage form. For example, tablets or capsules can be coated with gelatin, wax, shellac or sugar. Syrups may contain sucrose or fructose as a sweetener and as an active ingredient, methylparaben or propylparaben as a preservative, dyes and flavors (e.g., cherry or orange flavor). Of course, any material used in the preparation of any unit dosage form must be pharmaceutically acceptable and non-toxic in the amounts used. Further, the active ingredient can be incorporated into sustained release formulations and devices.

[0078] The active ingredient can also be administered intravenously or intraperitoneally by infusion or injection. Optionally, a non-toxic surfactant can be used to prepare an aqueous solution of the active ingredient or its salt. It is also possible to prepare glycerin, liquid polyethylene glycol, triacetate, as well as mixtures thereof and dispersants of oils. Under general storage and use conditions, these formulations contain preservatives that prevent the growth of microorganisms.

[0079] A pharmaceutical combination dosage form suitable for injection or infusion can contain a sterile aqueous solution or dispersion or a sterile powder containing the active ingredient in a sterile, injectable or insoluble solution or dispersion (optionally sealed in liposomes) suitable for immediate use formulations. In all cases, the final dosage form must be sterile, transparent and stable under production and storage conditions. The liquid carrier can be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyols (such as glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by liposome formation, maintenance of the desired particle size in the case of dispersion, or the use of surfactants. Prevention of microorganisms can be achieved by using various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to contain isotonic agents such as sugars, buffers or sodium chloride. Prolongation of the absorption of injectable compositions can be achieved by using compositions containing absorption delaying agents (such as aluminum monostearate and gelatin).

[0080] Sterile injection solutions are prepared by combining the required amount of the active ingredient with the various other ingredients listed above in a suitable solvent and then filtering and sterilizing. For the preparation of sterile powders suitable for sterile injection solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, as a result of which powders of the active ingredient and any additional desired ingredients present in the sterile filtered solution are obtained.

[0081] Useful solid carriers include ground solids (such as talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, ethanol or ethylene glycol or water-ethanol / ethylene glycol mixtures, and the pharmaceutical compositions of the present invention can optionally be dissolved or dispersed in an effective amount in the liquid carrier with the aid of a non-toxic surfactant. To optimize performance for a given application, adjuvants (such as fragrances) and additional antibacterial agents can be added.

[0082] Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, aliphatic alcohols, modified celluloses or modified inorganic materials) can also be used with the liquid carrier to form spreadable pastes, gels, ointments, soaps, etc. for direct application to the skin of the user.

[0083] The therapeutically effective amount of the active ingredient depends not only on the particular salt selected, but also on the route of administration, the nature of the disease being treated, the age and condition of the patient, and ultimately the decision of the attending physician or clinician. The above formulations can be provided in unit dosage forms, which are physically discrete units containing unit dosages suitable for administration to the bodies of humans and other mammals, and the unit dosage forms can be capsules or tablets. Depending on the specific treatment involved, the amount of the active ingredient in the unit dose can vary or be adjusted between about 0.01 to 1000 mg or more.

[0084] As used herein, the term "treated / treating / treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect can be prophylactic in that it prevents the disease or all or part of the disease, and / or therapeutic in that it partially or completely stabilizes or treats the disease and / or side effects caused by the disease. As used herein, "treated / treating / treatment" includes any treatment of a patient's disease that (a) prevents the disease or condition in a patient who is susceptible to but not diagnosed with the disease or condition; (b) inhibits the disease condition, i.e., prevents the progression of the disease; or (c) alleviates the disease condition, i.e., resolves all or part of the disease or condition.

[0085] The compounds described herein or pharmaceutically acceptable salts thereof can also be administered in combination with one or more additional therapeutic agents for the treatment of cancer. These additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, cisplatin, and the like.

[0086] Unless otherwise specified, all percentages, ratios, proportions or parts used in this application are calculated by weight or volume. The amounts used in this application are weight or volume amounts. This can be easily determined by those skilled in the art.

[0087] Hereinafter, this application demonstrates the beneficial effects of this application in the form of examples. Those skilled in the art will understand that these examples are illustrative and not limiting. These examples do not limit the scope of this application in any form. The experimental methods described in the following examples are all conventional methods unless otherwise specified, and the reagents and materials are all commercially available unless otherwise specified.

[0088] Preparation of Isoindolinone Carboxamide Compounds Overall scheme 1: [Chemical formula] As shown in the overall scheme 1, the isoindolinone compound of formula (I) can be prepared using conventional organic synthesis methods and commercially available raw materials. Add t-butylsulfenamide to an organic solvent (e.g., THF, DCM) of compound A, and in the presence of CuSO 4 or Ti(OEt) 4 , generate compound B. For example, the imine intermediate in THF or DCM solvent forms the sulfonamide intermediate D with the Grignard reagent C. Use an acidic reagent such as hydrochloric acid in dioxane to deprotect the imide and generate the amine compound E. Couple the carboxylic acid F in a solvent (e.g., DMF, THF, and DCM) in the presence of a coupling agent (e.g., T 3 P, HATU, and EDCI) and a base (e.g., DIEA and TEA) to generate the compound of formula (I), where the W ring group and the Q ring group are as defined herein. If necessary, further purify the crude mixture by chiral HPLC or SFC to separate the optical isomers.

[0089] Overall scheme 2: [Chemical formula] Another synthetic route for preparing the compound of formula (I) is shown in the overall scheme 2. The isoindolinone compound of formula (I) can be prepared using conventional organic synthesis methods and commercially available starting materials. Add t-butylsulfenamide to an organic solvent (e.g., THF, DCM) of compound A-2, and in the presence of CuSO 4 or Ti(OEt) 4 , generate compound B-2. For example, react the imine intermediate in THF or DCM solvent with the Grignard reagent C-2 to form the sulfonamide intermediate D-2. Use an acidic reagent such as hydrochloric acid in dioxane to deprotect the imide and generate the amine compound E-2. Couple the carboxylic acid F in a solvent (e.g., DMF, THF, and DCM) in the presence of a coupling agent (e.g., T 3In the presence of P, HATU and EDCI and a base (e.g., DIEA and TEA), coupling is carried out in a solvent (e.g., DMF, THF and DCM) to produce a compound of formula (I), where the W ring group and the Q ring group are as defined herein. Optionally, the crude product can be further purified by chiral HPLC or SFC to separate the optical isomers from the mixture.

[0090] Chemistry Some methods for preparing the compounds of the present invention are described below. Unless otherwise specified, all starting materials are available from commercial suppliers and can be used without further purification. Hereinafter, CAN is acetonitrile, AcOH is acetic acid, Boc is a t-butyloxycarbonyl group, Bn is a benzyl group, calcd. is calculated, Cbz is a phenoxycarbonyl group, col. is column, conc. is concentration, DCM is dichloromethane, DEA is diethanolamine, DIPEA is N,N-diisopropylethylamine, DMF is dimethylformamide, DMP is Dess-Martin periodinane, DMSO is dimethyl sulfoxide, DPPP is 1,3-bis(diphenylphosphino)propane, Et 3 N is triethylamine, EtOAc is ethyl acetate, ee is enantiomeric excess, ESI is electrospray ionization, HATU is 2-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethylammonium bromide hexafluorophosphate, Hex is hexane, HNMR is 11H NMR, HPLC is high performance liquid chromatography, IPA is isopropyl alcohol, LC-MS or LCMS is liquid chromatography-mass spectrometry, LDA is lithium diisopropylamide, Ms is methanesulfonyl, PE is petroleum ether, PMB is 4-methoxybenzyl group, PPTS is pyridinium p-toluenesulfonate, prep. is preparation, Prep-HPLC is preparative HPLC, t R or Rt is retention time, (s) or (s) is solid, sat. is saturated, SFC is supercritical fluid chromatography, TBAF is tetrabutylammonium fluoride, TBS is t-butyldimethylsilyl, TEA is triethylamine, T 3 TP is n-propylphosphine cyclic anhydride, THF is tetrahydrofuran, T or Temp is average temperature, TsCl is 4-toluenesulfonyl chloride, T-BuOK is potassium t-butoxide, W is wavelength.

[0091] Example 1: Synthesis of Intermediate 1: Preparation of Intermediate 1: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid

Chemical Structure

[0092] Synthesis of Intermediate 2:

Chemical Structure

Chemical Structure

[0093] Step 2. Synthesis of 2-[(1S)-4-tert-butyl-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindoline-5-carboxylic acid (Intermediate 2)

Chemical formula

[0094] Example 2 Preparation of Compound 1: N-(Cyclopropyl(2,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)1-oxoisoindoline-5-carboxamide

Chemical Structure

[0095] Step 2: (R)-N-(Cyclopropyl(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide 1-3 At -50 °C, under N 2 protection, a solution of (R)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.63 mmol) in THF (5 mL) was added dropwise with cyclopropylmagnesium bromide (0.5 M, 6.52 mL). After the addition, the reaction system was stirred at this temperature for 2 h. The residue was poured into a saturated NH 4 Cl solution (10 mL) in ice water and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated by vacuum filtration to give the product (165 mg, yield 28%) after purification by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate, which was a colorless oil. 1 H NMR (400 MHz, CDCl 3)δ 7.42 - 7.32 (m, 1H), 6.91 - 6.77 (m, 2H), 3.90 - 3.83 (m, 1H), 3.59 (s, 1H), 1.45 - 1.38 (m, 1H), 1.22 - 1.17 (m, 9H), 0.77 - 0.64 (m, 1H), 0.59 - 0.36 (m, 3H). LCMS(ESI+): m / z 288.04 [M + H] + 。

[0096] Step 3: Cyclopropyl(2,4 - difluorophenyl)methanamine 1 - 4 (R)-N-((S)-Cyclopropyl(2,4 - difluorophenyl)methyl)-2 - methylpropane - 2 - sulfinamide (160 mg, 557 μmol) in DCM (1 mL) and hydrochloric acid / dioxane (4N, 1 mL) were mixed and degassed, and purged with N 2 three times. Then under N 2 protection, it was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the target compound (180 mg, HCl salt, crude product), which was a yellow solid and used directly in the next step without further purification. Step 4: N-(Cyclopropyl(2,4 - difluorophenyl)methyl)-2-(2,6 - dioxopiperidin - 3 - yl)1 - oxoisoindoline - 5 - carboxamide Compound 1 A mixture of cyclopropyl-(2,4 - difluorophenyl)methanamine (50.0 mg, 228 μmol), 2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindoline - 5 - carboxylic acid (54.6 mg, 190 μmol), Et 3 N (57.6 mg, 569 μmol), and T 3 P (181 mg, 285 μmol) was dissolved in DCM (2 mL) and degassed, and purged with N 2 three times, and stirred at 20 °C under N 2 protection for 16 hours. After completion of the reaction, the solvent of the reaction mixture was removed while concentrating under reduced pressure. The crude product was purified by preparative high - performance liquid chromatography to obtain the product (34.2 mg, yield 39.8%), which was a white solid. 1 1H NMR(400MHz, DMSO - d 6)δ 11.01(s,1H),9.33 - 9.14(m,1H),8.08(s,1H),8.03 - 7.95(m,1H),7.85 - 7.79(m,1H),7.72 - 7.63(m,1H),7.24 - 7.15(m,1H),7.14 - 7.05(m,1H),5.24 - 5.04(m,1H),4.70 - 4.62(m,1H),4.56 - 4.48(m,1H),4.44 - 4.35(m,1H),2.99 - 2.85(m,1H),2.63(br s,1H),2.45 - 2.39(m,1H),2.07 - 1.96(m,1H),1.43 - 1.31(m,1H),0.64 - 0.27(m,4H). LCMS(ESI+): m / z 454.1[M + H] + 。

[0097] Example 3 Compounds 10 and 11 are prepared by the same condensation reaction as Compound 1, using commercially available chiral amines and the raw materials of Intermediate 1.

Table 1

[0098] Example 4 The preparation of the following compounds is the same as the steps described for Compound 1, and the corresponding starting materials are aldehydes and Grignard reagents. For Compounds 12, 13, 17, 18, 21, 24, 64, and 71, before Steps 3 and 4, the main diastereomeric intermediates corresponding to Step 2 are separated using preparative high-performance liquid chromatography or SFC.

[0099]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

[0100] Example 5 Preparation of Compound 2 and Compound 3: N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide, and N-((*S)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chem.

[0101] Step 2: (R)-N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (2-3-1) and (R)-N-((*S)-(4-chlorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (2-3-2) At -78 °C, a solution of (R)-N-(4-chlorobenzylidene)-2-methylpropane-2-sulfinamide 2-2 (3 g, 12.3 mmol) in THF is added dropwise with cyclopropylmagnesium bromide (1 M, 36.9 mL). After the addition is complete, the reaction mixture is stirred at 25 °C for 2 hours. The reaction mixture is quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic phases are washed with water (5 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. After purification by flash silica gel column (SiO 2 , PE / EtOAc = 1:0~3:1), further purification by SFC (DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 um), 0.1% NH 3 .H 2 OETOH, B: 10%, flow rate: 60 mL / min) gives the title product 2-3-1 (500 mg, yield 13%) as a white solid and 2-3-2 (200 mg, yield 5%) as a colorless oil. 2-3-1: 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.29 - 7.07 (m, 4H), 5.52 (d, J = 7.2 Hz, 1H), 3.35 - 3.23 (m, 1H), 0.87 (s, 10H), 0.40 - 0.28 (m, 1H), 0.25 - 0.14 (m, 2H), 0.10 - 0.01 (m, 1H); LCMS(ESI+): m / z 286.01 [M+H] + 。 2-3-2: 11H NMR (400 MHz, DMSO-d 6 ) δ 7.20 - 7.09 (m, 4H), 5.13 (d, J = 5.6 Hz, 1H), 3.28 (dd, J = 5.6, 9.2 Hz, 1H), 0.97 - 0.82 (m, 10H), 0.37 - 0.31 (m, 1H), 0.25 - 0.09 (m, 3H); LCMS (ESI+): m / z 286.2 [M+H] + 。

[0102] Step 3: (*R)-(4-Chlorophenyl)(cyclopropyl)methanamine 2-4-1 To a solution of N-[(*R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-methylpropane-2-sulfinamide (150 mg, 525 μmol) in DCM (2 mL) is added hydrochloric acid / dioxane (2 mL, 4 M). The reaction mixture is stirred at 25 °C for 1 hour. The reaction mixture is concentrated under reduced pressure to afford the crude product (150 mg, yield 69%, HCl salt), which is a white solid. LCMS (ESI+): m / z 164.93 [M-NH 2 +。 (*S)-(4-Chlorophenyl)(cyclopropyl)methanamine 2-4-2 Using Intermediate 2-3-2 as the starting material, Intermediate 2-4-2 is prepared according to the same process as Intermediate 2-4-1.

[0103] Preparation of Compound 2: N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide Using Intermediate 2-3-1 as the starting material, Compound 2 is prepared according to the same process as Compound 1. 1 1H NMR (400 MHz, DMSO-d 6)δ 11.03 (broad singlet, 1H), 9.26 (doublet, J = 8.0 Hz, 1H), 8.10 (singlet, 1H), 8.05 - 7.99 (multiplet, 1H), 7.86 - 7.80 (multiplet, 1H), 7.53 - 7.46 (multiplet, 2H), 7.44 - 7.36 (multiplet, 2H), 5.23 - 5.09 (multiplet, 1H), 4.60 - 4.48 (multiplet, 1H), 4.47 - 4.30 (multiplet, 2H), 3.00 - 2.84 (multiplet, 1H), 2.74 - 2.58 (multiplet, 1H), 2.46 - 2.29 (multiplet, 1H), 2.11 - 1.96 (multiplet, 1H), 1.42 - 1.25 (multiplet, 1H), 0.65 - 0.51 (multiplet, 2H), 0.49 - 0.33 (multiplet, 2H). LCMS (ESI+): m / z 452.0 [M+H] + 。

[0104] Preparation of Compound 3: N - ((*S)-(4 - chlorophenyl)(cyclopropyl)methyl)-2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindoline - 5 - carboxamide Using Intermediate 2 - 3 - 1 as the starting material, Compound 2 is prepared according to the same process as Compound 2. 1 H NMR (400 MHz, DMSO - d 6 ): δ 11.03 (broad singlet, 1H), 9.31 (doublet, J = 8.0 Hz, 1H), 8.06 (singlet, 1H), 8.03 - 7.95 (multiplet, 1H), 7.86 - 7.78 (multiplet, 1H), 7.51 - 7.44 (multiplet, 2H), 7.42 - 7.34 (multiplet, 2H), 5.18 - 5.05 (multiplet, 1H), 4.58 - 4.48 (multiplet, 1H), 4.45 - 4.26 (multiplet, 2H), 2.98 - 2.81 (multiplet, 1H), 2.71 - 2.57 (multiplet, 1H), 2.48 - 2.31 (multiplet, 1H), 2.09 - 1.97 (multiplet, 1H), 1.40 - 1.24 (multiplet, 1H), 0.63 - 0.49 (multiplet, 2H), 0.47 - 0.31 (multiplet, 2H). LCMS (ESI+): m / z 452.0 [M+H] + 。

[0105] Example 6 The preparation of the following compound is the same as the steps described for Compound 2, and the corresponding starting materials are aldehyde and Grignard reagent (Example 5).

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

[0106] Example 7 Preparation of Compound 4: N-((3,3-Difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chem.

[0107] Step 3: (S)-N-((3,3-Difluorocyclobutyl)(4-fluorophenyl)methyl)-2-methylpropan-2-sulfinamide 4-4 At -48 °C, 4-fluorophenylmagnesium bromide (1 M, 3.54 mL) was added dropwise to a solution of (S)-N-((3,3-difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide intermediate 4-3 (316 mg, 1.42 mmol) in DCM (2.4 mL). After the addition was complete, the reaction mixture was stirred at this temperature for 5 h. The resulting mixture was stirred at 25 °C for 16 h. At 25 °C, saturated NH 4 Cl solution was added to the reaction solution to quench it, then diluted with DCM (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 , PE / EtOAc = 5 / 1 - 0 / 1) and further purified by preparative high performance liquid chromatography to obtain the title product (340 mg, yield 75%), which is a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.49 - 7.42 (m, 1H), 7.42 - 7.35 (m, 1H), 7.15 (t, J = 8.8 Hz, 2H), 5.82 - 5.56 (m, 1H), 4.31 - 4.09 (m, 1H), 2.74 - 2.51 (m, 3H), 2.39 - 2.20 (m, 2H), 1.17 - 1.06 (m, 6H), 1.04 (s, 3H). LCMS (ESI+): m / z 319.98 [M+H] + .

[0108] Step 4: (3,3-Difluorocyclobutyl)(4-fluorophenyl)methanamine 4-5 Hydrochloric acid / dioxane (4 M, 2.0 mL) was added to a solution of (S)-N-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide intermediate 4-4 (100 mg, 313 μmol) in DCM (2 mL). The mixture was stirred at 25 °C for 4 h and then concentrated under reduced pressure. The title product (90 mg, crude product, HCl salt) was obtained, which is a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ 8.60(s,2H),7.72 - 7.50(m,2H),7.29(t,J = 8.8Hz,2H),4.36(s,1H),3.57(s,1H),2.78 - 2.68(m,2H),2.42 - 2.22(m,2H). LCMS(ESI+):m / z 215.99[M + H] + 。

[0109] Step 5: N - ((3,3 - Difluorocyclobutyl)(4 - fluorophenyl)methyl)-2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindoline - 5 - carboxamide Compound 4 (3,3 - Difluorocyclobutyl)(4 - fluorophenyl)methanamine Intermediate 4 - 5 (40.0 mg, 159 μmol) and a solution of 2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindoline - 5 - carboxylic acid Intermediate 1 in DCM (2 mL) were added with TEA (42.0 mg, 416 μmol) and T 3 P (177 mg, 278 μmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative high - performance liquid chromatography to give the title product, Compound 4 (50.0 mg, yield 74%), which is a white solid. 1 H NMR(400 MHz, DMSO - d 6 )δ 11.01(s,1H),9.07(d,J = 8.4Hz,1H),8.06(s,1H),7.98(d,J = 8.0Hz,1H),7.83(d,J = 7.6Hz,1H),7.55 - 7.45(m,2H),7.18(t,J = 8.4Hz,2H),5.22 - 5.03(m,2H),4.56 - 4.48(m,1H),4.44 - 4.36(m,1H),3.02 - 2.84(m,1H),2.71(s,2H),2.61(d,J = 16.8Hz,1H),2.47 - 2.30(m,4H),2.11 - 1.96(m,1H); LCMS(ESI+):m / z 486.1[M + H] + 。

[0110] Example 8 Preparation of Compound 5 and Compound 6: N-((*R)-((3,3-Difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide and N-((*S)-((3,3-Difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical Structure

[0111] Example 9 Preparation of Compound 7: N - ((S) - cyclobutyl(4 - fluorophenyl)methyl) - 2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindoline - 5 - carboxamide

Chemical Structure

[0112] Step 2: Synthesis of (S)-N-(((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide 7-3 At -78 °C under N 2 Under protection, to a solution of (S)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide intermediate 7-2 (600 mg, 3.20 mmol) in THF (10 mL) was added 1 M (4-fluorophenyl)magnesium bromide (9.61 mL, 9.61 mmol), and then the mixture was stirred at 25 °C under N 2 Under protection for 12 h. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with water (5 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification was performed by flash silica gel chromatography (ISCO (registered trademark); quickly passing 4 g of SepaFlash (registered trademark) silica gel through the column, with an eluent gradient of 0 - 100% ethyl acetate / petroleum ether at 30 mL / min). The compound (S)-N-(((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide intermediate 7-3 (90 mg, yield 9%) was obtained as a white oil. LCMS (ESI+): m / z 284.3 [M + H] + .

[0113] Step 3: Synthesis of (*S)-cyclobutyl(4-fluorophenyl)methanamine 7-4 At -78 °C under N 2Under protection, hydrochloric acid / dioxane (4 M, 1.59 mL) is added to a solution of (S)-N-(((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide intermediate 7-3 (90.0 mg, 318 μmol) in DCM (20 mL). After the mixture is stirred at 25 °C for 30 minutes, it is concentrated under reduced pressure. (*S)-Cyclobutyl(4-fluorophenyl)methanamine intermediate 7-4 (65 mg, crude product, HCl salt) is obtained as a white solid. LCMS (ESI+): m / z 180.2 [M+H] + .

[0114] Step 4: N-(((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide Compound 7 (*S)-Cyclobutyl(4-fluorophenyl)methanamine intermediate 7-4 (65.0 mg, 301 μmol) and 2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid intermediate 1 (95.6 mg, 331 μmol) in DCM (2 mL) are added with TEA (192 mg, 301 μmol) and T 3 P (30.5 mg, 301 μmol). The mixture is stirred at 25 °C for 16 hours. The reaction mixture is concentrated under reduced pressure to obtain a residue, which is purified by preparative high performance liquid chromatography to obtain Compound N-(((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide Compound 7 (80.9 mg, yield 60%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ 11.04(s,1H),8.90(d,J=8.4Hz,1H),8.05(s,1H),7.97(d,J=8.0Hz,1H),7.82(d,J=7.0Hz,1H),7.44(dd,J=5.6,8.4Hz,2H),7.19-7.11(m,2H),5.14(dd,J=5.2,13.2Hz,1H),5.05-4.95(m,1H),4.58-4.34(m,2H),2.98-2.87(m,1H),2.84-2.72(m,1H),2.68-2.59(m,1H),2.47-2.33(m,1H),2.13-1.98(m,2H),1.86-1.69(m,5H);LCMS(ESI+):m / z 450.1[M+H] + 。

[0115] Example 10 Preparation of Compound 8 and Compound 9: N-((S)-Cyclobutyl(4-fluorophenyl)methyl)-2-((R)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide, and N-((S)-Cyclobutyl(4-fluorophenyl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical Structure

[0116] Example 11 The preparation of the following compounds is the same as the steps described for Compound 4, and the corresponding starting materials are aldehydes and Grignard reagents (Example 7). For Compounds 35, 36, 38, 58, 59, 66, 67, 69 and 70, before Steps 3 and 4, the corresponding major diastereomeric intermediates of Step 2 are separated using preparative liquid chromatography or SFC.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

[0117] Example 12 Preparation of Compound 65: 2-(2,6-Dioxopiperidin-3-yl)-N-((R)-(4-fluorophenyl)(1-hydroxycyclopropyl)methyl)-1-oxoisoindoline-5-carboxamide

Chem.

[0118] Step 2: (R)-1-((Dibenzylamino)(4-fluorophenyl)methyl)cyclopropanol 65-3 At 20 °C, Ti(i-PrO) 4 (193 mg, 678 μmol) is added to a solution of (2R)-2-(dibenzylamino)-2-(4-fluorophenyl)acetate (500 mg, 1.38 mmol) in THF (5 mL). React for 1.5 h, then add EtMgBr (3 M, 1.67 mL). After the addition is complete, quench the reaction mixture with saturated NH 4 Cl solution. Stir at room temperature for 30 min, then filter the mixture through diatomaceous earth, transfer it to a separatory funnel, and dilute with ethyl acetate (250 mL). Separate each layer and extract the aqueous layer with ethyl acetate (50 mL × 3). Combine the organic extracts, dry over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a residue. Purify the residue by preparative liquid chromatography (TFA conditions). Compound 1-[(R)-(dibenzylamino)-(4-fluorophenyl)methyl]cyclopropanol (269 mg, yield 32%) is a colorless oil. LCMS (ESI+): m / z 362.10 [M+H] + .

[0119] Step 3: (R)-1-(Amino(4-fluorophenyl)methyl)cyclopropanol 65-4 N 2 Under N 2 protection, Pd / C (10%, 50 mg) is added to a solution of 1-[(R)-(dibenzylamino)-(4-fluorophenyl)methyl]cyclopropanol (80 mg, 221 μmol) in EtOH (3 mL). Degas the suspension and purge with H 2(35 Psi), stir for 20 hours. After 20 hours, add diatomaceous earth and filter the slurry. Wash the filter cake with ethanol (25 mL x 5), combine the filtrates, concentrate after adding 4.0 M hydrochloric acid / dioxane (0.12 mL), and triturate the residue with ethyl acetate (1 mL). Compound 1-[(R)-amino-(4-fluorophenyl)methyl]cyclopropanol (22 mg, crude product, hydrochloride) is a white solid. LCMS (ESI+): m / z 182.1 [M+H] + .

[0120] Step 4: 2-(2,6-dioxopiperidin-3-yl)-N-((R)-(4-fluorophenyl)(1-hydroxycyclopropyl)methyl)-1-oxoisoindoline-5-carboxamide Compound 65 The preparation of the compound is the same as the steps described for Compound 1. Compound 65: 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (br s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 5.55 (s, 1H), 5.18 - 5.10 (m, 1H), 4.85 (d, J = 8.8 Hz, 1H), 4.60 - 4.48 (m, 1H), 4.45 - 4.36 (m, 1H), 2.98 - 2.85 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.41 (d, J = 4.4 Hz, 1H), 2.08 - 1.97 (m, 1H), 0.86 - 0.75 (m, 1H), 0.72 - 0.60 (m, 3H)). LCMS (ESI+): m / z 452.1 [M+H] + .

[0121] Example 13 Preparation of Compound 76 and Compound 77: N-((*S)-(5-Chloropyridin-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide, and N-((*R)-(5-Chloropyridin-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chem.

Chem.

[0122] Step 2: Synthesis of N-((5-Chloropyridin-2-yl)(cyclobutyl)methyl)-2-methylpropan-2-sulfinamide

Chem.

[0123] Step 3: Synthesis of (5-chloropyridin-2-yl)(cyclobutyl)methanamine

Chem.

[0124] Step 4: Synthesis of N-((5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical Structure

[0125] Step 5: N-((*S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (Compound 76, Peak 1), and N-((*R)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (Compound 77, Peak 2)

Chem.

[0126] Example 14 The preparation of the following compounds is the same as the steps described for Compounds 76 and 77, and the corresponding starting materials are aldehydes and Grignard reagents, and the following coupling steps (Example 13). For Compounds 77, 78, 79, 80 and 81, before the following steps, the corresponding main diastereomeric intermediates are separated using preparative high performance liquid chromatography or SFC.

Table 5-1

Table 5-2

[0127] Example 15 Preparation of Compound 82: N-(((*S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical formula

[0128] Step 1: Synthesis of (R)-N-(cyclobutylmethylene)-2-methylpropan-2-sulfinamide

Chemical formula

[0129] Step 2: Synthesis of (R)-N-(((*S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-methylpropan-2-sulfinamide

Chemical formula

[0130] Step 3: Synthesis of (*S)-(5-chloropyridin-2-yl)(cyclobutyl)methanamine

Chemical formula

[0131] Step 4: Synthesis of t-butyl (S)-5-amino-4-(5-((*S))-(5-chloropyridin-2-yl)(cyclobutyl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (*S)-(5-chloro-2-pyridyl)-cyclobutylmethanamine (3.25 g, 12.3 mmol, HCl salt), (S)-2-(1-amino-5-(t-butyl)-1,5-dioxopentan-2-yl)-1-oxoisoindoline-5-carboxylic acid (4.67 g, 12.9 mmol) and NMM (6.2 g, 61.3 mmol) are mixed in DMAC (50 mL), and HATU (5.6 g, 14.7 mmol) is added. The mixture is degassed and purged with N 2 three times. At 25 °C, it is stirred for 12 hours under N 2 protection. The mixture is poured into saturated NaCl solution (100 mL) and washed with water (100 mL) after filtration. The filter cake is dissolved in DCM (200 mL) and washed with saturated NaHCO 3 (100 mL), and then with anhydrous Na 2 SO 4Dry it and filter and concentrate under reduced pressure. The compound t-butyl (S)-5-amino-4-(5-((*S))-(5-chloropyridin-2-yl)(cyclobutyl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (6.5 g, yield 95.0%) is a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ 8.96(d,J=8.0Hz,1H),8.61(d,J=2.4Hz,1H),8.12(s,1H),8.03(d,J=7.6Hz,1H),7.96(dd,J=2.4,8.4Hz,1H),7.84(d,J=7.6Hz,1H),7.67(s,1H),7.56(d,J=8.4Hz,1H),7.29(s,1H),5.30-5.11(m,1H),4.81(m,1H),4.75-4.52(m,2H),2.98-2.86(m,1H),2.27-2.12(m,4H),1.98-1.78(m,6H),1.39(s,9H);LCMS(ESI+):m / z 541.4[M+H] + 。

[0132] Step 5: Synthesis of Compound 82: N-((*S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical Structure

[0133] Example 16 Preparation of Compound 83: N-((*S)-cyclobutyl(3-(4-fluorophenyl)pyridin-2-yl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical formula

[0134] Step 1: Synthesis of 3-(4-fluorophenyl)-pyridinealdehyde

Chemical formula

[0135] Step 2: Synthesis of (S)-N-((3-(4-chlorophenyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

Chemical formula

[0136] Step 3: Synthesis of (*S)-N-(cyclobutyl(3-(4-fluorophenyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

Chemical formula

[0137] Step 4: Synthesis of cyclobutyl(3-(4-fluorophenyl)pyridin-2-yl)methanamine

Chemical formula

[0138] Step 5: N-((*S)-cyclobutyl(3-(4-fluorophenyl)pyridin-2-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (Compound 83)

Chemical formula

[0139] Example 17 Preparation of Compound 84: N-(((*S)-Cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chem.

Chem.

[0140] Step 2: Synthesis of 2-methyl-N-((3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methylene)propan-2-sulfinamide

Chem.

[0141] Step 3: Synthesis of N-(cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-methylpropan-2-sulfinamide

Chem.

[0142] Step 4: Synthesis of cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methanamine

Chemical formula

[0143] Step 5: Synthesis of tert-butyl (4S)-5-amino-4-(5-((cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

Chemical formula

[0144] Step 6: tert-butyl (S)-5-amino-4-(5-(((S)-cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

Chemical formula

[0145] Step 7: N-((*S)-cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyrrol-2-yl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (Compound 84) [Chemical formula] t-butyl (S)-5-amino-4-(5-(((*S)-cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (70 mg, 119 μmol) and benzenesulfonic acid (56.6 mg, 358 μmol) were mixed in CH 3 CN (10 mL), degassed, and purged 3 times with N 2 . 2Under protection, stir at 90 °C for 3 hours. Concentrate the mixture under reduced pressure. Purify the crude product by reverse-phase high-performance liquid chromatography (FA conditions). The compound N-((*S)-cyclobutyl(3-(1-methyl-1H-pyrazol-4-yl)pyrrol-2-yl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (18.09 mg, yield 29.6%, purity 100%) is a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.01 (br.s., 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 8.03 - 7.99 (m, 1H), 7.88 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.33 - 7.24 (m, 1H), 5.70 - 5.60 (m, 1H), 5.18 - 5.08 (m, 1H), 4.57 - 4.34 (m, 2H), 3.95 (s, 3H), 2.99 - 2.80 (m, 2H), 2.68 - 2.56 (m, 1H), 2.47 - 2.36 (m, 1H), 2.08 - 1.92 (m, 2H), 1.86 - 1.75 (m, 1H), 1.74 - 1.55 (m, 3H), 1.47 - 1.35 (m, 1H); LCMS (ESI+): m / z 513.4 [M+H] + , retention time: 2.221 min; SFC retention time: 3.581 min.

[0146] Example 18 Preparation of Compound 85: N-((*R)-(3-chloro-5-fluoropyridin-2-yl)(1-fluorocyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

Chemical formula

[0147] Step 1: Synthesis of 1-fluorocyclobutane-1-acetaldehyde

Chemical formula

[0148] Step 2: Synthesis of (R)-N-(1-fluorocyclobutylmethylene)-2-methylpropan-2-sulfinamide [Chemical formula] To a solution of 1-fluorocyclobutanecarboxaldehyde (400 mg, 3.92 mmol, crude product) and (R)-2-methylpropan-2-sulfinamide (950 mg, 7.83 mmol) in DCM (10 mL) are added PPTS (98.5 mg, 39.0 μmol) and CuSO 4 (1.25 g, 7.83 mmol). Stir at 20 °C for 12 hours, filter, and concentrate the filtrate under reduced pressure. Purify by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica gel flash column 20 g, eluent 0 - 100% ethyl acetate / petroleum ether gradient @ 20 mL / min). The compound (R)-N-(1-fluorocyclobutylmethylene)-2-methylpropan-2-sulfinamide (600 mg, yield 74.6%) is a colorless oil. LCMS (ESI+): m / z 206.9 [M+H] +

[0149] Step 3: Synthesis of (R)-N-((*R)-(3-chloro-5-fluoropyridin-2-yl)(1-fluorocyclobutane)methyl)-2-methylpropane-2-sulfinamide

Chemical formula

[0150] Step 4: Synthesis of (*R)-(3-chloro-5-fluoropyridin-2-yl)(1-fluorocyclobutane)methylene

Chem.

[0151] Step 5: Synthesis of N-((*R)-(3-chloro-5-fluoropyridin-2-yl)(1-fluorocyclobutane)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (Compound 85):

Chem.

[0152] Example 19 The preparation of the following compounds is the same as the steps described for compound 84, and the corresponding starting materials are aldehydes and Grignard reagents, and the following coupling step (Example 18). For compounds 86, 87, 88, and 89, before the following steps, the corresponding sulfenamide diastereomer intermediates are separated by preparative liquid chromatography or SFC. [Table 6-1] [Table 6-2]

[0153] Example 20 CK1α and GSPT1 degradation assay (HiBiT assay) The following is a test experiment that can be used to determine the dose-dependent CK1α and GSPT1 degradation activities of test compounds against human cell lines such as HT-1080 (ATCC Cat# CRL-9591). Using an acoustic dispenser (Echo, Beckman Coulter), dispense test compounds in a concentration range increasing in 3.16-fold increments from 3.162×10 -4 μM to 10 μM into a 384-well plate (Cat# 3764, Corning). Using complete DMEM cell medium (containing 10% heat-inactivated FBS), seed wild-type CRBN, GSPT1Δ(1-138) / G575N mutant, and HT-1080 cells stably overexpressing HiBiT-tagged CK1α or GSPT1 into 384-well plates pre-dispensed with DMSO or test compounds, inoculating approximately 10,000 cells per well. Incubate the measurement plates in a cell incubator at 37 °C and 5% CO 2 for 20 hours. Then, according to the manufacturer's instructions, add Nano-Glo HiBiT Thermostable Detection Reagent (Cat# N3050, Promega) to evaluate the degradation of CK1α or GSPT1. Next, measure the bioluminescence values using an EnVision (PerkinElmer) or PHERAstar (BMG Labtech) multifunctional plate reader. All CK1α or GSPT1 degradation curves are processed using Collaborative Drug Discovery Library software (Burlingame, CA, www.collaborativedrug.com). Normalize the CK1α or GSPT1 levels in the compound test wells to the DMSO control and express as a percentage (PoC, y) relative to the DMSO control. Use a four-parameter logistic regression model to determine the EC 50 and DC 50 of the compound, and the calculation formula is as follows. y=(A+((B - A) / (1+((C / x) A D)))) where A = Y min (the minimum value of the CK1α or GSPT1 reading after treatment of the test sample, calculated by the fitting curve) B = Y max(Maximum value, i.e., the reading of CK1α or GSPT1 in the sample treated with DMSO) C = EC 50 Half-maximal concentration D = Hill slope x = Concentration of the compound EC 50 = y = (Y max - Y min ) / 2 in the case of the test sample concentration DC 50 = y = Test sample concentration when the reading of CK1α or GSPT1 in the sample treated with DMSO is 50% y = Reading of CK1α or GSPT1 after treatment with the test sample (normalized to the reading of CK1α or GSPT1 in the sample treated with DMSO) D max =(1 - Y min / Y max ) * 100% D max represents the maximum percentage of degradation of CK1α or GSPT1 protein that can be achieved after treatment with the compound under the highest compound concentration. Results: Using the above method, D max and DC 50 data of the representative compounds in Table 7 are measured.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

[0154]

Chemical Structure

[0155] Example 21 MV4 - 11 Cell Proliferation Experiment The following is a test experiment that can be used to determine the dose - dependent anti - proliferative activity of CK1α - degrading compounds in AML cell lines (e.g., MV4 - 11 (ATCC Cat# CRL - 9591)). Using an acoustic dispenser (Echo, Beckman Coulter), dispense test compounds in a concentration range that increases in 3.162 - fold increments from 1×10 -3 μM to 10 μM (test with 10 data points) or from 3.162×10 -4 μM to 10 μM (test with 11 data points) into a 384 - well plate (Cat# 3764, Corning). Using complete IMDM cell medium (containing 10% heat - inactivated FBS), inoculate MV4 - 11 cells into the 384 - well plate pre - dispensed with DMSO or test compounds, inoculating approximately 2000 cells into 50 μL of medium per well. Incubate the experimental plate at 37°C and 5% CO 2Incubate for 120 hours in a cell incubator. Then, add 20 μL of CellTiter-Glo luminescent cell viability assay reagent (Cat# G7573, Promega) to each well and incubate for 30 minutes at room temperature. Next, measure the bioluminescence values using an EnVision (PerkinElmer) or PHERAstar (BMGLabtech) multifunctional plate reader. All cell growth inhibition curves are processed using Collaborative Drug Discovery Libarary software (Burlingame, CA, www.collaborativedrug.com). Normalize the cell viability reading levels in the compound test wells to the DMSO control and express as a percentage (PoC, y) relative to the DMSO control. Use a four-parameter logistic regression model to determine the EC 50 and DC 50 as follows. The calculation formula is as follows. y=(A+((B-A) / (1+((C / x) A D)))) Here, A = Y min (The minimum value of the cell viability reading after treatment of the test sample, calculated by the fitting curve) B = Y max (The maximum value, i.e., the cell viability reading in the sample treated with DMSO) C = EC 50 Half inhibitory concentration D = Hill slope x = Concentration of the compound EC 50 = y = (Y max - Y min ) / 2 of the test sample concentration IC 50 = y = The test sample concentration when the cell viability reading in the sample treated with DMSO is 50% y = Cell viability reading after treatment of the test sample (normalized to the cell viability reading in the sample treated with DMSO) Y min=A / B*100% Y min represents the lowest cell viability % achievable by compound treatment in the experiment.

Table 8

[0156] KG-1a cell proliferation experiment Consistent with the reported unique mechanism of the antitumor response by CK1α inactivation in AML (Jaras et al., J Exp Med (2014) 211(4):605 - 612), we discovered that AML cell lines with lost p53 function are insensitive to CK1α degradation. On the other hand, according to reports, most AML cell lines are sensitive to GSPT1 degradation induced by CC-885 or CC-90009 regardless of their p53 mutation status (Matyskiela et al., Nature (2016) 535:252 - 257; Surka et al., Blood (2021) 137(5):661 - 677). Since even mild to moderate GSPT1 degradation induced by CK1α degraders may cause in vivo toxicity in humans, to determine the GSPT1-mediated cytotoxicity in vitro, we perform a reverse screening using the AML cell line KG-1a (ATCC Cat# CCL-246.1) containing p53 mutations. The following are examples of measurements that can be used to determine the potential GSPT1-dependent cytotoxicity of test compounds (when the test compound can degrade GSPT1). Using an acoustic dispenser (Echo, Beckman Coulter), add DMSO or 1×10 -3 μM to 10 μM (test with 10 data points) or 3.162×10 -4Dispense test compounds in a concentration range that increases in 3.16-fold increments from μM to 10 μM (test with 11 data points). Using complete IMDM cell medium (containing 10% heat-inactivated FBS), inoculate KG-1a cells into 384-well plates pre-dispensed with DMSO or test compounds, inoculating approximately 2000 cells into 50 μL of medium per well. Incubate the experimental plates in a cell incubator at 37 °C and 5% CO 2 for 120 hours. Then, add 20 μL of CellTiter-Glo luminescent cell viability assay reagent (Cat# G7573, Promega) to each well and incubate for 30 minutes at room temperature. Next, measure the bioluminescence values using an EnVision (PerkinElmer) or PHERAstar (BMGLabtech) multifunctional plate reader. All cell growth inhibition curves are processed using Collaborative Drug Discovery Libarary software (Burlingame, CA, www.collaborativedrug.com). Normalize the cell viability reading levels in the compound test wells to the DMSO control and express as a percentage (PoC, y) relative to the DMSO control. Use a four-parameter logistic regression model to determine the EC 50 and DC 50 of the compound, and the calculation formula is as follows. y = (A + ((B - A) / (1 + ((C / x) A D)))) Here,[[]] A = Y min (The minimum value of the cell viability reading after treatment of the test sample is calculated by the fitting curve) B = Y max (The maximum value, i.e., the cell viability reading in the sample treated with DMSO) C = EC 50 Half-inhibitory concentration D = Hill slope x = Concentration of the compound EC 50 = y = (Y max - Y minTest sample concentration in the case of () / 2 IC 50 = y = Test sample concentration when the cell viability reading value in the sample treated with DMSO is 50% y = Cell viability reading value after treatment with the test sample (normalized to the cell viability reading value in the sample treated with DMSO) Y min = A / B * 100% Y min represents the lowest percentage of cell viability that can be achieved by compound treatment in the experiment.

Table 9

[0157] Example 22 Pharmacokinetic study of single intravenous and oral administration in CD1 mice Sample collection and preparation: After intravenous injection or oral administration of the test compound, blood samples are collected and the blood collection time is recorded. Immediately after collecting the blood samples, transfer them to a labeled centrifuge tube containing K 2 -EDTA, and collect plasma after centrifugation. Next, transfer the plasma to a pre-cooled centrifuge tube, rapidly freeze it on dry ice, and store it in an ultra-low temperature freezer at -70 ± 10 °C until LC-MS / MS analysis. Pharmacokinetic data analysis: Using pharmacokinetic software, process the blood drug concentration data of the compound under a non-compartmental model. The blood drug concentration-time graph can directly obtain the peak concentration (C max ), the time to reach the peak (T max ), and the quantifiable end time. Using the log-linear trapezoidal method, calculate the following pharmacokinetic parameters: half-life (T 1 / 2 ), apparent volume of distribution (V dss ), clearance (Cl), area under the time-blood drug concentration curve (AUC 0-inf ).

Table 10

[0158] Experimental conclusion: The compounds of the present invention exhibit low clearance, good oral exposure, and higher oral bioavailability.

Claims

1. A compound represented by Structural Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein herein 【Chemical Formula 2】 The moiety is C optionally substituted by 1 to 6 R ａ - a 4- to 10-membered monocyclic heterocyclyl group having 1 to 3 heteroatoms selected from cycloalkyl group, N, O, S, optionally substituted by 1 to 6 R ３ - ８ and is ａ optionally substituted by R Each R ａ independently represents hydrogen, halogen, hydroxy group, nitro group, cyano group, amino group, mercapto group, -COOH, C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, C １ -C ６ alkoxy group, C ２ -C ６ alkenyloxy group, C ２ -C ６ alkynyloxy group, C ２ -C ６ alkanoyl group, C ２ -C ６ alkyl ester, C １ -C ６ thioalkyl group, C １ -C ６ halogenated alkyl group, C １ -C ６ halogenated alkoxy group, hydroxy C １ -C ６ alkyl group, amino C １ -C ６ alkyl group, (mono- and bis-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -C ０ -C ４ alkyl-(phenyl), -C ０ -C ４ alkylOC(O)OC １ -C ６ alkyl group, -C ０ -C ４ alkylOC(O)C １ -C ６ alkyl group, -C ０ -C ４ alkyl C(O)OC １ -C ６ C having 1, 2 or 3 heteroatoms independently selected from alkyl groups, N, O and S ０ -C ４ alkyl-(4-7 membered heterocycloalkyl), C having 1, 2 or 3 heteroatoms independently selected from N, O and S ０ -C ４ alkyl-(5-6 membered unsaturated or aromatic heterocycle), -C(O)OR １１ , -C ０ -C ４ alkylNR １１ R １２ , -C(O)NR １１ R １２ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -OC(O)R １１ and -C(NR １１ )NR １１ R １２ selected from the group consisting of, wherein R １１ and R １２ are independently hydrogen, C １ -C ６ alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl) and -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl) selected from the group consisting of, herein [Chemical Formula 3] The moiety is a 6- to 10-membered aryl group optionally substituted by 1 to 6 Rs ｂ and a 5- to 10-membered heteroaryl group optionally substituted by 1 to 6 Rs ｂ having 1 to 3 heteroatoms selected from N, O, and S Each R ｂ independently represents hydrogen, a halogen, a hydroxy group, a nitro group, a cyano group, an amino group, a mercapto group, -COOH, C １ -C ６ an alkyl group, C ２ -C ６ an alkenyl group, C ２ -C ６ an alkynyl group, C １ -C ６ an alkoxy group, C ２ -C ６ an alkenyloxy group, C ２ -C ６ an alkynyloxy group, C ２ -C ６ an alkanoyl group, C ２ -C ６ an alkyl ester, C １ -C ６ a thioalkyl group, C １ -C ６ a halogenated alkyl group, C １ -C ６ a halogenated alkoxy group, hydroxy C １ -C ６ an alkyl group, amino C １ -C ６ an alkyl group, (mono- and bis-C １ -C ６ alkylamino)C ０ -C ４ an alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -C ０ -C ４ alkyl(phenyl), -C ０ -C ４ alkylOC(O)OC １ -C ６ an alkyl group, -C ０ -C ４ alkylOC(O)C １ -C ６ an alkyl group, -C ０ -C ４ alkyl C(O)OC １ -C ６ C having 1, 2 or 3 heteroatoms independently selected from alkyl groups, N, O and S ０ -C ４ alkyl-(4-7 membered heterocycloalkyl), C having 1, 2 or 3 heteroatoms independently selected from N, O and S ０ -C ４ alkyl-(5-6 membered unsaturated or aromatic heterocycle), -C(O)OR １１ , -C ０ -C ４ alkylNR １１ R １２ , -C(O)NR １１ R １２ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -OC(O)R １１ and -C(NR １１ )NR １１ R １２ selected from the group consisting of, wherein R １１ and R １２ are independently hydrogen, C １ -C ６ alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl) and -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), the said compound.

2. The compound is a compound represented by Structural Formula (I-1) or (I-2), 【Chemical Formula 6】 [Chemical Formula 7] or a pharmaceutically acceptable salt thereof, wherein herein 【Chemical 8】 the moiety and 【Chemical Formula 9】 the moiety are as defined in Claim 1, characterized in that the compound according to Claim 1.

3. 【Fig. 10】 The moiety is 【Chemical 11】 selected from the group consisting of herein in each case, n is independently 0, 1, 2, 3, 4, 5 or 6, In each case, X １ is, independently, C, N, O or S, In each case, X ２ is, independently, C, N, O or S, In each case, X ３ is, independently, C, N, O or S, In each case, X ４ is, independently, C, N, O or S, In each case, X ５ is, independently, C, N, O or S, In each case, X ６ is independently C, N, O or S, and R ａ is as defined in claim 1, characterized in that the compound according to Claim 1 above.

4. 【Fig. 12】 The moiety is 【Chemical 13】 selected from the group consisting of herein, in each case, n is independently 0, 1, 2, 3, 4 or 5, R ａ is as defined in claim 3, characterized in that the compound according to Claim 3 above.

5. 【Fig. 14】 The moiety is 【Chemical Formula 15】 wherein, herein in each case, m is independently 0, 1, 2, 3, 4 or 5, In each case, Y １ is independently C, N, O, or S, In each case, Y ２ is independently C, N, O or S, In each case, Y ３ is independently C, N, O or S, In each case, Y ４ is independently C, N, O or S, In each case, Y ５ is independently C, N, O or S, and R ｂ is as defined in claim 1, characterized in that the compound according to Claim 1 above.

6. 【Fig. 16】 The moiety is 【Chemical 17】 selected from the group consisting of herein in each case, m is independently 0, 1, 2, 3, 4 or 5, R ｂ is as defined in claim 5, characterized in that the compound according to Claim 5 above.

7. The compound is a compound selected from the group consisting of the following Structural Formulas (II), (III), (IV), (V) and (VI), 【Chemical 18】 or a pharmaceutically acceptable salt thereof, wherein herein in each case, m is independently 0, 1, 2, 3, 4 or 5, in each case, n is independently 0, 1, 2, 3, 4, 5 or 6, In each case, X １ is, independently, C, N, O or S, In each case, X ２ is, independently, C, N, O or S, In each case, X ３ is, independently, C, N, O or S, In each case, X ４ is, independently, C, N, O or S, In each case, X ５ is independently C, N, O or S, In each case, X ６ is, independently, C, N, O or S, In each case, Y １ is independently C, N, O or S, In each case, Y ２ is independently C, N, O or S, In each case, Y ３ is independently C, N, O or S, In each case, Y ４ is independently C, N, O or S, In each case, Y ５ is independently C, N, O or S, and R ａ and R ｂ is as defined in claim 1, characterized in that the compound according to Claim 1 above.

8. The compound is a compound represented by Structural Formula (I-7) or (I-8), 【Chemical 19】 or a pharmaceutically acceptable salt thereof, wherein herein m, n, R ａ and R ｂ is as defined in claim 7, characterized in that the compound according to Claim 7 above.

9. The compound is a compound represented by Structural Formula (I-9) or (I-10), 【Chemical 20】 or a pharmaceutically acceptable salt thereof, wherein herein m, n, R ａ and R ｂ are as defined in claim 7, characterized in that the compound according to Claim 7 above.

10. Each R ａ is independently selected from the group consisting of hydrogen, halogen, hydroxy group, nitro group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ halogenated alkyl group, C １ -C ６ heterocycloalkyl group, -N-(C １ -C ６ alkyl), ２ C １ -C ６ alkyl-C １ -C ６ heterocycloalkyl group, characterized in that it is selected from the group consisting of The compound according to Claim 1 above.

11. Each R ｂ independently represents hydrogen, halogen, hydroxy group, nitro group, cyano group, amino group, mercapto group, C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, C １ -C ６ alkoxy group, C １ -C ６ halogenated alkyl group, C １ -C ６ halogenated alkoxy group, amino C １ -C ６ alkyl group, (mono- and bis-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), C having 1, 2 or 3 heteroatoms independently selected from N, O and S ０ -C ４ alkyl-(4- to 7-membered heterocycloalkyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S ０ -C ４ alkyl-(5- to 6-membered unsaturated or aromatic heterocyclic ring), -C(O)OR １１ , -C ０ -C ４ alkylNR １１ R １２ , -C(O)NR １１ R １２ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -OC(O)R １１ and -C(NR １１ )NR １１ R １２ selected from the group consisting of, wherein R １１ and R １２ are each independently hydrogen, C １ -C ６ alkyl group, -C ０ -C ４ alkyl (C ３ -C ７ cycloalkyl) and -O-C ０ -C ４ alkyl (C ３ -C ７ cycloalkyl), characterized in that it is selected from the group consisting of The compound according to Claim 1 above.

12. The compound or a pharmaceutically acceptable salt thereof is characterized in that it is selected from the group consisting of the compound or a pharmaceutically acceptable salt thereof according to Claim 1 above. 【Chemical Formula 21-1】 【Chemical Formula 21-2】 [[Chemical Formula 21-3]] 【Chemical 21-4】 [[Chemical 21-5]] [[Chemical 21-6]] 【Chemical 21-7】 ​ 【Chemical Formula 21-9】

13. The compound is 【Chemical 22】 【Chemical 23】 characterized in that it is selected from the group consisting of the compound according to Claim 1 above.

14. A pharmaceutical composition, wherein The pharmaceutical composition is characterized by comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, said pharmaceutical composition.

15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for treating a proliferative disease, wherein the proliferative disease includes breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, lymphatic organ cancer and hematological malignancy, the use.

16. The use according to claim 15, wherein the hematological malignancy includes leukemia, lymphoma and multiple myeloma.

17. The use according to claim 15, wherein the hematological malignancy is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, small lymphocytic lymphoma (SLL), Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphoblastic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, mycosis fungoides / Sézary syndrome, primary cutaneous CD30-positive T-cell proliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, plasmacytic myeloma and Kahl disease, the use according to claim 15.

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