Indolone derivative and application thereof

Abstract

The invention relates to an indolone derivative and application thereof, and the indolone derivative can enhance degradation of target protein and can be used for preparing antitumor drugs.

Description

Indolinone derivative and its application Technical Field

[0001] The present invention relates to an indolinone derivative and application thereof. Background Art

[0002] A proteolysis targeting chimera (PROTAC) is a small molecule that recruits E3 ubiquitin ligases to target proteins to promote their degradation. Bifunctional PROTACs can recognize and simultaneously bind to target proteins and E3 ubiquitin ligases, inducing spatial proximity between the target protein and the E3 ubiquitin ligase, facilitating ubiquitination of the target protein and subsequent degradation by the proteasome, thereby selectively reducing the target protein's levels in vivo.

[0003] HPK1 (hematopoietic progenitor kinase 1), also known as MAP4K1, belongs to the MAP4K family and is a serine / threonine kinase primarily expressed in hematopoietic cells. HPK1 negatively regulates T and B cell immune responses through the AP-1, NF-κB, Erk2, and Fos pathways, inhibiting T cell proliferation and downregulating B cell receptor signaling. Studies have shown that inhibiting HPK1 can enhance T and B cell activity, thereby improving anti-tumor immunity. Therefore, HPK1 inhibition holds promise as an innovative cancer treatment, potentially enabling its combination with existing cancer immunotherapies to enhance therapeutic efficacy.

[0004] Compared to traditional small-molecule HPK1 inhibitors, PROTAC compounds possess dual functionality, not only inhibiting HPK1 activity but also catalytically promoting multiple rounds of HPK1 degradation, reducing HPK1 levels. This allows PROTAC compounds to effectively inhibit HPK1 resistance mutations and / or upregulation, resulting in improved tolerability. Therefore, PROTACs offer a novel mechanism for treating HPK1-mediated diseases.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide an indolinone derivative capable of enhancing the degradation of target protein and its application in the preparation of anti-tumor drugs.

[0007] One or more embodiments of the present invention provide a compound capable of enhancing target protein degradation, a compound represented by formula (I), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof:

[0008] PTM-L-ULM (I);

[0009] in,

[0010] The L is

[0011] Said R2 does not exist; or said R2 is selected from

[0012] The A ring and the B ring are each independently selected from a 3-12 membered carbocyclylene group and a 3-12 membered heterocyclylene group;

[0013] The PTM is

[0014] The ULM is

[0015] The R1, R3, R9, R 11 are independently selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -NHR 1b -, -C(=O)NH-, -NHC(=O)-, -C(=O)NHR 1b -、-NHC(=O)R 1b -、-OC(=O)R 1b -、-C(=O)OR 1b -、-C(=O)R 1b -、-SO2R 1b -、-OR 1b -, -O-, or -S-;

[0016] The R 1b Selected from C 1-6 Alkylene, C 1-6 a haloalkylene or imino group;

[0017] X1, X2, X3, X6, X7, X8, X9, X 10 are independently selected from C, N, O, S, -C(O)NH-;

[0018] Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl;

[0019] Said R4, R6, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl, C 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-8-membered aryl or 5-8-membered heteroaryl;

[0020] The a, b, c, h, and k are independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0021] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compound represented by general formula (II):

[0022] PTM-R1-R2-ULM (II);

[0023] in,

[0024] The R1 is selected from carbonyl, C 1-6 Alkylene, imino, -NHR 1b -, -C(=O)NH-, -NHC(=O)-, -C(=O)NHR 1b - or -NHC(=O)R 1b -;

[0025] The R 1b Selected from C 1-6 Alkylene or C 1-6 halogenated alkylene;

[0026] Said R2 does not exist; or said R2 is selected from

[0027] The A ring and the B ring are each independently selected from a 3-8 membered monocyclic carbocyclylene, a 6-12 membered bicyclic carbocyclylene, a 3-8 membered monocyclic heterocyclylene, a 6-12 membered bicyclic heterocyclylene; the 6-12 membered bicyclic carbocyclylene and the 6-12 membered bicyclic heterocyclylene are selected from a fused bicyclic, a bridged bicyclic or a spiro-connected bicyclic;

[0028] The e is selected from 0, 1, 2, 3, 4, 5 or 6;

[0029] The definitions of PTM and ULM are the same as above.

[0030] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compound represented by formula (II), wherein:

[0031] The R1 is selected from carbonyl, C 1-6 Alkylene, imino, -NHR 1b -, -C(=O)NH-, or -C(=O)NHR 1b -;

[0032] The R 1b Selected from C1-6 Straight chain alkylene or C 1-6 branched chain alkylene;

[0033] Said R2 does not exist; or said R2 is selected from

[0034] The A ring and the B ring are each independently selected from 3-8 membered monocyclic cycloalkylene, 6-12 membered bicyclic cycloalkylene, 3-8 membered monocyclic heterocycloalkylene, 6-12 membered bicyclic heterocycloalkylene; the 6-12 membered bicyclic cycloalkylene and 6-12 membered bicyclic heterocycloalkylene are selected from fused bicyclic, bridged bicyclic or spiro bicyclic;

[0035] The e is selected from 0, 1, 2, 3, 4, 5 or 6.

[0036] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compounds represented by general formula (I) or general formula (II), wherein:

[0037] The PTM is

[0038] X1, R5, a, R6, and h are the same as defined above.

[0039] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compounds represented by general formula (I) or general formula (II), wherein:

[0040] The PTM is

[0041] Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl;

[0042] Said R6 is selected from halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0043] The a's are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0044] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compounds represented by general formula (I) or general formula (II), wherein:

[0045] The ULM is

[0046] The R3 is selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -O-, or -S-;

[0047] Said X2, X6, X7, X8 are each independently selected from C, N, O;

[0048] The X3 is selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -O-, -S-, or -C(O)NH-;

[0049] Said R4, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl;

[0050] The b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0051] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compounds represented by general formula (I) or general formula (II), wherein:

[0052] The ULM is

[0053] The R3 is selected from -C(=O)-, -C 1-3 Alkylene-, -C 1-3 Haloalkylene-, -NH-, -O-, or -S-;

[0054] Said X2, X6, X7, X8 are each independently selected from C, N, O;

[0055] The X3 is selected from -C 1-3 Alkylene-, -NH-, -O-, -S- or -C(O)NH-;

[0056] Said R4, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl;

[0057] The b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0058] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compound represented by formula (I), wherein:

[0059] Wherein, the PTM is

[0060] The L is

[0061] The ULM is

[0062] Said X1, X2, X3 are each independently selected from C, N or O;

[0063] The R1 is independently selected from carbonyl, methylene, imino, -NHR 1b -、-C(=O)NHR 1b -or-NHC(=O)R 1b -;

[0064] The R 1b Independently selected from C 1-6 Alkylene or C 1-6 halogenated alkylene;

[0065] The R2 is selected from

[0066] The A ring and the B ring are each independently selected from a 3-10 membered carbocyclic group and a 3-10 membered heterocyclic group;

[0067] Said R3 is selected from carbonyl, methylene or imino;

[0068] Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl;

[0069] Said R4, R6, R7 are independently selected from halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group, a cyano group, or a hydroxy group;

[0070] Said a, b, c, d, e are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0071] The h is selected from 0 or 1.

[0072] In one or more embodiments, the provided compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compounds represented by general formula (I) or general formula (II), wherein:

[0073] The PTM is

[0074] Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl;

[0075] Said R6 is selected from halogen, C 1-3 Alkyl, C 1-3 alkyl halide;

[0076] The a's are each independently selected from 0, 1, 2, 3 or 4;

[0077] The ULM is

[0078] Said R3 is selected from carbonyl or methylene;

[0079] Said R4 and R7 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl;

[0080] Said b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0081] The L is

[0082] The R1 is selected from -C(=O)NH- or -C(=O)NH-C 1-6 Alkylene-;

[0083] Said R2 does not exist; or said R2 is selected from

[0084] The A ring and the B ring are each independently selected from

[0085] X4, X5, X 11 are each independently selected from C, N or O;

[0086] The e, f, g, i, and j are each independently selected from 0, 1, 2, 3, or 4.

[0087] In one or more embodiments, a compound is provided, or all stereoisomers, solvates, prodrugs, metabolites, deuterated forms, pharmaceutically acceptable salts, or cocrystals thereof, wherein:

[0088] The R2 is selected from

[0089] In one or more embodiments, a compound is provided, or all stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts, or cocrystals thereof, selected from:

[0090] One or more embodiments of the present application provide a compound represented by formula (I'), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof:

[0091] in,

[0092] W is selected from

[0093] R1 is selected from carbonyl, methylene or amino;

[0094] R2 is selected from Wherein, n is an integer from 1 to 4;

[0095] R3 is selected from methylene or carbonyl;

[0096] R 10 is selected from H or halogen.

[0097] One or more embodiments of the present application provide a compound represented by formula (I"), or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof:

[0098] PTM-L-ULM (I”);

[0099] Wherein, the PTM is

[0100] The L is

[0101] The ULM is

[0102] Said X1, X2, X3 are each independently selected from C, N or O;

[0103] The R1 is independently selected from carbonyl, methylene, imino, -NHR 1b -、-C(=O)NHR1b -or-NHC(=O)R 1b -;

[0104] The R 1b Independently selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0105] R2 is selected from

[0106] The A ring and the B ring are each independently selected from a 3-10 membered carbocyclic group and a 3-10 membered heterocyclic group;

[0107] Said R3 is selected from carbonyl, methylene or imino;

[0108] Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl;

[0109] Said R4, R6, R7 are independently selected from halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group, a cyano group, or a hydroxy group;

[0110] Said a, b, c, d, e are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0111] The h is selected from 0 or 1.

[0112] In one or more embodiments, the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compound represented by formula (II), wherein:

[0113] The PTM is

[0114] The ULM is

[0115] Said R3 is selected from carbonyl or methylene;

[0116] The definitions of X2, R4, R5, R6, R7, a, b, and c are the same as above.

[0117] In one or more embodiments, the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, is selected from the compound represented by general formula (II"):

[0118] PTM-R1-R2-ULM (II”);

[0119] in,

[0120] The R1 are each independently selected from carbonyl, methylene, imino, -NHR 1b -or-C(=O)NHR 1b -;

[0121] The R 1b Each independently selected from C 1-6 alkyl;

[0122] The R2 is selected from

[0123] In one or more embodiments, the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein:

[0124] The A ring and the B ring are each independently selected from

[0125] Said X4 and X5 are each independently selected from C or N;

[0126] The f and g are each independently selected from 1, 2, 3 or 4.

[0127] In one or more embodiments, the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein:

[0128] The A ring and the B ring are each independently selected from

[0129] At least one of X4 and X5 is selected from N.

[0130] In one or more embodiments, the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein:

[0131] The R2 is selected from

[0132] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0133] (1) the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals;

[0134] (2) Pharmaceutically acceptable carriers and / or excipients.

[0135] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0136] (1) the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals;

[0137] (2) one or more other active ingredients; and

[0138] (3) Pharmaceutically acceptable carriers and / or excipients.

[0139] One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of anti-tumor drugs.

[0140] One or more embodiments of the present application provide use of the compound described herein or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of the present application in the preparation of a drug for degrading HPK1 protein.

[0141] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0142] The isotopes of hydrogen involved in the groups and compounds described in the present invention include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium).

[0143] "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof. When an alkyl group is substituted, it may optionally be further substituted with one or more substituents.

[0144] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0145] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3-10 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-20 membered polycyclic ring system, preferably having 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When substituted, it may optionally be further substituted with zero or more substituents.

[0146] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic ring. The N and S atoms optionally substituted in the heterocycloalkyl ring may be oxidized to various oxidation states; the heterocycloalkyl group may be attached to a heteroatom or a carbon atom; and the heterocycloalkyl group may be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocycloalkyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0147] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0148] "Alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms, preferably an alkynyl group of 2 to 12 carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and even more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, and dodecyn-4-yl. The alkynyl group may be optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, straight-chain alkenyl, straight-chain alkynyl, amino, nitro, cyano, thiol, amide, carbocyclic or heterocyclic groups.

[0149] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, it has the same definition as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocycle, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, or 4) optionally substituted N or S groups in a "heterocyclic group" or "heterocycle" ring may be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" may be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" may be fused, bridged, or spirocyclic. The "heterocyclic group" or "heterocycle" may be further substituted with one or more substituents.

[0150] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "heterocyclyl", "heterocycle", "cycloalkyl" or "heterocycloalkyl" is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 、=NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6Alkyl, -C(=O)NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6- 10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 、R q3 Selected from H or C 1-6 Alkyl; R q4、R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0151] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0152] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0153] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0154] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0155] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0156] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0157] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0158] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0159] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0160] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in the form of solvates with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in the form of non-solvates. Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and they can be formed with pharmaceutically acceptable solvents such as water, ethanol, etc. during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in the form of non-solvates as well as solvates. Generally, for the purposes of the compounds and methods provided herein, the solvate forms are considered to be equivalent to the non-solvate forms.

[0161] One or more embodiments of the present application provide compounds and compositions of the present application for use in treating and / or preventing diseases.

[0162] One or more embodiments of the present application provide compounds and compositions of the present application for treating and / or preventing cancer and / or tumors.

[0163] One or more embodiments of the present application provide the compounds and compositions of the present application for degrading HPK1 protein.

[0164] One or more embodiments of the present application provide a method for treating and / or preventing a disease, which comprises administering the compounds and compositions of the present application to a subject in need thereof.

[0165] One or more embodiments of the present application provide a method for treating and / or preventing cancer and / or tumors, which comprises administering the compounds and compositions of the present application to a subject in need thereof.

[0166] One or more embodiments of the present application provide a method for degrading HPK1 protein, comprising applying the compound and composition of the present application to the HPK1 protein. DETAILED DESCRIPTION

[0167] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0168] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0169] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0170] HPLC determinations were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0171] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0172] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0173] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0174] Example

[0175] Intermediate 1

[0176] first step:

[0177] 3-(4-(Ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)propanoic acid A2

[0178] 3-(4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)propanoic acid A2

[0179] At 25°C, sodium acetate (196.0 g, 2.4 mol) was added to a solution of Compound A1, 5-aminolevulinic acid hydrochloride (200.0 g, 1.2 mol) and ethyl acetoacetate (155.0 g, 1.2 mol) in water (1.2 L). The mixture was stirred at 100°C under nitrogen for 6 h. The reaction was complete by TLC. The mixture was cooled to 25°C, filtered, washed with 30% ethanol (300 mL), and the filter cake was dried to obtain the title compound A2 (white solid, 238.0 g, yield: 89.0%).

[0180] 1 H NMR (400MHz, DMSO) δ11.95 (s, 1H), 10.95 (s, 1H), 6.40 (d, 1H), 4.13 (q, 2H), 2.86-2.71 (m, 2H), 2.44-2.38 (m, 2H), 2.35 (s, 3H), 1.25 (t, 3H)

[0181] LC-MS m / z (ESI) = 226.3 [M+1]

[0182] Step 2:

[0183] 2-Methyl-6-oxo-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxylic acid ethyl ester A3

[0184] ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate A3

[0185] Methanesulfonic acid (491.0 g, 5.1 mol) was slowly added dropwise to phosphorus pentoxide (49.0 g, 0.4 mol) at 25°C under nitrogen. The temperature was raised to 100°C for 1 h, then lowered to 40°C. Compound A2 (65.0 g, 0.3 mol) was added portionwise, and the temperature was allowed to react at 40°C for 1 h. The temperature was then lowered to 25°C for 10 h. The reaction was monitored by TLC until completion. The temperature was lowered to 0°C, and saturated sodium bicarbonate solution (10 L) was added dropwise to quench the reaction. The pH was adjusted to 8, the mixture was filtered, washed with water (1.0 L), and the filter cake was dried to obtain the title compound A3 (yellow solid, 60 g, yield: 99.0%).

[0186] 1 H NMR (400MHz, CDCl3) δ11.48 (s, 1H), 4.29 (q, 2H), 3.03 (dd, 2H), 2.92-2.87 (m, 2H), 2.69 (s, 3H), 1.36 (t, 3H).

[0187] LC-MS m / z (ESI) = 208.4 [M+1]

[0188] Step 3:

[0189] (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b]pyrrole-3-carboxylic acid ethyl ester Compound A4

[0190] ethyl(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate A4

[0191] At T = 25 ° C, under nitrogen protection, piperidine (20.00 g, 0.24 mol) was added dropwise to a solution of compound A3 (9.80 g, 0.05 mol) and 5-fluoro-2-oxoindole (7.9 g, 52.0 mmol) in N,N-dimethylformamide (100 mL). After addition, the temperature was raised to T = 110 ° C, and the mixture was stirred for 21 h. LC-MS was used to monitor the reaction until completion. The mixture was cooled to room temperature and allowed to stand for 10 h. The mixture was filtered, and the filter cake was slurried with anhydrous ethanol (150 mL) for 30 min. The filter cake was then filtered and dried to obtain the title compound A4 (yellow solid, 10.0 g, yield: 62.0%).

[0192] 1H NMR (400MHz, DMSO) δ11.76 (s, 1H), 10.62 (s, 1H), 7.21 (d, 1H), 6.93 (t, 1H), 6. 83(dd, 1H), 4.20(q, 2H), 3.53(s, 2H), 3.04(d, 2H), 2.62(s, 3H), 1.29(t, 3H).

[0193] LC-MS m / z (ESI) = 341.2 [M+1]

[0194] Step 4:

[0195] (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1

[0196] (Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid intermediate 1

[0197] At T = 25 ° C, under nitrogen protection, lithium hydroxide monohydrate (6.20 g, 0.12 mol) was added to a solution of compound A4 (10.0 g, 24.0 mmol) in dioxane (180 mL) and water (90 mL), methanol (2 mL) and dimethyl sulfoxide (2 mL) were added dropwise, and the temperature was raised to T = 110 ° C with stirring to react for 8.0 h. LC-MS was used to detect the completion of the reaction. The temperature was lowered to 20 ° C, and aqueous hydrochloric acid (1N) was added dropwise to adjust the pH to 2. The mixture was filtered, and the mixture was slurried with ethanol (100 mL) for 30 min, filtered, and the filter cake was dried to obtain the title intermediate 1 (yellow solid, 8.5 g, yield: 94.0%).

[0198] 1 H NMR (400MHz, DMSO) δ11.51 (s, 1H), 10.61 (s, 1H), 7.18 (dd, 1H), 6.92-6.76 (m, 2H), 3.54-3.48 (m, 2H), 3.02 (d, 2H), 2.61 (s, 3H).

[0199] LC-MS m / z (ESI) = 313.4 [M+1]

[0200] Example 1

[0201] first step:

[0202] tert-Butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)carbamate 1b

[0203] tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)carbamate 1b

[0204] At 25°C, under nitrogen protection, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione compound 1a (0.50 g, 1.81 mmol) and 1-(N-Boc-aminoethyl)piperazine (0.50 g, 2.17 mmol) in N,N-dimethylformamide (20 mL). After addition, the temperature was raised to 90°C and stirred for 6.0 h. The reaction was detected by TLC until completion. Water (40 mL) was added dropwise and stirred for 10 min. The mixture was filtered with suction and the filter cake was dried to give the title compound 1b (yellow solid, 0.48 g, yield: 55.0%).

[0205] LC-MS m / z (ESI) = 486.3 [M+1]

[0206] Step 2:

[0207] Compound 1c of 2,2,2-trifluoroacetaldehyde and 4-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0208] 2,2,2-trifluoroacetaldehyde compound with 4-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound 1c

[0209] At 25°C, under nitrogen, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 1b (0.48 g, 0.98 mmol) in dichloromethane (10 mL). The mixture was stirred for 4 h. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 1c (yellow solid, 0.49 g, yield: 99.0%).

[0210] LC-MS m / z (ESI) = 386.4 [M+1]

[0211] Step 3:

[0212] (Z)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 1

[0213] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 1

[0214] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (124.0 mg, 0.96 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to the intermediate 1 (Z) -6- (5-fluoro-2-oxoindole-3-ylidene) -2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid (100.0 mg, 0.32 mmol). mol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 1c (176.0 mg, 0.35 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 1 (yellow solid, 84.0 mg, yield: 38.7%).

[0215] 1H NMR (400MHz, DMSO) δ11.66 (s, 1H), 11.10 (s, 1H), 10.58 (s, 1H), 7.73-7.69 (m, 1H), 7.36 (d, J=7.7 Hz, 2H), 7.24-7.20 (m, 1H), 7.06 (s, 1H), 6.90 (dd, J=12.6, 5.4Hz, 1H), 6.82 (dd, J=8.4, 4.8Hz, 1H) , 5.10 (dd, J=12.9, 5.3Hz, 1H), 3.58 (d, J=4.5Hz, 2H), 3.39 (d, J=5.5Hz, 4H), 3.14 (s, 2H), 2.93-2 .81 (m, 1H), 2.65 (s, 5H), 2.60 (s, 3H), 2.54 (dd, J=11.0, 6.8Hz, 5H), 2.02 (dd, J=13.7, 8.6Hz, 1H).

[0216] LC-MS m / z(ESI)=680.5[M+1].

[0217] Example 2

[0218] first step:

[0219] tert-Butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 2b

[0220] tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 2b

[0221] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (0.70 g, 5.43 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione compound 2a (0.50 g, 1.81 mmol) and 1-(N-Boc-aminoethyl)piperazine (0.41 g, 1.81 mmol) in N, N-dimethylformamide (20 mL). After the addition, the temperature was raised to 40 ° C. The reaction was stirred at 90°C for 7.0 h; TLC was performed until the reaction was complete; water (40 mL) was added dropwise and stirred for 10 min, extracted with ethyl acetate (100 mL*2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give the title compound 2b (yellow solid, 0.22 g, yield: 25.0%).

[0222] 1H NMR (400MHz, DMSO) δ11.08 (s, 1H), 7.96 (d, J=9.3Hz, 1H), 7.67 (d, J=8.5Hz, 1H), 7.25 (dd, J=8.6, 2.2Hz, 1H), 6.69 (d, J=5.9Hz, 1H), 5.07 (dd, J=12.9, 5 .4Hz, 1H), 3.42 (s, 3H), 3.06 (dd, J=14.9, 6.5Hz, 2H), 2.89 (s, 3H), 2.73 (d, J=0.5Hz, 3H), 2.39-2.29 (m, 4H), 2.00 (dd, J=11.1, 3.7Hz, 1H), 1.37 (s, 9H).

[0223] LC-MS m / z (ESI) = 486.3 [M+1]

[0224] Step 2:

[0225] Compound 2c of 2,2,2-trifluoroacetaldehyde and 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0226] 2,2,2-trifluoroacetaldehyde compound with 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound2c

[0227] At 25°C, under nitrogen, trifluoroacetic acid (0.51 g, 4.50 mmol) was added dropwise to a solution of compound 2b (0.22 g, 0.45 mmol) in dichloromethane (10 mL). The mixture was stirred for 4 h. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 2c (yellow solid, 0.22 g, yield: 99.0%).

[0228] LC-MS m / z (ESI) = 386.4 [M+1]

[0229] Step 3:

[0230] (Z)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 2

[0231] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound2

[0232] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (103.0 mg, 0.80 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (60.0 mg, 0.16 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (50.0 mg, 0.16 mmol) ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 2c (90.0 mg, 0.17 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 2 (yellow solid, 29.0 mg, yield: 26.0%).

[0233] 1H NMR (400MHz, DMSO) δ11.66 (s, 1H), 11.09 (s, 1H), 10.58 (s, 1H), 7.68 (d, J=8.5Hz, 1H), 7.37 (d, J=1. 9Hz, 1H), 7.28 (dd, J=8.6, 2.1Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 7.07 (t, J=5.1Hz, 1H), 6.94-6.87 (m, 1 H), 6.83 (dt, J=8.4, 3.6Hz, 1H), 5.08 (dd, J=12.9, 5.4Hz, 1H), 3.58 (d, J=5.2Hz, 3H), 3.47 (s, 3H), 3 .44-3.35(m, 3H), 3.14(s, 2H), 2.94-2.82(m, 1H), 2.62-2.52(m, 10H), 2.01(dd, J=11.3, 6.4Hz, 1H).

[0234] LC-MS m / z (ESI) = 680.5 [M+1]

[0235] Example 3

[0236] first step:

[0237] tert-Butyl (2-(4-(2,6-dioxapiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazin-1-yl)ethyl)carbamate 3b

[0238] tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 3b

[0239] Under nitrogen at 25°C, N-tert-butoxycarbonyl-2-aminoacetaldehyde (0.44 g, 2.76 mmol) was slowly added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindole-1,3-dione hydrochloride compound 3a (1.0 g, 2.52 mmol) in dichloroethane (20 mL) and anhydrous methanol (2 mL). The reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.58 g, 2.76 mmol) and glacial acetic acid (0.01 mL) were added, and the reaction was stirred for another 2.5 h. The reaction was monitored by TLC until completion. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give the title compound 3b (yellow solid, 0.82 g, yield: 65.0%).

[0240] 1H NMR (400MHz, DMSO) δ11.11 (s, 1H), 7.73 (d, J=11.5Hz, 1H), 7.45 (d, J=7.3Hz, 1H), 6.70 (s, 1H), 5.10 (dd, J=12.8, 5.3 Hz, 1H), 3.23 (s, 5H), 3.07 (s, 2H), 2.88 (ddd, J=16.5, 13.7, 5.1Hz, 1H), 2.62-2.52 (m, 6H), 2.39 (s, 2H), 1.38 (s, 9H).

[0241] LC-MS m / z (ESI) = 504.5 [M+1]

[0242] Step 2:

[0243] Compound 3c of 2,2,2-trifluoroacetaldehyde and 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0244] 2,2,2-trifluoroacetaldehyde compound with 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione compound3c

[0245] At 25°C, under nitrogen, trifluoroacetic acid (1.80 g, 15.90 mmol) was added dropwise to a solution of compound 3b (0.80 g, 1.59 mmol) in dichloromethane (10 mL). The mixture was stirred for 7 h. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 3c (yellow solid, 0.82 g, yield: 99.0%).

[0246] LC-MS m / z (ESI) = 404.5 [M+1]

[0247] Step 3:

[0248] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 3

[0249] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)- 6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound3

[0250] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (206.0 mg, 1.6 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol). ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 3c (182.0 mg, 0.35 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (6 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 3 (yellow solid, 32.0 mg, yield: 14.0%).

[0251] 1H NMR (400MHz, DMSO) δ11.67 (s, 1H), 11.12 (s, 1H), 10.59 (s, 1H), 7.75 (d, J=11.3Hz, 1H), 7.49 (d, J=6.4Hz, 1H), 7.23 (dd, J=9.8, 2.2Hz, 1H), 7.08 (s, 1H), 6.95-6.88 (m, 1H), 6.83 (dd, J=8.5, 4.8Hz, 1H), 5.11 (dd, J=13.0, 5.1Hz, 1H), 3.60 (s, 2H), 3.31-3 .24(m, 6H), 3.15(s, 2H), 2.93-2.82(m, 1H), 2.70-2.54(m, 11H), 2.06-1.98(m, 1H).

[0252] LC-MS m / z(ESI)=698.4[M+1].

[0253] Example 4

[0254] first step:

[0255] tert-Butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 4b

[0256] tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 4b

[0257] At 25°C, under nitrogen, N-tert-butoxycarbonyl-2-aminoacetaldehyde (0.24 g, 1.50 mmol) was slowly added to a solution of 3-(1-oxy-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione hydrochloride compound 4a (0.5 g, 1.37 mmol) in dichloroethane (10 mL) and anhydrous methanol (1 mL). The reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.50 mmol) and glacial acetic acid (0.01 mL) were added, and the reaction was stirred for 2.5 h. The reaction was monitored by TLC until completion. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give the title compound 4b (gray solid, 0.52 g, yield: 81.0%).

[0258] 1H NMR (400MHz, DMSO) 10.95 (s, 1H), 7.52 (d, J = 8.7Hz, 1H), 7.06 (d, J = 8.2Hz, 2H), 6.70 (s, 1H), 5.05 (dd, J = 13.3, 5.1Hz, 1H), 4.26 (dd, J=50.5, 17.0Hz, 2H), 3.27(s, 6H), 3.08(s, 2H), 3.00-2.84(m, 2H), 2.60(s, 2H), 2.42-2.31(m, 3H), 2.00-1.92(m, 1H), 1.38(s, 9H).

[0259] LC-MS m / z (ESI) = 472.3 [M+1]

[0260] Step 2:

[0261] 2,2,2-Trifluoroacetaldehyde compound and 3-(5-(4-(2-aminoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione compound 4c

[0262] 2,2,2-trifluoroacetaldehyde compound with 3-(5-(4-(2-aminoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione compound 4c

[0263] Trifluoroacetic acid (1.27 g, 11.0 mmol) was added dropwise to a solution of compound 4b (0.52 g, 1.10 mmol) in dichloromethane (15 mL) at 25°C under nitrogen. The mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 4c (yellow solid, 0.54 g, 99.0% yield).

[0264] LC-MS m / z (ESI) = 372.4 [M+1]

[0265] Step 3:

[0266] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoindole-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 4

[0267] (Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 4

[0268] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (206.0 mg, 1.6 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol). ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 4c (170.0 mg, 0.35 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (6 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 4 (yellow solid, 55.0 mg, yield: 26.0%).

[0269] 1H NMR (400MHz, DMSO) δ11.66 (s, 1H), 10.96 (s, 1H), 10.59 (s, 1H), 7.53 (d, J=9.2Hz, 1H), 7.22 (dd, J= 9.7, 2.4Hz, 1H), 7.08 (d, J=9.5Hz, 3H), 6.94-6.87 (m, 1H), 6.82 (dd, J=8.4, 4.8Hz, 1H), 5.05 (dd, J =13.3, 5.0Hz, 1H), 4.27 (dd, J = 50.0, 17.0Hz, 2H), 3.57 (s, 2H), 3.39 (d, J = 5.8Hz, 2H), 3.33-3.25 ( m, 4H), 3.13 (s, 2H), 2.97-2.84 (m, 1H), 2.68-2.52 (m, 10H), 2.44-2.29 (m, 1H), 2.04-1.87 (m, 1H).

[0270] LC-MS m / z (ESI) = 666.5 [M+1]

[0271] Example 5

[0272] first step:

[0273] tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)carbamate 5b

[0274] tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)carbamate 5b

[0275] At 25°C, under nitrogen protection, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione compound 1a (0.50 g, 1.81 mmol) and (3-(piperazin-1-yl)propyl)carbamic acid tert-butyl ester (0.53 g, 2.18 mmol) in N,N-dimethylformamide (20 mL). After the addition, the temperature was raised to 90°C and stirred for 7.0 h. The reaction was detected by TLC until completion. Water (40 mL) was added dropwise and stirred for 10 min. The mixture was filtered with suction and the filter cake was dried to give the title compound 5b (yellow solid, 0.13 g, yield: 15.0%).

[0276] 1H NMR (400MHz, DMSO) δ11.09 (s, 1H), 7.70 (dd, J=8.3, 7.2Hz, 1H), 7.34 (t, J=7.6Hz, 2H), 6.82 (t, J=5.3Hz, 1H), 5.09 (dd, J=12.9, 5.4Hz, 1H), 3.29 (s, 4H), 3.00-2.82 (m, 3H), 2.55 (dd, J=26.9, 11.9Hz, 6H), 2.33 (t, J=7.0Hz, 2H), 2.06-1.97 (m, 1H), 1.56 (dd, J=13.6, 6.7Hz, 2H), 1.37 (s, 9H).

[0277] LC-MS m / z (ESI) = 500.3 [M+1]

[0278] Step 2:

[0279] Compound 5c of 2,2,2-trifluoroacetaldehyde and 4-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0280] 2,2,2-trifluoroacetaldehyde compound with 4-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound5c

[0281] Trifluoroacetic acid (0.15 g, 1.32 mmol) was added dropwise to a solution of compound 1b (0.13 g, 0.27 mmol) in dichloromethane (10 mL) at 25°C under nitrogen. The mixture was stirred for 7 h. LC-MS was used to monitor the reaction until completion. The solution was concentrated under reduced pressure to give the title compound 5c (yellow solid, 0.13 g, 99.0% yield).

[0282] LC-MS m / z (ESI) = 400.3 [M+1]

[0283] Step 3:

[0284] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 5

[0285] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 5

[0286] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (103.0 mg, 0.8 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (60.0 mg, 0.16 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (50.0 mg, 0.16 mmol) ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 5c (90.0 mg, 0.17 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (3 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 5 (yellow solid, 37.0 mg, yield: 33.0%).

[0287] 1H NMR (400MHz, DMSO) δ11.65 (s, 1H), 11.09 (s, 1H), 10.58 (s, 1H), 7.75-7.63 (m, 1H), 7.35 (dd , J=7.7, 4.4Hz, 2H), 7.22 (dd, J=9.9, 2.4Hz, 2H), 6.95-6.87 (m, 1H), 6.83 (dd, J=8.4, 4.8Hz, 1H), 5.09 (dd, J=12.8, 5.4Hz, 1H), 3.58 (d, J=4.3Hz, 2H), 3.27 (s, 6H), 3.15 (s, 2H), 2.93-2 .81 (m, 1H), 2.56 (d, J=15.9Hz, 9H), 2.42 (s, 2H), 2.01 (dd, J=13.3, 6.1Hz, 1H), 1.72 (s, 2H).

[0288] LC-MS m / z (ESI) = 694.5 [M+1]

[0289] Example 6

[0290] first step:

[0291] tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 6b

[0292] tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 6b

[0293] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (0.70 g, 5.43 mmol) was added dropwise to a solution of 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione compound 2a (0.50 g, 1.81 mmol) and (3-(piperazin-1-yl)propyl)carbamic acid tert-butyl ester (0.53 g, 2.21 mmol) in N, N-dimethylformamide (20 mL). The mixture was stirred at 90°C for 7.0 h and the reaction was completed by TLC. Water (40 mL) was added dropwise and stirred for 10 min. The mixture was extracted with dichloromethane (60 mL*2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give the title compound 6b (yellow solid, 0.20 g, yield: 22.0%).

[0294] 1H NMR (400MHz, DMSO) δ11.08 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 7.34 (d, J=1.9Hz, 1H), 7.25 (dd, J=8.6, 2.1Hz, 1H), 6.82 (s, 1H), 5.07 (dd, J=12.9, 5.4H z, 1H), 3.43 (s, 4H), 2.99-2.85 (m, 5H), 2.58 (d, J=17.3Hz, 1H), 2.30 (dd , J=13.6, 6.1Hz, 5H), 2.05-1.97(m, 1H), 1.57-1.52(m, 2H), 1.37(s, 9H).

[0295] LC-MS m / z (ESI) = 500.3 [M+1]

[0296] Step 2:

[0297] Compound 6c of 2,2,2-trifluoroacetaldehyde and 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0298] 2,2,2-trifluoroacetaldehyde compound with 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound6c

[0299] At 25°C, under nitrogen, trifluoroacetic acid (1.0 g, 8.0 mmol) was added dropwise to a solution of compound 6b (0.20 g, 0.40 mmol) in dichloromethane (10 mL). The mixture was stirred for 6 h. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 6c (yellow solid, 0.2 g, yield: 99.0%).

[0300] LC-MS m / z (ESI) = 400.4 [M+1]

[0301] Step 3:

[0302] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 6

[0303] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamid e compound 6

[0304] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (103.0 mg, 0.80 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (60.0 mg, 0.16 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (50.0 mg, 0.16 mmol) ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 6c (90.0 mg, 0.17 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (3 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 6 (yellow solid, 17.0 mg, yield: 16.0%).

[0305] 1H NMR (400MHz, DMSO) δ11.65 (s, 1H), 11.08 (s, 1H), 10.58 (s, 1H), 7.67 (d, J=8.8Hz, 1H), 7.35 (s, 1H) , 7.24 (dd, J=17.1, 9.1Hz, 3H), 6.90 (dd, J=13.7, 6.6Hz, 1H), 6.83 (dd, J=8.4, 4.8Hz, 1H), 5.07 (dd , J=12.8, 5.2Hz, 1H), 3.57 (s, 2H), 3.44 (s, 4H), 3.28 (d, J=6.1Hz, 2H), 3.15 (s, 2H), 2.87 (d, J=13. 8Hz, 1H), 2.57 (d, J=7.9Hz, 6H), 2.36 (d, J=29.7Hz, 3H), 1.99 (dd, J=14.4, 7.0Hz, 3H), 1.71 (s, 2H).

[0306] LC-MS m / z (ESI) = 694.5 [M+1]

[0307] Example 7

[0308] first step:

[0309] tert-Butyl (3-(4-(2-(2,6-dioxapiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazin-1-yl)propyl)carbamate 7b

[0310] tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 7b

[0311] At 25°C, under nitrogen, tert-butyl (3-oxopropyl)carbamate (0.48 g, 2.77 mmol) was slowly added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindole-1,3-dione hydrochloride compound 3a (1.0 g, 2.52 mmol) in dichloroethane (20 mL) and anhydrous methanol (2 mL). The reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.58 g, 2.76 mmol) and glacial acetic acid (0.01 mL) were added, and the reaction was stirred for another 2.5 h. The reaction was monitored by TLC until completion. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound 7b (yellow solid, 0.55 g, yield: 42.0%).

[0312] 1H NMR (400MHz, DMSO) δ11.11 (s, 1H), 7.72 (d, J = 11.5Hz, 1H), 7.45 (d, J = 7.4Hz, 1H), 6.82 (s, 1H), 5.10 (dd, J = 12.8, 5.1Hz, 1H), 3.24(s, 4H), 2.99-2.82(m, 3H), 2.66-2.51(m, 6H), 2.33(d, J=1.7Hz, 2H), 2.07-2.00(m, 1H), 1.61-1.52(m, 2H), 1.37(s, 9H).

[0313] LC-MS m / z (ESI) = 518.3 [M+1]

[0314] Step 2:

[0315] Compound 7c of 2,2,2-trifluoroacetaldehyde and 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0316] 2,2,2-trifluoroacetaldehyde compound with 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione 7c

[0317] At 25°C, under nitrogen protection, trifluoroacetic acid (1.2 g, 10.6 mmol) was added dropwise to a solution of compound 7b (0.55 g, 1.06 mmol) in dichloromethane (10 mL). The mixture was stirred for 7 h after addition. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 7c (yellow solid, 0.56 g, yield: 99.0%).

[0318] LC-MS m / z (ESI) = 418.4 [M+1]

[0319] Step 3:

[0320] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 7

[0321] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl) -6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound7

[0322] At 25°C, under nitrogen protection, N,N-diisopropylethylamine (206.0 mg, 1.6 mmol) and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to a solution of (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h. Compound 7c (186.0 mg, 0.35 mmol) was added and the mixture was stirred for 2 h. LC-MS was used to monitor the reaction until completion. Water (6 mL) was added dropwise and stirred for 10 min, and the mixture was filtered. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give the title compound 7 (yellow solid, 40.0 mg, yield: 17.0%).

[0323] 1H NMR (400MHz, DMSO) δ11.65 (s, 1H), 11.11 (s, 1H), 10.58 (s, 1H), 7.73 (d, J=11.5Hz, 1H ), 7.46 (d, J=7.2Hz, 1H), 7.23 (dd, J=9.8, 2.6Hz, 2H), 6.94-6.88 (m, 1H), 6.83 (dd, J= 8.4, 4.8Hz, 1H), 5.10 (dd, J=12.7, 5.2Hz, 1H), 3.57 (s, 2H), 3.26 (s, 6H), 3.15 (s, 2H) , 2.94-2.82(m, 1H), 2.62-2.53(m, 9H), 2.41(s, 2H), 2.04-1.97(m, 1H), 1.71(s, 2H).

[0324] LC-MS m / z (ESI) = 712.3 [M+1]

[0325] Example 8

[0326] first step:

[0327] tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 8b

[0328] tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 8b

[0329] At 25°C, under nitrogen, N-tert-butoxycarbonyl-2-aminopropanal (0.26 g, 1.50 mmol) was slowly added to a solution of compound 3-(1-oxy-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione hydrochloride compound 4a (0.5 g, 1.37 mmol) in dichloroethane (10 mL) and anhydrous methanol (1 mL). The reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.50 mmol) and glacial acetic acid (0.01 mL) were added, and the stirring reaction was continued for 2.5 h. The reaction was monitored by TLC until completion. The product was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 8b (gray solid, 0.33 g, yield: 50.0%).

[0330] LC-MS m / z (ESI) = 486.3 [M+1]

[0331] Step 2:

[0332] Compound 8c of 2,2,2-trifluoroacetaldehyde and 3-(5-(4-(3-aminopropyl)piperazin-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione

[0333] 2,2,2-trifluoroacetaldehyde compound with 3-(5-(4-(3-aminopropyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8c

[0334] At 25°C, under nitrogen, trifluoroacetic acid (0.8 g, 6.8 mmol) was added dropwise to a solution of compound 8b (0.33 g, 0.68 mmol) in dichloromethane (10 mL). The mixture was stirred for 4 h after addition. The reaction was detected by LC-MS until completion. The mixture was concentrated under reduced pressure to give the title compound 8c (yellow solid, 0.34 g, yield: 99.0%).

[0335] LC-MS m / z (ESI) = 386.4 [M+1]

[0336] Step 3:

[0337] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoindole-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 8

[0338] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 8

[0339] At 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (206.0 mg, 1.6 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol). ol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 8c (175.0 mg, 0.35 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (6 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 8 (yellow solid, 27.0 mg, yield: 13.0%).

[0340] 1H NMR (400MHz, DMSO) δ11.65 (s, 1H), 10.95 (s, 1H), 10.59 (s, 1H), 7.52 (d, J=9.1Hz, 1H), 7.22 (dd, J= 13.6, 3.8Hz, 2H), 7.07 (d, J=7.2Hz, 2H), 6.96-6.87 (m, 1H), 6.83 (dd, J=8.4, 4.8Hz, 1H), 5.05 (dd, J =13.2, 5.0Hz, 1H), 4.26 (dd, J = 48.8, 16.9Hz, 2H), 3.57 (d, J = 4.4Hz, 2H), 3.30 (d, J = 13.0Hz, 8H), 3 .15(s, 2H), 2.96-2.84(m, 1H), 2.58(s, 8H), 2.39(d, J=8.6Hz, 1H), 2.02-1.90(m, 1H), 1.72(s, 2H).

[0341] LC-MS m / z(ESI)=680.3[M+1].

[0342] Example 9

[0343] first step:

[0344] tert-Butyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 9b

[0345] tert-butyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 9b

[0346] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.50 g, 1.81 mmol) and 2-Boc-octahydropyrrolyl[3,4-C]pyrrole (0.46 g, 2.17 mmol) in N,N-dimethylformamide (20 mL). The temperature was raised to T = 90°C and stirred for 6.0 h. TLC confirmed the reaction completion. Water (40 mL) was added dropwise and stirred for 10 min. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give the title compound 9b (yellow solid, 0.49 g, yield: 58%).

[0347] LC-MS m / z (ESI) = 469.3 [M+1]

[0348] Step 2:

[0349] Compound 9c of trifluoroacetic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindole-1,3-dione

[0350] Trifluoroacetic acid compound with 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione 9c

[0351] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 9b (0.50 g, 1.07 mmol) in dichloromethane (10 mL), and the mixture was stirred for 4 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound 9c (orange-red solid, 0.50 g, yield: 99.0%).

[0352] LC-MS m / z (ESI) = 369.2 [M+1]

[0353] Step 3:

[0354] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(6-(5-fluoro-2-oxindol-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindole-1,3-dione compound 9

[0355] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahy drocyclopenta[b]pyrrole-3-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione compound 9

[0356] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.6 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol). mol) in N,N-dimethylformamide (2 mL), the reaction mixture was added dropwise with stirring for 0.5 h; compound 9c (154.0 mg, 0.32 mmol) was added, and the reaction mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise with stirring for 10 min, and the mixture was filtered with suction. The filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound 9 (yellow solid, 80.0 mg, yield: 38%).

[0357] 1 H NMR (400 MHz, DMSO-d c)δ11.67(s, 1H), 11.07(s, 1H), 10.57(s, 1H), 7.66(d, 1H), 7.18(dd, 1H), 6.96-6.87(m, 2H), 6.87-6.78(m, 2H), 5.05(dd, 1H), 3.77 (dd, 2H), 3.65 (d, 2H), 3.60-3.49 (m, 3H), 3.10 (s, 2H), 2.99-2.82 (m, 3H), 2.64-2.54 (m, 2H), 2.06-1.92 (m, 1H), 1.45-1.14 (m, 6H).

[0358] LC-MS m / z (ESI) = 663.2 [M+1]

[0359] Example 10

[0360] first step:

[0361] tert-Butyl 1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-[3,3′-azidetidine]-1-carboxylate 10b

[0362] tert-butyl 1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[3,3′-biazetidine]-1-carbo xylate 10b

[0363] At T = 25°C, under nitrogen, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.50 g, 1.81 mmol) and [3,3′-diazetidine]-1-carboxylic acid tert-butyl ester hydrochloride (0.54 g, 2.17 mmol) in N,N-dimethylformamide (20 mL). The temperature was raised to T = 90°C, and the reaction was stirred for 6.0 h. TLC was performed to confirm the reaction was complete. Water (40 mL) was added dropwise, and the mixture was stirred for 10 min. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give the title compound 10b (yellow solid, 0.51 g, yield: 59%).

[0364] LC-MS m / z (ESI) = 469.1 [M+1]

[0365] Step 2:

[0366] 5-([3,3′-diazetidine]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate 10c

[0367] 5-([3,3′-biazetidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate: Trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 10b (0.51 g, 1.09 mmol) in dichloromethane (10 mL) at T = 25°C under nitrogen protection. The mixture was stirred for 4 h. The reaction was detected by LC-MS until completion. The product was concentrated under reduced pressure to give the title compound 10c (yellow solid, 0.51 g, yield: 99.0%).

[0368] LC-MS m / z (ESI) = 369.1 [M+1]

[0369] Step 3:

[0370] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(1′-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-[3,3′-diazetidine]-1-yl)isoindole-1,3-dione compound 10

[0371] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(1′-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-[3,3′-biazetidin]-1-yl)isoindoline-1,3-dione compound 10

[0372] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.33 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 The mixture was added dropwise to a solution of 5-nitropropene (5-nitropropene) in N,N-dimethylformamide (2 mL), and the reaction was stirred for 0.5 h. Compound 10c (154.0 mg, 0.32 mmol) was added, and the reaction was stirred for 2 h. LC-MS was used to detect the completion of the reaction. Water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound 10 (yellow solid, 75.0 mg, yield: 35%).

[0373] 1 H NMR (400MHz, DMSO-d6) δ11.75 (s, 1H), 11.07 (s, 1H), 10.59 (s, 1H), 7.65 (d, 1 H), 7.19(dd, 1H), 6.91(ddd, 1H), 6.86-6.77(m, 2H), 6.66(dd, 1H), 5.05(dd, 1 H), 4.16 (t, 3H), 3.75 (dd, 3H), 3.54 (d, 2H), 3.09 (d, 1H), 2.98 (s, 3H), 2.51 (s, 3H), 2.05-1.95 (m, 1H), 1.23 (m, 5H).

[0374] LC-MS m / z (ESI) = 663.2 [M+1]

[0375] Example 11

[0376] first step:

[0377] tert-Butyl 9-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-1-oxo-4,9-diazaspiro[5.5]undecane-4-carboxylate 11b

[0378] tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate 11b

[0379] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.50 g, 1.81 mmol) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (0.56 g, 2.17 mmol) in N,N-dimethylformamide (20 mL). The temperature was raised to T = 90°C and stirred for 6.0 h. The reaction was complete by TLC. Water (40 mL) was added dropwise and stirred for 10 min. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 1) to give the title compound 11b (yellow solid, 0.63 g, yield: 68%).

[0380] LC-MS m / z (ESI) = 513.2 [M+1]

[0381] Step 2:

[0382] 2-(2,6-dioxapiperidin-3-yl)-5-(1-oxa-4,9-diaza[5.5]undec-9-yl)isoindole-1,3-dione trifluoroacetate 11c

[0383] 2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione trifluoroacetate 11c

[0384] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a dichloromethane (10 mL) solution of compound 11b (0.63 g, 1.23 mmol), and the mixture was stirred for 4 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to obtain the title compound 11c (yellow solid, 0.64 g, yield: 99.0%).

[0385] LC-MS m / z (ESI) = 413.2 [M+1]

[0386] Step 3:

[0387] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diaza[5.5]undec-9-yl)isoindole-1,3-dione Compound 11

[0388] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahyd rocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione compound 11

[0389] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (124.0 mg, 0.96 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of the mixture of 4-[ ...

[0390] 1 H NMR (400MHz, DMSO-c6) δ11.64 (s, 1H), 11.06 (s, 1H), 10.56 (s, 1H), 7.63 (d, 1H), 7.31 (s, 1H), 7.20 (t, 2 H), 6.86 (dt, 2H), 5.10-4.98 (m, 1H), 3.80-3.51 (m, 11H), 2.88 (d, 4H), 2.43 (m, 4H), 2.07-1.40 (m, 6H).

[0391] LC-MS m / z (ESI) = 707.2 [M+1]

[0392] Example 12

[0393] first step:

[0394] tert-Butyl 9-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-1-oxo-4,9-diazaspiro[5.5]undecane-4-carboxylate 12b

[0395] tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate 12b

[0396] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.50 g, 1.81 mmol) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (0.56 g, 2.17 mmol) in N,N-dimethylformamide (20 mL). The temperature was raised to T = 90°C and stirred for 6.0 h. The reaction was complete by TLC. Water (40 mL) was added dropwise and stirred for 10 min. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 1) to give the title compound 12b (yellow solid, 0.63 g, yield: 68%).

[0397] LC-MS m / z (ESI) = 513.2 [M+1]

[0398] Step 2:

[0399] 2-(2,6-dioxapiperidin-3-yl)-5-(1-oxa-4,9-diaza[5.5]undec-9-yl)isoindole-1,3-dione trifluoroacetate 12c

[0400] 2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione trifluoroacetate 12c

[0401] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a dichloromethane (10 mL) solution of compound 12b (0.63 g, 1.23 mmol), and the mixture was stirred for 4 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to obtain the title compound 12c (yellow solid, 0.64 g, yield: 99.0%).

[0402] LC-MS m / z (ESI) = 413.2 [M+1]

[0403] Step 3:

[0404] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diaza[5.5]undec-9-yl)isoindole-1,3-dione compound 12

[0405] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahyd rocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione compound 12

[0406] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (124.0 mg, 0.96 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added a solution of 4-nitropropene (0.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h; compound 12c (169.0 mg, 0.32 mmol) was added, and the mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered and slurried with ethanol (10 mL) to give the title compound 12 (yellow solid, 190.0 mg, yield: 84%).

[0407] 1H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 11.06 (s, 1H), 10.56 (s, 1H), 7.63 (d, 1H), 7.31 (s, 1H), 7.20 (t, 2 H), 6.86 (dt, 2H), 5.10-4.98 (m, 1H), 3.80-3.51 (m, 11H), 2.88 (d, 4H), 2.43 (m, 4H), 2.07-1.40 (m, 6H).

[0408] LC-MS m / z (ESI) = 707.2 [M+1]

[0409] Example 13

[0410] first step:

[0411] tert-Butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)prop-2-yn-1-yl)piperazine-1-carboxylate 13b

[0412] tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)piperazine-1-carboxylate 13b

[0413] At T = 25 ° C, under nitrogen protection, 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione 13a (0.50 g, 1.48 mmol), tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (0.33 g, 1.48 mmol), cuprous iodide (56 mg, 0.30 mmol), bistriphenylphosphine palladium dichloride (104 mg, 0.15 mmol), and triethylamine (0.45 g, 4.45 mmol) were added to a round-bottom flask. N,N-dimethylformamide (5 mL) was then added and the nitrogen atmosphere was replaced. Under nitrogen protection, the reaction temperature was raised to T = 80 ° C and stirred for 8.0 h. The reaction was completed by LC-MS. Aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 13b (yellow solid, 0.47 g, yield: 66%).

[0414] LC-MS m / z (ESI) = 481.2 [M+1]

[0415] Step 2:

[0416] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)prop-1-yn-1-)isoindole-1,3-dione trifluoroacetate 13c

[0417] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione trifluoroacetate 13c

[0418] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 13b (0.47 g, 0.98 mmol) in dichloromethane (10 mL), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 13c (yellow solid, 0.48 g, yield: 99.0%).

[0419] LC-MS m / z (ESI) = 381.2 [M+1]

[0420] Step 3:

[0421] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)prop-1-yn-1-yl]isoindole-1,3-dione Compound 13

[0422] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione

[0423] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.35 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100 0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), the mixture was added dropwise and stirred for 0.5 h; compound 13c (158.0 mg, 0.32 mmol) was added and the mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise and stirred for 10 min, the mixture was filtered, and the filter cake was washed with ethanol (10 mL) twice to obtain the title compound 13 (yellow solid, 110.0 mg, yield: 51%).

[0424] 1H NMR (400MHz, DMSO-d6) δ11.66 (s, 1H), 11.14 (s, 1H), 10.57 (s, 1H), 7.92 (s, 3H), 7.20 (d, J=9.8Hz, 1H), 6 .92-6.77(m, 2H), 5.17(dd, 1H), 3.61(d, 8H), 2.91(d, 3H), 2.58(s, 5H), 2.41(d, 4H), 2.14-2.00(m, 1H).

[0425] LC-MS m / z (ESI) = 675.3 [M+1]

[0426] Example 14

[0427] first step:

[0428] Tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)ethynyl)piperazine-1-carboxylate 14b

[0429] tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperazine-1-carboxylate 14b

[0430] At T = 25°C, under nitrogen, 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione 13a (0.50 g, 1.48 mmol), tert-butyl 4-ethynylpiperazine-1-carboxylate (0.31 g, 1.48 mmol), cuprous iodide (56 mg, 0.30 mmol), bistriphenylphosphine palladium dichloride (104 mg, 0.15 mmol), and triethylamine (0.45 g, 4.45 mmol) were added to a round-bottom flask. N,N-dimethylformamide (5 mL) was then added and the atmosphere was replaced with nitrogen. Under nitrogen, the reaction mixture was heated to T = 80°C and stirred for 8.0 h. LC-MS confirmed the reaction was complete. Aqueous ammonium chloride (10 mL) was added dropwise to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give the title compound 14b (yellow solid, 0.33 g, yield: 48%).

[0431] LC-MS m / z (ESI) = 466.3 [M+1]

[0432] Step 2:

[0433] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-ylethylidene)isoindole-1,3-dione trifluoroacetate 14c

[0434] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-ylethynyl)isoindoline-1,3-dione trifluoroacetate

[0435] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 14b (0.33 g, 0.71 mmol) in dichloromethane (10 mL), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 14c (yellow solid, 0.34 g, yield: 99.0%).

[0436] LC-MS m / z (ESI) = 366.2 [M+1]

[0437] Step 3:

[0438] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)ethynyl)isoindole-1,3-dione Compound 14

[0439] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione compound 14

[0440] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (154.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (100. 0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), the mixture was added dropwise and stirred for 0.5 h; compound 14c (154.0 mg, 0.32 mmol) was added and stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise and stirred for 10 min, the mixture was filtered, and the filter cake was slurried twice with methanol (10 mL) to obtain the title compound 14 (yellow solid, 110.0 mg, yield: 52%).

[0441] 1H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 11.14 (s, 1H), 10.57 (s, 1H), 7.91 (d, 3H), 7.20 (d, 1H), 6.96-6.79 (m, 2H), 5.16 ( dd, 1H), 3.85 (s, 2H), 3.56 (s, 2H), 3.40 (d, 2H), 3.11-2.80 (m, 5H), 2.60 (d, 1H), 2.43 (s, 3H), 2.00 (d, 3H), 1.65 (d, 2H).

[0442] LC-MS m / z (ESI) = 660.2 [M+1]

[0443] Example 15

[0444] first step:

[0445] (Z)-3-(3-amino-2-methyl-4,5-dihydrocyclopenta[b]pyrrole-6(1H)-ylidene)-5-fluoroindol-2-one 15b

[0446] (Z)-3-(3-amino-2-methyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-ylidene)-5-fluoroindolin-2-one 15b

[0447] Under nitrogen at T = 25°C, (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (500.0 mg, 1.60 mmol) was dissolved in tetrahydrofuran (20 mL). Triethylamine (325 mg, 3.20 mmol) and diphenylphosphoryl azide (530 mg, 1.90 mmol) were added sequentially. The reaction was stirred for 16.0 h. TLC confirmed the completion of the reaction. Water (40 mL) was added to quench the reaction, the mixture was filtered, and the filter cake was dried to obtain the azide intermediate. The azide intermediate was dissolved in a solution of hydrochloric acid and 1,4-dioxane (4 M, 10 mL). A small amount of water (2 mL) was added, and the mixture was heated to T = 100°C for reaction. The reaction was complete as determined by LC-MS, and the residue was concentrated under reduced pressure to give the title compound 15b (yellow solid, 0.29 g, yield: 59%).

[0448] LC-MS m / z (ESI) = 284.1 [M+1]

[0449] Step 2:

[0450] 5-(4-(2-(1,3-dioxolan-2-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione 15c

[0451] 5-(4-(2-(1,3-dioxolan-2-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 15c

[0452] At T = 25°C under nitrogen, 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione 15a (100 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (55 mg, 0.39 mmol) and 2-(2-bromoethyl)-1,3-dioxane (57 mg, 0.32 mmol) were added sequentially. The reaction was heated to T = 60°C. LC-MS confirmed the reaction was complete, and the organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound 15c (yellow solid, 51 mg, yield: 50%).

[0453] LC-MS m / z (ESI) = 443.3 [M+1]

[0454] Step 3:

[0455] 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazin-1-yl)propanal 15d

[0456] 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanal 15d

[0457] At T = 25 ° C, compound 15c (51 mg, 0.12 mmol) was dissolved in a mixed solution of acetone and hydrochloric acid (9:1, 5 mL) and stirred for 4 h; LC-MS was used to detect the completion of the reaction; and the mixture was concentrated under reduced pressure to obtain the title compound 15d (yellow solid, 45 mg, yield: 99.0%).

[0458] LC-MS m / z (ESI) = 399.2 [M+1]

[0459] Step 4:

[0460] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-((6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-3-yl]amino)propyl)piperazin-1-yl)isoindole-1,3-dione Compound 15

[0461] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-((6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-3-yl)amino)propyl)piperazin-1-yl)isoindoline-1,3-dion was dissolved in dichloromethane (45 mg, 0.11 mmol) at T = 25°C under nitrogen protection and stirred for 10 minutes. Subsequently, sodium triacetoxyborohydride (120 mg, 0.56 mmol) and glacial acetic acid (0.1 mL) were added. The reaction was stirred for 8 hours. The reaction was complete as determined by LC-MS, and the reaction was quenched with saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound 15.

[0462] LC-MS m / z (ESI) = 666.3 [M+1]

[0463] Example 16

[0464] first step:

[0465] tert-Butyl (2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)ethyl)carbamate 16b

[0466] tert-butyl(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)carbamate 16b

[0467] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and 4-(2-BOC-aminoethyl)piperidine (0.30 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 16b (yellow solid, 0.28 g, yield: 44%).

[0468] LC-MS m / z (ESI) = 485.2 [M+1]

[0469] Step 2:

[0470] 5-(4-(2-aminoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride 16c

[0471] 5-(4-(2-aminoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione chloricacid 16c

[0472] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 16b (0.28 g, 0.58 mmol), and the reaction was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The product was concentrated under reduced pressure to give the title compound 16c (yellow solid, 0.25 g, yield: 99.0%).

[0473] LC-MS m / z (ESI) = 385.2 [M+1]

[0474] Step 3:

[0475] (Z)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperidin-4-yl)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 16

[0476] (Z)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0477] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 1,4-dimethylformamide (5% dextrose, 0.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h. Compound 16c (148.0 mg, 0.35 mmol) was added, and the mixture was stirred for 2 h. The reaction was detected by LC-MS until completion. Water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was slurried with methanol (10 mL) to give the title compound 16 (yellow solid, 160.0 mg, yield: 74%).

[0478] 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 11.07 (s, 1H), 10.57 (s, 1H), 7.65 (s, 1H), 7.31 (d, J=2.3Hz, 1H), 7.22 (td, J=9.9, 9 .3, 3.0Hz, 3H), 6.90 (td, J=9.6, 9.1, 2.5Hz, 1H), 6.82 (dd, J=8.5, 4.8Hz, 1H), 5.06 (dd, J=12.9, 5.4Hz, 1H), 4.35 (t, J=5. 1Hz, 1H), 4.06 (d, J=12.9Hz, 2H), 3.61-3.52 (m, 2H), 3.44 (qd, J=7.0, 5.0Hz, 1H), 3.28 (q, J=6.7Hz, 2H), 3.17-3.09 (m, 2H ), 3.00-2.86 (m, 3H), 2.57 (s, 5H), 2.06-1.94 (m, 1H), 1.81 (d, J = 12.7Hz, 2H), 1.62 (d, J = 11.1Hz, 1H), 1.29-1.14 (m, 2H).

[0479] LC-MS m / z (ESI) = 679.2 [M+1]

[0480] Example 17

[0481] first step:

[0482] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylate 17a

[0483] tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[0484] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and N-Boc-piperazine (0.24 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated to T = 80°C and stirred for 6 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound 17a (yellow solid, 0.3 g, yield: 52%).

[0485] LC-MS m / z (ESI) = 443.20 [M+1]

[0486] Step 2:

[0487] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione 15a

[0488] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione 15a

[0489] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 17a (0.3 g, 0.67 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 15a (yellow solid, 0.23 g, yield: 99.0%).

[0490] LC-MS m / z (ESI) = 343.20 [M+1]

[0491] Step 3:

[0492] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)isoindole-1,3-dione Compound 17

[0493] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione compound 17

[0494] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 1% paraformaldehyde (5% paraformaldehyde, 0.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h; compound 15a (120.0 mg, 0.35 mmol) was added, and the mixture was stirred for 2 h; LC-MS was used to detect the end of the reaction; water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was slurried with methanol (10 mL) to obtain the title compound 17 (yellow solid, 70.0 mg, yield: 34%).

[0495] 1H NMR (400MHz, DMSO-d6) δ11.70 (s, 1H), 11.09 (s, 1H), 10.59 (s, 1H), 7.71 (d, 1H), 7.3 8(d, 1H), 7.28(dd, 1H), 7.21(dd, 1H), 6.97-6.88(m, 1H), 6.84(dd, 1H), 5.08(dd, 1H ), 3.69-6.66(m, 4H), 3.58-3.56(m, 2H), 3.54-3.51(m, 4H), 2.96-2.94(s, 2H), 2.92 -2.82(m, 1H), 2.61-2.59(m, 1H), 2.59-2.52(m, 1H), 2.45(s, 3H), 2.05-1.97(m, 1H).

[0496] LC-MS m / z (ESI) = 637.20 [M+1]

[0497] Example 18

[0498] first step:

[0499] tert-Butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)azetidine-1-carboxylate 18a

[0500] tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carboxylate

[0501] At T = 25°C, under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (0.31 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C, and the reaction was stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 18a (yellow solid, 0.4 g, yield: 62%).

[0502] LC-MS m / z (ESI) = 498.20 [M+1]

[0503] Step 2:

[0504] 5-(4-(azetidin-3-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl]isoindole-1,3-dione 18b

[0505] 5-(4-(azetidin-3-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 18b

[0506] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 18a (0.4 g, 0.8 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 18b (yellow solid, 0.31 g, yield: 98.0%).

[0507] LC-MS m / z (ESI) = 398.20 [M+1]

[0508] Step 3:

[0509] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl]piperazin-1-yl)isoindole-1,3-dione Compound 18

[0510] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)piperazin-1-yl)isoindoline-1,3-dione

[0511] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 1,4-dimethylformamide (5% hydroxypropyl 1,4-dimethylformamide) (0.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h. Compound 18b (127.0 mg, 0.35 mmol) was added, and the mixture was stirred for 2 h. The reaction was detected by LC-MS. Water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was slurried with methanol (10 mL) to give the title compound 18 (yellow solid, 40.0 mg, yield: 18%).

[0512] 1 H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 11.09 (s, 1H), 10.59 (s, 1H), 7.67 (d, 1H), 7.35 (d , 1H), 7.26(dd, 1H), 7.20(dd, 1H), 6.91(td, 1H), 6.84(p, 1H), 5.07(dd, 1H), 4.13(d, 2H ), 3.96(d, 2H), 3.62-3.52(m, 2H), 3.48-3.45(M, 4H), 3.24-3.17(m, 1H), 3.02(d, 2H), 2 .95-2.80(m, 1H), 2.65-2.53(m, 2H), 2.52-2.51(m, 4H), 2.47(s, 3H), 2.06-1.94(m, 1H).

[0513] LC-MS m / z (ESI) = 692.30 [M+1]

[0514] Example 19

[0515] first step:

[0516] tert-Butyl 4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidin-3-ylpiperazine-1-carboxylate 19a

[0517] tert-butyl 4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carboxylate 19a

[0518] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (0.31 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 19a (yellow solid, 0.36 g, yield: 55%).

[0519] LC-MS m / z (ESI) = 498.20 [M+1]

[0520] Step 2:

[0521] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidine-1-)isoindole-1,3-dione 19b

[0522] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione 19b

[0523] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 19a (0.36 g, 0.72 mmol), and the reaction was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The product was concentrated under reduced pressure to give the title compound 19b (yellow solid, 0.28 g, yield: 99.0%).

[0524] LC-MS m / z (ESI) = 398.20 [M+1]

[0525] Step 3:

[0526] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)azetidin-1-yl]isoindole-1,3-dione Compound 19

[0527] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione

[0528] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 1,4-dimethylformamide (5% dextrose, 0.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 h; compound 19b (127.0 mg, 0.35 mmol) was added, and the mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was slurried with methanol (10 mL) to obtain the title compound 19 (yellow solid, 45.0 mg, yield: 20%).

[0529] 1 H NMR (400MHz, Chloroform-d) δ10.39 (s, 1H), 8.68-8.56 (m, 1H), 7.76-7.63 ( m, 2H), 7.51-7.45 (m, 1H), 7.43-7.37 (m, 1H), 7.25-7.18 (m, 2H), 6.68-6.58 ( m, 2H), 5.04-4.87 (m, 1H), 4.81 (q, 1H), 3.87-3.57 (m, 9H), 3.43 (dt, 1H), 3.1 8(ddd, 1H), 2.84(q, 1H), 2.08(s, 3H), 1.68-1.62(m, 4H), 1.46-1.43(m, 1H).

[0530] LC-MS m / z (ESI) = 692.30 [M+1]

[0531] Example 20

[0532] first step:

[0533] tert-Butyl 2-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 20a

[0534] tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 20a

[0535] At T = 25°C, under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C, and the reaction was stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 20a (yellow solid, 0.45 g, yield: 71%).

[0536] LC-MS m / z (ESI) = 483.20 [M+1]

[0537] Step 2:

[0538] 2-(2,6-dioxapiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindole-1,3-dione 20b

[0539] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione 20b

[0540] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 20a (0.45 g, 0.93 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 20b (yellow solid, 0.35 g, yield: 97.0%).

[0541] LC-MS m / z (ESI) = 383.20 [M+1]

[0542] Step 3:

[0543] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(7-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,7-diazaspiro[3.5-]nonan-2-yl)isoindole-1,3-dione Compound 20

[0544] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(7-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione

[0545] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0546] 1H NMR (400MHz, DMSO-d6) δ11.66(s, 1H), 11.07(s, 1H), 10.57(s, 1H), 7.65(d, 1H), 7.21( dd, 1H), 6.91 (ddd, 1H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.66 (dd, 1H), 5.05 (dd, 1H), 3.84- 3.82(m, 4H), 3.64-3.41(m, 6H), 2.98-2.81(m, 3H), 2.63-2.53(m, 2H), 2.42(s, 3H), 2.06-1.95(m, 1H), 1.80-1.77(m, 4H).

[0547] LC-MS m / z (ESI) = 676.20 [M+1]

[0548] Example 21

[0549] first step:

[0550] tert-Butyl 9-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 21a

[0551] tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 21a

[0552] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.33 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 21a (yellow solid, 0.42 g, yield: 64%).

[0553] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 7.65 (d, 1H), 7.31 (d, 1H), 7.22 (dd, 1H), 5.06 (dd, 1H), 3.53-3.41 (m, 4H), 3.32-3 .30(M, 4H), 2.94-2.82(m, 2H), 2.58-2.53(m, 1H), 2.06-1.94(m, 1H), 1.55-1.52(M, 4H), 1.42-1.40(m, 4H), 1.39(s, 9H).

[0554] LC-MS m / z (ESI) = 510.20 [M+1]

[0555] Step 2:

[0556] 2-(2,6-dioxapiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undec-3-yl]isoindole-1,3-dione 21b

[0557] 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione 21b

[0558] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 21a (0.42 g, 0.82 mmol), and the reaction was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The product was concentrated under reduced pressure to give the title compound 21b (yellow solid, 0.33 g, yield: 99.0%).

[0559] LC-MS m / z (ESI) = 410.20 [M+1]

[0560] Step 3:

[0561] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl]isoindole-1,3-dione Compound 21

[0562] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione

[0563] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0564] 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 11.08 (s, 1H), 10.56 (s, 1H), 7.64 (d, 1H), 7.30 (d, 1H), 7.25-7.15 (m, 2H), 6.90 (ddd, 1H), 6.83 (dd, 1H), 5.07(dd, 1H), 3.65-3.42(m, 10H), 2.97-2.82(m, 3H), 2.65-2.53(m, 2H) , 2.42(s, 3H), 2.10-1.94(m, 1H), 1.70-1.54(m, 4H), 1.55-1.40(m, 4H).

[0565] LC-MS m / z (ESI) = 705.30 [M+1]

[0566] Example 22

[0567] first step:

[0568] tert-Butyl 4-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-1-oxa-4,9-diaza[5.5]undecane-9-carboxylate 22a

[0569] tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate 22a

[0570] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (0.34 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 22a (yellow solid, 0.43 g, yield: 62%).

[0571] 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 7.65 (d, 1H), 7.31 (d, 1H), 7.22 (dd, 1H), 5.06 (dd, 1H), 3.53-3.40 (m, 4H), 3.31-3 .29(m, 3H), 2.90-2.83(m, 2H), 2.62-2.50(m, 4H), 2.06-1.96(m, 1H), 1.54-1.51(m, 4H), 1.43-1.40(m, 4H), 1.39(s, 9H).

[0572] LC-MS m / z (ESI) = 529.30 [M+1]

[0573] Step 2:

[0574] 2-(2,6-dioxapiperidin-3-yl)-5-(1-oxa-4,9-diaza[5.5]undec-4-yl)isoindole-1,3-dione 22b

[0575] 2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)isoindoline-1,3-dione

[0576] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 22a (0.43 g, 0.81 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 22b (yellow solid, 0.34 g, yield: 97.0%).

[0577] LC-MS m / z (ESI) = 429.30 [M+1]

[0578] Step 3

[0579] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diaza[5.5]undecane-4-yl)isoindole-1,3-dione Compound 22

[0580] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahyd rocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)isoindoline-1,3-dione compound 22

[0581] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0582] 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 11.08 (s, 1H), 10.56 (s, 1H), 7.67 (d, 1H), 7.41 (d, 1H), 7.28(dd, 1H), 7.20(dd, 1H), 6.97-6.87(m, 1H), 6.83(dd, 1H), 5.07(dd, 1H), 3.82-3 .80(m, 2H), 3.63-3.51(m, 2H), 3.47-3.44(m, 4H), 3.26-3.22(m, 2H), 2.97-2.83(m, 3H), 2.64-2.51(m, 4H), 2.43(s, 3H), 2.08-1.95(m, 1H), 1.85-1.82(m, 2H), 1.67-1.54(m, 2H).

[0583] LC-MS m / z (ESI) = 707.30 [M+1]

[0584] Example 23

[0585] first step:

[0586] tert-Butyl 2-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate 23a

[0587] tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate 23a

[0588] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (0.31 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 23a (yellow solid, 0.35 g, yield: 54%).

[0589] 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 7.64 (d, 1H), 6.94 (d, 1H), 6.81 (dd, 1H), 5.05 (dd, 1H), 3.52-3.39 (m, 4H), 3.33 (s, 2H ), 3.31-3.23(m, 2H), 2.94-2.82(m, 1H), 2.61-2.53(m, 2H), 2.06-1.96(m, 1H), 1.91(t, 2H), 1.56-1.45(m, 4H), 1.40(s, 9H).

[0590] LC-MS m / z (ESI) = 497.20 [M+1]

[0591] Step 2

[0592] 2-(2,6-dioxapiperidin-3-yl)-5-(2,8-diazaspiro[4.5]dec-2-yl)isoindole-1,3-dione 23b

[0593] 2-(2,6-dioxopiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione 23b

[0594] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 23a (0.35 g, 0.70 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 23b (yellow solid, 0.27 g, yield: 97.0%).

[0595] LC-MS m / z (ESI) = 397.20 [M+1]

[0596] Step 3

[0597] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(8-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,8-diazaspiro[4.5]dec-2-yl)isoindole-1,3-dione Compound 23

[0598] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(8-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione compound 23

[0599] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2 -oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b]pyrrole-3-carboxylic acid intermediate 1 (100.0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL) was added dropwise and stirred for 0.5 h; compound 23b (139.0 mg, 0.35 mmol) was added and stirred for 2 h; LC-MS was used to detect the end of the reaction; water (2 mL) was added dropwise and stirred for 10 min, filtered, and the filter cake was slurried with methanol (10 mL) to obtain the title compound 23 (yellow solid, 55.0 mg, yield: 25%).

[0600] 1H NMR (400MHz, DMSO-d6) δ11.65(s, 1H), 11.07(s, 1H), 10.56(s, 1H), 7.64(d , 1H), 7.19(dd, 1H), 6.95(d, 1H), 6.94-6.87(m, 1H), 6.82(dt, 2H), 5.06(d d, 1H), 3.69-3.63 (m, 2H), 3.60-3.43 (m, 6H), 3.39 (s, 2H), 2.98-2.82 (m, 3 H), 2.65-2.53(m, 2H), 2.43(s, 3H), 2.07-1.92(m, 3H), 1.66-1.47(m, 4H).

[0601] LC-MS m / z (ESI) = 691.20 [M+1]

[0602] Example 24

[0603] first step:

[0604] tert-Butyl 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopiperidin-5-yl)piperidin-4-yl)azetidine-1-carboxylate 24a

[0605] tert-butyl 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-1-carboxylate 24a

[0606] At T = 25°C, under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 3-(piperidin-4-yl)azetidine-1-carboxylate (0.31 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C, and the reaction was stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 24a (yellow solid, 0.4 g, yield: 62%).

[0607] LC-MS m / z (ESI) = 497.20 [M+1]

[0608] Step 2:

[0609] 5-(4-(azetidin-3-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl]isoindole-1,3-dione 24b

[0610] 5-(4-(azetidin-3-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 24b

[0611] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 24a (0.40 g, 0.80 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to give the title compound 24b (yellow solid, 0.31 g, yield: 97.2%).

[0612] LC-MS m / z (ESI) = 397.20 [M+1]

[0613] Step 3:

[0614] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl]piperidin-1-yl)isoindole-1,3-dione Compound 24

[0615] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)piperidin-1-yl)isoindoline-1,3-dione

[0616] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0617] 1 H NMR (400MHz, DMSO-d6) δ11.75 (s, 1H), 11.07 (s, 1H), 10.59 (s, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 7.22 (ddd, 2H), 6.96-6.88 (m, 1H), 6.84 (dd, 1H), 5.06 (dd, 1H), 4.14-4.03 (m, 4H), 3.84-3.80(m, 2H), 3.57-3.55(m, 2H), 3.07-2.81(m, 5H), 2.63-2.53(m, 2H), 2.4 9(s, 3H), 2.42-2.36(m, 2H), 2.07-1.95(m, 1H), 1.77-1.73(m, 3H), 1.27-1.22(m, 1H).

[0618] LC-MS m / z (ESI) = 691.20 [M+1]

[0619] Example 25

[0620] first step:

[0621] Tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 25a

[0622] tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 25a

[0623] At T = 25 ° C, under nitrogen protection, 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione 13a (0.50 g, 1.48 mmol), tert-butyl 3-(prop-2-yn-1-yl)azetidine-1-carboxylate (0.29 g, 1.48 mmol), cuprous iodide (56 mg, 0.30 mmol), bistriphenylphosphine palladium dichloride (104 mg, 0.15 mmol), and triethylamine (0.45 g, 4.45 mmol) were added to a round-bottom flask. N,N-dimethylformamide (5 mL) was then added and the nitrogen atmosphere was replaced. Under nitrogen protection, the reaction temperature was raised to T = 80 ° C and stirred for 8.0 h. The reaction was completed by LC-MS. Aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 25a (yellow solid, 0.41 g, yield: 61%).

[0624] LC-MS m / z (ESI) = 452.20 [M+1]

[0625] Step 2:

[0626] 5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl]isoindole-1,3-dione 25b

[0627] 5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 25b

[0628] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a dichloromethane (10 mL) solution of compound 25a (0.41 g, 0.91 mmol), and the mixture was stirred for 4 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to obtain the title compound 25b (yellow solid, 0.31 g, yield: 97.2%).

[0629] LC-MS m / z (ESI) = 352.2 [M+1]

[0630] Step 3:

[0631] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl]prop-1-yn-1-yl)isoindole-1,3-dione Compound 25

[0632] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)prop-1-yn-1-yl)isoindoline-1,3-dione

[0633] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.35 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0634] 1 H NMR (400MHz, DMSO-d6) δ11.74 (s, 1H), 11.15 (s, 1H), 10.60 (s, 1H), 7.94-7.84 (m, 3H), 7.20 (dd, 1H), 6.90 (dd, 1H), 6.83 (dd, 1H), 5.16 (dd, 1H), 4.29-4.16 ( m, 2H), 3.94-3.90 (m, 2H), 3.54 (d, 2H), 2.98 (d, 2H), 2.94-2.92 (m, 1H), 2.90- 2.87(m, 1H), 2.82(d, 2H), 2.58-2.52(m, 2H), 2.46(s, 3H), 2.12-2.00(m, 1H).

[0635] LC-MS m / z (ESI) = 646.20 [M+1]

[0636] Example 26

[0637] first step:

[0638] tert-Butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 26b

[0639] tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 26b

[0640] At T = 25 ° C, under nitrogen protection, 3-(5-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione 26a (0.478 g, 1.48 mmol), tert-butyl 3-(prop-2-yn-1-yl)azetidine-1-carboxylate (0.29 g, 1.48 mmol), cuprous iodide (56 mg, 0.30 mmol), bistriphenylphosphine palladium dichloride (104 mg, 0.15 mmol) and triethylamine (0.45 g, 4.45 mmol) were added to a round-bottom flask, followed by N,N-dimethylformamide (5 mL) and nitrogen displacement. Under nitrogen protection, the reaction temperature was raised to T = 80 ° C and stirred for 8.0 h. The reaction was completed by LC-MS. Aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 26b (yellow solid, 0.38 g, yield: 58%).

[0641] LC-MS m / z (ESI) = 438.20 [M+1]

[0642] Step 2:

[0643] 3-(5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione 26c

[0644] 3-(5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26c

[0645] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a dichloromethane (10 mL) solution of compound 26b (0.38 g, 0.87 mmol), and the mixture was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The mixture was concentrated under reduced pressure to obtain the title compound 26c (yellow solid, 0.31 g, yield: 97.2%).

[0646] LC-MS m / z (ESI) = 338.2 [M+1]

[0647] Step 3:

[0648] (Z)-3-(5-(3-(1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione Compound 26

[0649] (Z)-3-(5-(3-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0650] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.35 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentano[b]pyrrole-3-carboxylic acid intermediate 1 (10 To the mixture was added aliquots of 2-[ ...

[0651] 1H NMR (400MHz, DMSO-d6) δ11.74(s, 1H), 11.01(s, 1H), 10.60(s, 1H), 7.70(d, 1H), 7.62(s, 1H), 7.51(d, 1H), 7.24-7.17(m, 1H), 6.92(t, 1H), 6.83(dd, 1H), 5.11(dd , 1H), 4.37(dd, 2H), 4.28-4.13(m, 2H), 3.93-3.88(m, 2H), 3.56-3.54(m, 2H), 3. 04-2.85(m, 4H), 2.79(d, 2H), 2.57-2.54(m, 2H), 2.45(s, 3H), 2.02-1.98(m, 1H).

[0652] LC-MS m / z (ESI) = 632.20 [M+1]

[0653] Example 27

[0654] first step:

[0655] (R,Z)-tert-Butyl 4-(2-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate 27a

[0656] tert-butyl(R,Z)-4-(2-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate

[0657] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.35 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid (100.0 mg, 0.32 The reaction mixture was added dropwise to a solution of 4-(2-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (94 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL), and the reaction was stirred for 0.5 h. (R)-4-(2-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (94 mg, 0.38 mmol) was added, and the reaction was stirred for 2 h. LC-MS was used to detect the completion of the reaction. Water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was washed twice with ethanol (10 mL) to obtain the title 27a (yellow solid, 160 mg, yield: 93%).

[0658] LC-MS m / z (ESI) = 538.30 [M+1]

[0659] Step 2:

[0660] (R,Z)-6-(5-Fluoro-2-oxoindole-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide 27b

[0661] (R,Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0662] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a dichloromethane (4 mL) solution of compound 27a (0.16 g, 0.30 mmol), and the mixture was stirred for 0.5 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound 27b (yellow solid, 0.13 g, yield: 99%).

[0663] LC-MS m / z (ESI) = 438.30 [M+1]

[0664] Step 3:

[0665] N-((2R)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-((Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 27

[0666] N-((2R)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-( (Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0667] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.15 g, 1.16 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.082 g, 0.29 mmol) and compound 27b (0.13 g, 0.29 mmol) in N,N-dimethylformamide (4 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. TLC was performed to confirm the reaction completion. 4 mL of water was added, stirred for 10 minutes, filtered, and dried. The crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound 27 (yellow solid, 20 mg, yield: 10%).

[0668] LC-MS m / z (ESI) = 694.30 [M+1]

[0669] 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 11.10 (s, 1H), 10.59 (s, 1H), 7.68 (d, 1H), 7 .35(d,1H),7.24(ddd,2H),6.97(d,1H),6.95-6.86(m,1H),6.83(dd,1H),5.10-5 .04(m, 1H), 4.16-4.07(m, 1H), 3.58(s, 2H), 3.45(s, 4H), 3.19-3.11(m, 2H), 2.93 -2.82(m, 1H), 2.61-2.53(m, 10H), 2.36(dd, 1H), 2.06-1.97(m, 1H), 1.19(d, 3H).

[0670] Example 28

[0671] first step:

[0672] tert-Butyl (S,Z)-4-(2-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate 28a

[0673] tert-butyl(S,Z)-4-(2-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate

[0674] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (133.0 mg, 0.35 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid (100.0 mg, 0.32 The reaction mixture was added dropwise to a solution of 4-(2-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (94 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL), and the reaction was stirred for 0.5 h. (S)-4-(2-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (94 mg, 0.38 mmol) was added, and the reaction was stirred for 2 h. LC-MS was used to detect the completion of the reaction. Water (2 mL) was added dropwise, and the mixture was stirred for 10 min. The mixture was filtered with suction, and the filter cake was washed twice with ethanol (10 mL) to obtain the title 28a (yellow solid, 155 mg, yield: 91%).

[0675] LC-MS m / z (ESI) = 538.30 [M+1]

[0676] Step 2:

[0677] (S,Z)-6-(5-Fluoro-2-oxoindole-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide 28b

[0678] (S,Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0679] At T = 25 ° C, under nitrogen protection, trifluoroacetic acid (0.28 g, 2.40 mmol) was added dropwise to a solution of compound 28a (0.155 g, 0.29 mmol) in dichloromethane (4 mL), and the mixture was stirred for 0.5 h. LC-MS was used to detect the completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound 28b (yellow solid, 0.12 g, yield: 95%).

[0680] LC-MS m / z (ESI) = 438.30 [M+1]

[0681] Step 3:

[0682] N-((2S)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-((Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 28

[0683] N-((2S)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-( (Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0684] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.14 g, 1.1 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.075 g, 0.27 mmol) and compound 28b (0.12 g, 0.27 mmol) in N,N-dimethylformamide (4 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was monitored by TLC until completion. 4 mL of water was added, stirred for 10 minutes, filtered, and dried. The crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 28 (yellow solid, 30 mg, yield: 16%).

[0685] LC-MS m / z (ESI) = 694.30 [M+1]

[0686] 1 H NMR (400MHz, DMSO-d6) δ11.63 (s, 1H), 11.09 (s, 1H), 10.58 (s, 1H), 7.67 (d, 1H), 7 .33(d,1H),7.23(ddd,2H),6.95(d,1H),6.94-6.85(m,1H),6.81(dd,1H),5.09-5 .02(m,1H),4.15-4.06(m,1H),3.56(s,2H),3.44(s,4H),3.18-3.10(m,2H),2.91 -2.80(m, 1H), 2.60-2.52(m, 10H), 2.35(dd, 1H), 2.04-1.95(m, 1H), 1.17(d, 3H).

[0687] Example 29

[0688] first step:

[0689] tert-Butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate 29a

[0690] tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0691] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.37 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 29a (yellow solid, 0.5 g, yield: 71%).

[0692] LC-MS m / z (ESI) = 540.30 [M+1]

[0693] Step 2:

[0694] 2-(2,6-dioxopidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole-1,3-dione 29b

[0695] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione

[0696] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 29a (0.5 g, 0.93 mmol), and the reaction was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The product was concentrated under reduced pressure to give the title compound 29b (yellow solid, 0.4 g, yield: 98.3%).

[0697] LC-MS m / z (ESI) = 440.30 [M+1]

[0698] Step 3:

[0699] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione Compound 29

[0700] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione

[0701] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid (100. 0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), the mixture was added dropwise and stirred for 0.5 h; compound 29b (155.0 mg, 0.35 mmol) was added and the mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise and stirred for 10 min, the mixture was filtered, and the filter cake was slurried with methanol (10 mL) to obtain the title compound 29 (yellow solid, 70.0 mg, yield: 30%).

[0702] LC-MS m / z (ESI) = 734.30 [M+1]

[0703] 1 H NMR (4()()MHz, DMSO-d6) δ11.64(s, 1H), 11.09(s, 1H), 10.58(s, 1H), 7.68(d, 1H) ,7.34(d,1H),7.29-7.17(m,2H),6.91(td,1H),6.83(dd,1H),5.07(dd,1H),4.26 -4.00(m, 2H), 3.57(s, 2H), 3.44(s, 4H), 2.93-2.83(m, 5H), 2.62-2.50(m, 6H), 2. 41(s, 3H), 2.22(d, 2H), 2.06-1.97(m, 1H), 1.85-1.76(m, 3H), 1.08-0.99(m, 2H).

[0704] Example 30

[0705] first step:

[0706] tert-Butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-1-carboxylate 30a

[0707] tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-1-carboxylate

[0708] At T = 25°C under nitrogen, N,N-diisopropylethylamine (0.50 g, 3.90 mmol) was added dropwise to a solution of compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione 1a (0.36 g, 1.31 mmol) and tert-butyl 4-(piperidin-4-methylene)-piperidine-1-carboxylate (0.368 g, 1.31 mmol) in N,N-dimethylformamide (10 mL). The temperature was raised to T = 80°C and stirred for 6.0 h. The reaction was complete by TLC. The organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated crude product was purified by column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give the title compound 30a (yellow solid, 0.5 g, yield: 70%).

[0709] LC-MS m / z (ESI) = 539.30 [M+1]

[0710] Step 2:

[0711] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperidin-1-yl)isoindole-1,3-dione 30b

[0712] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione

[0713] At T = 25 ° C, under nitrogen protection, a hydrochloric acid / 1,4-dioxane solution (4 M, 1.0 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 30a (0.5 g, 0.927 mmol), and the reaction was stirred for 4 h. LC-MS was used to monitor the reaction until completion. The product was concentrated under reduced pressure to give the title compound 30b (yellow solid, 0.38 g, yield: 95%).

[0714] LC-MS m / z (ESI) = 439.30 [M+1]

[0715] Step 3:

[0716] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindole-1,3-dione Compound 30

[0717] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene))-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0718] At T = 25 ° C, under nitrogen protection, N, N-diisopropylethylamine (207.0 mg, 1.60 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (122.0 mg, 0.32 mmol) were added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentanoic acid [b] pyrrole-3-carboxylic acid (100. 0 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL), the mixture was added dropwise and stirred for 0.5 h; compound 30b (1154.0 mg, 0.35 mmol) was added and the mixture was stirred for 2 h; LC-MS was used to detect the completion of the reaction; water (2 mL) was added dropwise and stirred for 10 min, the mixture was filtered, and the filter cake was slurried with methanol (10 mL) to obtain the title compound 30 (yellow solid, 65.0 mg, yield: 27%).

[0719] LC-MS m / z (ESI) = 733.30 [M+1]

[0720] 1H NMR (400MHz, DMSO-d6) δ11.63 (s, 1H), 11.08 (s, 1H), 10.58 (s, 1H), 7.64 (d, 1H) , 7.30 (d, 1H), 7.21 (td, 2H), 6.91 (td, 1H), 6.83 (dd, 1H), 5.06 (dd, 1H), 4.04 (d, 2H), 3.56(s, 2H), 3.39(s, 4H), 2.93-2.84(m, 4H), 2.64-2.51(m, 2H), 2.40(s, 3 H), 2.07-1.95(m, 1H), 1.79-1.58(m, 6H), 1.24-1.08(m, 5H), 1.07-0.95(m, 2H).

[0721] Example 31

[0722] first step:

[0723] tert-Butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate 31b

[0724] tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate

[0725] At T = 25 ° C, under nitrogen protection, di-tert-butyl dicarbonate (7.34 g, 33.6 mmol) and triethylamine (11.3 g, 112 mmol) were added to a solution of 4-(1-piperazinyl)phenol (5 g, 28 mmol) in dichloromethane (2 mL), and the mixture was stirred for 2 h after addition. LC-MS was used to monitor the reaction until completion. Concentrator column chromatography gave compound 31b (white solid, 7 g, yield: 90%).

[0726] LC-MS m / z (ESI) = 279.20 [M+1]

[0727] Step 2:

[0728] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate 31c

[0729] tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate

[0730] At T = 25 ° C, under nitrogen protection, 31b (7 g, 25 mmol) was dissolved in tetrahydrofuran (70 mL), and 60% sodium bicarbonate (1 g, 25 mmol) was added. Under reflux conditions, a tetrahydrofuran solution of 3-bromopiperidine-2,6-dione (7.55 g, 25 mmol) was then added. After the addition, the mixture was stirred at reflux for 2 h. The reaction was detected by LC-MS until completion. Ethyl acetate (100 mL) was added, the mixture was filtered, and the organic phase was concentrated and purified by column chromatography to obtain compound 31c (white solid, 6 g, yield: 62%).

[0731] LC-MS m / z (ESI) = 390.20 [M+1]

[0732] Step 3:

[0733] 3-(4-(Piperazin-1-yl)phenoxy)piperidine-2,6-dione 31d

[0734] 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione

[0735] At T = 25 ° C, under nitrogen protection, compound 31c (3 g, 7.71 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (7.5 mL) was added dropwise. The reaction was continued for 0.5 hours, and the mixture was concentrated under reduced pressure to obtain crude compound 31d (yellow liquid, 2.2 g, yield: 99%).

[0736] LC-MS m / z (ESI) = 290.20 [M+1]

[0737] Step 4:

[0738] tert-Butyl (3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)carbamate 31e

[0739] tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)carbamate

[0740] At T = 25°C under nitrogen, 31d (2.2 g, 7.6 mmol), N-Boc-3-aminopropyl bromide (2.18 g, 9.1 mmol), and potassium carbonate (3.15 g, 22.8 mmol) were dissolved in N,N-dimethylformamide (20 mL) and allowed to react overnight. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (80 mL*3). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate (50 g), concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound 31e (white solid, 3.0 g, yield: 88%).

[0741] LC-MS m / z (ESI) = 447.20 [M+1]

[0742] Step 5:

[0743] 3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione 31f

[0744] 3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione

[0745] Referring to the synthesis method of compound 31d, a crude compound 31f was obtained (yellow liquid, 2.2 g, yield: 97%).

[0746] LC-MS m / z (ESI) = 347.20 [M+1]

[0747] Step 6:

[0748] (Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 31

[0749] (Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0750] Referring to the synthesis method of compound 30, compound 31 was obtained (yellow solid, 40 mg, yield: 22%).

[0751] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.20 (m , 2H), 6.92-6.87(m, 4H), 6.83(dd, 1H), 5.04-4.98(m, 1H), 3.58(t, 2H), 3.31(dd , 2H), 3.27(d, 2H), 3.14(dt, 2H), 3.04-3.00(m, 2H), 2.75-2.60(m, 3H), 2.58(s, 3H), 2.52-2.45(m, 3H), 2.33-2.31(m, 1H), 2.18-2.05(m, 4H), 1.74-1.7(m, 2H)..

[0752] LC-MS m / z (ESI) = 641.30 [M+1]

[0753] Example 32

[0754] first step:

[0755] 2-(tert-Butyl) 5,6-diethylisoindoline-2,5,6-tricarboxylate 32c

[0756] 2-(tcrt-butyl)5,6-diethyl isoindoline-2,5,6-tricarboxylate

[0757] Under nitrogen at room temperature, N-Boc-dipropargylamine (17 g, 88 mmol) 32a, diethyl butynedioate (60 g, 352 mmol) 32b, and tris(triphenylphosphine)rhodium chloride (1.63 g, 1.76 mmol) were dissolved in ethanol (200 mL) and refluxed for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound 32c (a yellow oily liquid, 6 g, 19% yield).

[0758] LC-MS m / z (ESI) = 364.20 [M+1]

[0759] Step 2:

[0760] 2-(tert-Butoxycarbonyl)isoindoline-5,6-dicarboxylic acid 32d

[0761] 2-(tert-butoxycarbonyl)isoindoline-5,6-dicarboxylic acid

[0762] Under nitrogen at room temperature, compound 32c (6 g, 16.5 mmol) was dissolved in methanol (60 mL) and water (60 mL). Sodium hydroxide (1.98 g, 49.6 mmol) was then added to the reaction flask and allowed to react at 50°C for 2 hours. After the reaction, the methanol was removed by concentration under reduced pressure. After returning to room temperature, the pH was slowly adjusted to 3-4 with 1N dilute hydrochloric acid. A large amount of solid precipitated, and the mixture was stirred for another 30 minutes. Filtration and drying afforded compound 32d (yellow solid, 3.8 g, yield: 75%).

[0763] LC-MS m / z (ESI) = 308.10 [M+1]

[0764] Step 3:

[0765] 1,3-Dioxo-5,7-dihydro-1H-furo[3,4-f]isoindole-6(3H)-carboxylic acid tert-butyl ester 32e

[0766] tert-butyl 1,3-dioxo-5,7-dihydro-1H-furo[3,4-f]isoindole-6(3H)-carboxylate

[0767] Under nitrogen at room temperature, acetic anhydride (30 mL) was added to a reaction flask containing compound 32d (3.8 g, 12.34 mmol) and the reaction was incubated at 100°C for 4 hours. After completion of the reaction, ethyl acetate (300 mL) was added, and the organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude compound 32e (yellow liquid, 3.5 g).

[0768] LC-MS m / z (ESI) = 289.10 [M+1]

[0769] Step 4:

[0770] tert-Butyl 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-carboxylate 32f

[0771] tert-butyl 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-carboxylate

[0772] Under nitrogen at room temperature, 3-amino-2,6-piperidinedione (1.6 g, 12.46 mmol) and triethylamine (3.77 g, 37.4 mmol) were added to compound 32e (3.6 g, 12.46 mmol) in acetone (40 mL). The reaction was allowed to proceed at 100°C for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound 32f (yellow solid, 1.8 g, 36% yield).

[0773] LC-MS m / z (ESI) = 400.10 [M+1]

[0774] Step 5:

[0775] 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione 32g

[0776] 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione

[0777] Under nitrogen at room temperature, 4N hydrochloric acid / dioxane solution (9 mL) was slowly added to a reaction flask containing compound 32f (0.9 g, 2.25 mmol) and allowed to react at room temperature for 0.5 h. After completion of the reaction, the mixture was filtered and dried to afford compound 32g (yellow solid, 0.65 g, yield: 96%).

[0778] LC-MS m / z (ESI) = 300.10 [M+1]

[0779] Step 6:

[0780] tert-Butyl (3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)propyl)carbamate 32h

[0781] tert-butyl(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)propyl)carbamate

[0782] At T = 25°C under nitrogen, 32 g (0.65 g, 2.17 mmol), N-Boc-3-aminopropyl bromide (0.618 g, 2.6 mmol), and potassium carbonate (0.9 g, 6.5 mmol) were dissolved in N,N-dimethylformamide (7 mL) and allowed to react overnight. After completion of the reaction, saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate (5 g), concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound 32h (white solid, 0.78 g, 79% yield).

[0783] LC-MS m / z (ESI) = 457.20 [M+1]

[0784] Step 7:

[0785] 6-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione 32i

[0786] 6-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione

[0787] Referring to the synthesis method of compound 32g, compound 32i was obtained (yellow solid, 600 mg, yield: 98%).

[0788] LC-MS m / z (ESI) = 357.20 [M+1]

[0789] Step 8:

[0790] (Z)-N-(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentyl[b]pyrrole-3-carboxamide Compound 32

[0791] (Z)-N-(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)pro pyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0792] Referring to the synthesis method of compound 30, compound 32 was obtained (yellow solid, 45 mg, yield: 25%).

[0793] 1 H NMR (400MHz, DMSO-d6) δ11.64(s, 1H), 11.13(s, 1H), 10.58(s, 1H), 7.33(t, 1H), 7.30-7 .21(m,1H),7.18(dd,1H),7.02-6.86(m,2H),6.82(dd,1H),5.12(dd,1H),3.57-3.55(m, 1H), 3.53-3.45(m, 2H), 3.33-3.21(m, 4H), 3.20-3.17(m, 1H), 3.09-3.07(m, 2H), 2.94-2 .84(m, 1H), 2.82-2.74(m, 2H), 2.60-2.55(m, 5H), 2.05-1.97(m, 1H), 1.82-1.71(m, 2H).

[0794] LC-MS m / z (ESI) = 651.20 [M+1]

[0795] Example 33

[0796] first step:

[0797] Tert-butyl (3-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)propyl)carbamate 33b

[0798] tert-butyl(3-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)propyl)carbamate

[0799] Compound 33a (3.0 g, 13.3 mmol), N-Boc-3-aminopropyl bromide (4.7 g, 19.8 mmol), potassium iodide (2.2 g, 13.2 mmol), and potassium carbonate (5.5 g, 39.8 mmol) were dissolved in acetonitrile (30 mL). The reaction flask was replaced with nitrogen and then placed at 60°C for reaction. After 3 hours of reaction, the reaction solution was concentrated under reduced pressure to obtain compound 33b (yellow solid, 4.0 g).

[0800] LCMS m / s=383.55[M+1].

[0801] Step 2:

[0802] tert-Butyl (3-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)propyl)carbamate 33c

[0803] tert-butyl(3-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)propyl)carbamate

[0804] Compound 33b (4.0 g, 10.4 mmol), zinc powder (3.4 g, 51.9 mmol), and ammonium chloride (5.5 g, 102.8 mmol) were dissolved in methanol:water = 3:1 (40 mL). The reaction flask was purged with nitrogen and then placed at 60°C for reaction. After 2 hours of reaction, the mixture was cooled to room temperature and filtered to obtain compound 33c (yellow solid, 3.25 g).

[0805] LCMS m / s=353.55[M+1].

[0806] Step 3:

[0807] tert-Butyl (3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate 33d

[0808] tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate

[0809] Compound 33c (1.0 g, 2.8 mmol), 3-bromopiperidine-2,6-dione (0.8 g, 4.1 mmol), and sodium bicarbonate (1.4 g, 16.6 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction flask was replaced with nitrogen and then placed at 85°C for reaction. After 8 hours of reaction, the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (3×30 mL). After extraction, the organic phase was washed with saturated brine (3×30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 25:1) to give compound 33d (yellow solid, 200 mg).

[0810] LCMS m / s=464.26[M+1].

[0811] Step 4:

[0812] 3-((4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 33e

[0813] 3-((4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0814] According to the synthesis method of compound 3c, compound 33e (yellow solid, 156 mg) was obtained.

[0815] LCMS m / s=364.56[M+1].

[0816] Step 5:

[0817] (Z)-N-(3-(4-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 33

[0818] (Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0819] According to the synthesis method of compound 3, compound 33 (yellow solid, 80 mg, yield 46%) was obtained.

[0820] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.20 (m , 2H), 6.92-6.87(m, 3H), 6.83(dd, 1H), 5.01-4.98(m, 1H), 3.57(t, 2H), 3.31(dd , 2H), 3.27(d, 2H), 3.15(dt, 2H), 3.03-3.00(m, 2H), 2.75-2.60(m, 3H), 2.55(s, 3H), 2.52-2.45(m, 3H), 2.34-2.31(m, 1H), 2.18-2.05(m, 4H), 1.74-1.72(m, 2H).

[0821] LCMS m / s=658.26[M+1]

[0822] Example 34

[0823] first step:

[0824] tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate 34c

[0825] tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

[0826] Under nitrogen at room temperature, compound 34a (2 g, 4.8 mmol), compound 34b (1.6 g, 4.8 mmol), tetrakistriphenylphosphine palladium (555 mg, 0.48 mmol), and sodium carbonate (1.02 g, 9.6 mmol) were dissolved in N,N-dimethylformamide:water = 1:6 (20 mL) and heated at 100°C for 4 hours. After the reaction, water (20 mL) was added, and the mixture was washed with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (10 mL*2), dried, and concentrated under reduced pressure. The mixture was purified by column chromatography on silica gel to afford compound 34c (white solid, 2.2 g, 85% yield).

[0827] LC-MS m / z (ESI) = 552.30 [M+1]

[0828] Step 2:

[0829] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 34d

[0830] tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate

[0831] Under hydrogen protection at room temperature, palladium / carbon (440 mg) was added to compound 34c (2.2 g, 4 mmol) in ethanol (20 mL) and reacted overnight at room temperature. After completion of the reaction, the mixture was filtered and concentrated to obtain compound 34d (yellow solid, 880 mg, yield: 60%).

[0832] LC-MS m / z (ESI) = 374.20 [M+1]

[0833] Step 3:

[0834] 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione 34e

[0835] 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[0836] Referring to the synthesis method of compound 32g, compound 34e was obtained (yellow solid, 600 mg, yield: 93%).

[0837] LC-MS m / z (ESI) = 274.20 [M+1]

[0838] Step 4:

[0839] tert-Butyl (3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)carbamate 34f

[0840] tert-butyl(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)carbamate

[0841] Referring to the synthesis method of compound 32h, compound 34f was obtained (white solid, 800 mg, yield: 85%).

[0842] LC-MS m / z (ESI) = 431.20 [M+1]

[0843] Step 5:

[0844] 3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenyl)piperidine-2,6-dione 34g

[0845] 3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0846] Referring to the synthesis method of compound 32g, compound 34g (yellow solid, 600 mg, yield: 97%) was obtained.

[0847] LC-MS m / z (ESI) = 331.20 [M+1]

[0848] Step 6:

[0849] (Z)-N-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 34

[0850] (Z)-N-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0851] Referring to the synthesis method of compound 30, compound 34 was obtained (yellow solid, 20 mg, yield: 15%).

[0852] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.78 (s, 1H), 10.59 (s, 1H), 7.26-7.20 (m, 2H), 7.04 (d, 2H), 6.92-6.88 (m, 3H), 6.83 (dd, 1H), 3.71 (dd, 1H) ,3.57(d,2H),3.32-3.22(m,4H),3.15-3.10(m,6H),2.67-2.60(m,2H),2 .58(s, 3H), 2.44-2.36(m, 4H), 2.11(dd, 1H), 1.98(dd, 1H), 1.71(d, 2H).

[0853] LC-MS m / z (ESI) = 625.30 [M+1]

[0854] Example 35

[0855] first step:

[0856] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione 35b

[0857] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0858] Referring to the synthesis method of compound 32g, compound 35b was obtained (yellow solid, 3.8 g, yield: 98%).

[0859] LC-MS m / z (ESI) = 343.10 [M+1]

[0860] Step 2:

[0861] tert-Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)carbamate 35c

[0862] tert-butyl(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)carbamate

[0863] Compound 35b (300 mg, 0.87 mmol), tert-butyl (3-bromo-1-methylpropyl)carbamate (264 mg, 1.05 mmol) were synthesized by referring to the method of compound 32h to obtain compound 35c (yellow solid, 160 mg, yield: 36%).

[0864] LC-MS m / z (ESI) = 514.20 [M+1]

[0865] Step 3:

[0866] 5-(4-(3-aminobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 35d

[0867] 5-(4-(3-aminobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0868] Referring to the synthesis method of compound 32g, compound 35d was obtained (yellow solid, 3.8 g, yield: 98%).

[0869] LC-MS m / z (ESI) = 343.10 [M+1]

[0870] Step 4:

[0871] (Z)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 35

[0872] (Z)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)-6- (5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0873] Intermediate 1 (100 mg, 0.32 mmol) was prepared by referring to the synthesis method of compound 30 to obtain compound 35 (yellow solid, 60 mg, yield: 26%).

[0874] 1H NMR (400MHz, DMSO-d6) δ 11.60 (s, 1H), 11.05 (s, 1H), 10.55 (s, 1H), 7.63 (d, J = 8.7Hz, 1H), 7.30 (d, J = 2.5Hz, 1H), 7 .19 (ddd, J=19.2, 9.2, 2.5Hz, 2H), 7.00 (d, J=8.5Hz, 1H), 6.91-6.83 (m, 1H), 6.79 (dd, J=8.4, 4.8Hz, 1H), 5.03 (dd, J=12.9, 5.4Hz, 1H), 3.98 (p, J=7.4Hz, 1H), 3.52 (s, 2H), 3.40 (d, J=5.4Hz, 4H), 3.23-2.99 (m, 2H), 2.94-2.75 (m, 1H ), 2.54 (s, 10H), 2.37 (t, J=6.9Hz, 1H), 2.03-1.92 (m, 1H), 1.67 (ddt, J=28.2, 13.3, 6.9Hz, 2H), 1.24-1.07 (m, 3H).

[0875] LC-MS m / z (ESI) = 708.30 [M+1]

[0876] Example 36

[0877] first step:

[0878] tert-Butyl (1-(2-oxoethyl)cyclopropyl)carbamate 36b

[0879] tert-butyl(1-(2-oxoethyl)cyclopropyl)carbamate

[0880] Under nitrogen at room temperature, compound 36a (1 g, 5 mmol), 2,2,6,6-tetramethylpiperidinyl oxide (23 mg, 0.15 mmol), and potassium bromide (59 mg, 0.5 mmol) were dissolved in dichloromethane (10 mL) and water (30 mL). A mixed solution of sodium bicarbonate (2.6 g, 31 mmol) and sodium hypochlorite (50 mL) was slowly added dropwise at -10°C to 0°C. The mixture was allowed to react for 30 minutes. After the reaction, saturated aqueous sodium sulfite solution (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure to afford crude compound 36b (white solid, 800 mg, 81% yield).

[0881] LC-MS m / z (ESI) = 200.10 [M+1]

[0882] Step 2:

[0883] tert-Butyl (1-(2-(4-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropyl)carbamate 36c

[0884] tert-butyl(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropyl)carbamate

[0885] Under nitrogen at room temperature, compound 36b (100 mg, 0.5 mmol), compound 35b (160 mg, 0.46 mmol), and sodium acetate (136 mg, 1 mmol) were dissolved in dichloromethane:methanol = 1:10 (1 mL) and stirred for 30 minutes. Sodium triacetoxyborohydride (212 mg, 1 mmol) was then added and the mixture was allowed to stand overnight at room temperature. After completion of the reaction, saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography to afford compound 36c (yellow solid, 100 mg, 41% yield).

[0886] LC-MS m / z (ESI) = 526.20 [M+1]

[0887] Step 3:

[0888] 5-(4-(2-(1-aminocyclopropyl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Compound 36d

[0889] 5-(4-(2-(1-aminocyclopropyl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0890] Referring to the synthesis method of compound 32g, compound 36d was obtained (yellow solid, 80 mg, yield: 98%).

[0891] LC-MS m / z (ESI) = 426.20 [M+1]

[0892] Step 4:

[0893] (Z)-N-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 36

[0894] (Z)-N-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropy l)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0895] Intermediate 1 (50 mg, 0.16 mmol) was prepared by referring to the synthesis method of compound 30 to obtain compound 36 (yellow solid, 20 mg, yield: 17%).

[0896] 1 H NMR (400MHz, DMSO-d6) δ11.55 (s, 1H), 11.03 (s, 1H), 10.48 (s, 1H), 7.54 (d, J=8.5Hz, 1H), 7.35 (d, J=2. 4Hz, 1H), 7.15 (dd, J=8.7, 2.3Hz, 1H), 7.07-6.98 (m, 2H), 6.80 (td, J=9.4, 9.0, 2.6Hz, 1H), 6.72 (dd, J=8 .5, 4.8Hz, 1H), 5.68 (s, 1H), 4.99 (dd, J=12.8, 5.4Hz, 1H), 3.45-3.32 (m, 6H), 3.07-2.98 (m, 2H), 2.85- 2.74 (m, 1H), 2.53-2.40 (m, 10H), 2.26 (s, 2H), 1.99-1.88 (m, 1H), 0.68-0.55 (m, 2H), 0.32-0.18 (m, 2H).

[0897] LC-MS m / z (ESI) = 720.30 [M+1]

[0898] Example 37

[0899] first step:

[0900] tert-Butyl (2-methyl-3-oxopropyl)carbamate 37b

[0901] tert-butyl(2-methyl-3-oxopropyl)carbamate

[0902] Under nitrogen at room temperature, Dess-Martin reagent (1.46 g, 3.44 mmol) was slowly added to a solution of compound 37a (500 mg, 2.65 mmol) in dichloromethane (5 mL). The reaction was allowed to proceed for 2 hours. After completion of the reaction, saturated aqueous sodium sulfite (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure to afford compound 37b (white solid, 180 mg, 36% yield).

[0903] LC-MS m / z (ESI) = 188.10 [M+1]

[0904] Step 2:

[0905] tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl)carbamate 37c

[0906] tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl)carbamate

[0907] Referring to the synthesis method of compound 36c, compound 37c was obtained (yellow solid, 180 mg, yield: 38%).

[0908] LC-MS m / z (ESI) = 514.20 [M+1]

[0909] Step 3:

[0910] 5-(4-(3-amino-2-methylpropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 37d

[0911] 5-(4-(3-amino-2-methylpropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0912] Referring to the synthesis method of compound 32g, compound 37d was obtained (yellow solid, 140 mg, yield: 96%).

[0913] LC-MS m / z (ESI) = 141.20 [M+1]

[0914] Step 4:

[0915] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 37

[0916] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl) -6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0917] Intermediate 1 (100 mg, 0.16 mmol) was prepared by referring to the synthesis method of compound 30 to obtain compound 37 (yellow solid, 30 mg, yield: 14%).

[0918] 1 H NMR (400MHz, DMSO-d6) δ11.58 (s, 1H), 11.04 (s, 1H), 10.52 (s, 1H), 7.59 (d, J=8.4Hz, 1H), 7. 32-7.07(m, 4H), 6.90-6.72(m, 2H), 5.01(dd, J=12.9, 5.4Hz, 1H), 3.55-3.34(m, 7H), 3.06(d d, J=20.6, 5.6Hz, 3H), 2.89-2.76 (m, 1H), 2.58-2.45 (m, 9H), 2.26 (dd, J=12.0, 6.8Hz, 1H), 2 .15-2.05 (m, 1H), 1.94 (dd, J=8.0, 5.2Hz, 2H), 1.18 (d, J=8.0Hz, 1H), 0.86 (d, J=6.5Hz, 3H).

[0919] LC-MS m / z (ESI) = 708.30 [M+1]

[0920] Example 38

[0921] first step:

[0922] tert-Butyl (1-formylcyclopropyl)methylcarbamate 38b

[0923] tert-butyl((1-formylcyclopropyl)methyl)carbamate

[0924] Compound 38a (500 mg, 2.48 mmol) was synthesized by referring to the method of compound 36b to obtain compound 38b (white solid, 250 mg, yield: 50%).

[0925] LC-MS m / z (ESI) = 200.10 [M+1]

[0926] Step 2:

[0927] tert-Butyl (1-((4-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)methyl)carbamate 38c

[0928] tert-butyl((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)methyl)carbamate

[0929] Compound 38b (250 mg, 1.56 mmol) was synthesized by referring to the method of compound 36c to obtain compound 38c (yellow solid, 480 mg, yield: 78%).

[0930] LC-MS m / z (ESI) = 526.20 [M+1]

[0931] Step 3:

[0932] 5-(4-((1-(aminomethyl)cyclopropyl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 38d

[0933] 5-(4-((1-(aminomethyl)cyclopropyl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0934] Compound 38c (250 mg, 0.47 mmol) was synthesized by referring to the method of compound 32g to obtain compound 38d (yellow solid, 200 mg, yield: 99%).

[0935] LC-MS m / z (ESI) = 426.20 [M+1]

[0936] Step 4:

[0937] (Z)-N-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)methyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentyl[b]pyrrole-3-carboxamide Compound 38

[0938] (Z)-N-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)m ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0939] Intermediate 1 (100 mg, 0.16 mmol) was prepared by referring to the synthesis method of compound 30 to obtain compound 38 (yellow solid, 42 mg, yield: 18%).

[0940] 1 H NMR (400MHz, DMSO-d6) δ11.55 (s, 1H), 11.03 (s, 1H), 10.48 (s, 1H), 7.54 (d, J=8.5Hz, 1 H), 7.24 (d, J=2.4Hz, 1H), 7.13 (dd, J=8.7, 2.3Hz, 1H), 7.07-6.98 (m, 2H), 6.80 (td, J= 9.4, 9.0, 2.6Hz, 1H), 6.72 (dd, J=8.5, 4.8Hz, 1H), 5.68 (s, 1H), 4.99 (dd, J=12.8, 5.4Hz, 1H), 3.45-3.32 (m, 6H), 3.07-2. 98(m, 2H), 2.85-2.74(m, 1H), 2.53-2.40(m, 10H), 2.26(s, 2H), 1.99-1.88(m, 1H), 0.54-0.44(m, 2H), 0.26-0.15(m, 2H).

[0941] LC-MS m / z (ESI) = 720.30 [M+1]

[0942] Example 39

[0943] first step:

[0944] tert-Butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate 39b

[0945] tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate

[0946] Compound 39a (2.8 g, 10 mmol) was added to N,N-dimethylformamide (30 ml), and NaH (645 mg, 27 mmol) was added under ice bath and stirred for 30 minutes. 3-bromopiperidine-2,6-dione (1.73 g, 9 mmol) was then added. The reaction flask was replaced with nitrogen and placed under ice bath to react for 2 hours. Saturated ammonium chloride (50 mL) was added to quench the reaction, and ethyl acetate (3×35 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 8:1) to obtain 39b as a yellow solid, 2.64 g.

[0947] LCMS m / s=391.34[M+1].

[0948] Step 2:

[0949] 3-((6-(Piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione 39c

[0950] 4-((6-(piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione

[0951] Compound 39b (2.35 g, 6 mol) was dissolved in dichloromethane:trifluoroacetic acid = 4:1 (25 mL). The reaction flask was purged with nitrogen and then allowed to react at 25°C. After 1.5 hours of reaction, N,N-diisopropylethylamine (20 mL) was added to adjust the pH to 8. The mixture was concentrated under reduced pressure to obtain a crude product, thereby obtaining compound 39c as a yellow solid (2.0 g).

[0952] LCMS m / s=291.34[M+1].

[0953] Step 3:

[0954] tert-Butyl (3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)carbamate 39d

[0955] tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)carbamate

[0956] Compound 39c (1.7 g, 6 mol), N-Boc-3-aminopropyl bromide (1.2 g, 5 mol), potassium iodide (830 mg, 5 mmol), and potassium carbonate (0.7 g, 5 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction flask was replaced with nitrogen and then placed at 25°C for reaction. After 3 hours of reaction, water (40 mL) was added to dilute the mixture, and ethyl acetate (3×30 mL) was added to extract the mixture. After extraction, the organic phase was washed with saturated brine (3×30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 15:1) to obtain compound 39d as a yellow solid, 130 mg.

[0957] LCMS m / s=448.34[M+1].

[0958] Step 4:

[0959] 3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione 39e

[0960] 3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione

[0961] Compound 39d (130 mg, 0.29 mmol) was dissolved in dichloromethane:trifluoroacetic acid = 4:1 (5 mL). The reaction flask was purged with nitrogen and then allowed to react at 25°C. After 1.5 hours of reaction, N,N-diisopropylethylamine (5 mL) was added to adjust the pH to about 8. The mixture was concentrated under reduced pressure to obtain a crude product, thereby obtaining 100 mg of compound 39e as a yellow solid.

[0962] LCMS m / s=348.24[M+1].

[0963] Step 5:

[0964] (Z)-N-(3-(4-(5-(((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)-2-methyl-6-(2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 39

[0965] (Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)-2-methyl-6-(2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[0966] Compound 39e (111 mg, 0.36 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (164 mg, 0.5 mmol), and N,N-diisopropylethylamine (185 mg, 1.0 mmol) were added to N,N-dimethylformamide (5 mL). The reaction flask was replaced with nitrogen and placed at 25°C for 30 minutes. After 30 minutes, intermediate 1 (100 mg, 0.29 mmol) was added to the reaction solution. The reaction flask was replaced with nitrogen and placed at 25°C for reaction. Water (20 mL) was added after 3 hours of reaction, and the filter cake was obtained by filtration. The filter cake was washed with ethanol (5 mL) to obtain compound 39 (yellow solid, 20 mg, yield 50%).

[0967] 1 H NMR (400MHz, DMSO-d6) δ12.00(m, 1H), 11.08(m, 1H), 10.00(m, 1H), 7.88-7.02(m, 4H) , 3.21-2.12 (m, 17H), 2.33 (d, J = 12.0Hz, 3H), 2.31 (d, J = 8.0Hz, 1H), 2.17 (m, 4H), 2.09 (m, 3H), 2.06 (dd, J=12.0Hz, 1H).

[0968] LCMS m / s=641.23[M+1].

[0969] Example 40

[0970] first step:

[0971] Dimethyl 4-iodo-1H-pyrazole-3,5-dicarboxylate 40b

[0972] dimethyl 4-iodo-1H-pyrazole-3,5-dicarboxylate

[0973] Compound 40a, dimethyl 1H-pyrazole-3,5-dicarboxylate (10 g, 54 mmol), was placed in acetonitrile (200 mL), and cerium ammonium nitrate (29 g, 54 mmol) and elemental iodine (13.74 g, 54 mmol) were added. The mixture was heated under reflux for 48 hours. 200 mL of saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to obtain 12 g of crude compound 40b. LC-MS m / z (ESI) = 311.2 [M+1]

[0974] Step 2:

[0975] Dimethyl 4-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3,5-dicarboxylate 40c

[0976] dimethyl 4-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3,5-dicarboxylate

[0977] Compound 40b, dimethyl 4-iodo-1H-pyrazole-3,5-dicarboxylate (12 g, 38.7 mmol), was placed in N,N-dimethylformamide (120 mL), and palladium acetate (870 mg, 3.87 mmol), diisopropylethylamine (10 g, 77.4 mmol), and ethyl 3-butenoate (4.4 g, 38.7 mmol) were added. After nitrogen was replaced, the mixture was reacted at 120°C for 12 hours. Saturated ammonium chloride (200 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (150 mL*3). The combined organic phases were concentrated under reduced pressure and separated (petroleum ether:ethyl acetate = 2:1) to give Compound 40c (8 g, 73% yield) as a yellow solid.

[0978] Step 3:

[0979] 5-Ethyl 3-methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3,5-dicarboxylic acid 40d

[0980] 5-ethyl 3-methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3,5-dicarboxylate

[0981] Compound 40c, dimethyl 4-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3,5-dicarboxylate (8 g, 28 mmol), was placed in tetrahydrofuran (80 mL). Potassium tert-butoxide (3.2 g, 28 mmol) was added at -78 °C. The reaction solution was naturally warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride (50 mL) was added to quench the reaction. Ethyl acetate (50 mL*3) was added, and the concentrated organic phases were combined to give Compound 40d (5 g) as a yellow solid.

[0982] Step 4:

[0983] 6-Oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid methyl ester 40e

[0984] methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate

[0985] 5-Ethyl 3-methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3,5-dicarboxylic acid compound 40d (5 g, 20 mmol) was placed in a 1 M / L hydrochloric acid / 1,4-dioxane solution (30 mL). Water (3 mL) was added, and the reaction solution was stirred at 90°C for three hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (230 mL). The organic phase was extracted with ethyl acetate (100 × 3). The combined organic phases were dried and concentrated to give 4 g of compound 40e.

[0986] Step 5:

[0987] (Z)-3-(3-acetyl-4,5-dihydrocyclopentadienyl[c]pyrazol-6(1H)-ylidene)-5-fluoroindolin-2-one compound 40f

[0988] (Z)-3-(3-acetyl-4,5-dihydrocyclopenta[c]pyrazol-6(1H)-ylidene)-5-fluoroindolin-2-one

[0989] Compound 40e (4 g, 22 mmol) was added and the synthesis method of compound A4 was referred to to obtain compound 40f (3 g).

[0990] Step 6

[0991] (Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid 40g

[0992] (Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid

[0993] Compound 40f (3 g, 10 mmol) was added and the synthesis method of Intermediate 1 was referred to to obtain Compound 40g (2.5 g).

[0994] Step 7:

[0995] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[c]pyrazole-3-carboxamide Compound 40

[0996] (Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide

[0997] Compound 40g (80 mg, 0.27 mmol) was prepared by referring to the synthesis method of compound 30 to obtain compound 40 (yellow solid, 23 mg, yield: 13%).

[0998] 1 H NMR (400MHz, DMSO) δ11.08 (s, 1H), 7.96 (d, J=9.3Hz, 1H), 7.67 (d, J=8.5Hz, 1H), 7.25 (dd, J=8.6, 2.2Hz, 1H), 6.69 (d, J=5.9Hz, 1H), 5.07 (dd, J= 12.9, 5.4Hz, 1H), 3.42 (s, 3H), 3.06 (dd, J=14.9, 6.5Hz, 2H), 2.89 (s, 3H), 2.73 (d, J=0.5Hz, 3H), 2.39-2.29 (m, 4H), 2.00 (dd, J=11.1, 3.7Hz, 1H), 1.37 (s, 6H).

[0999] LC-MS m / z (ESI) = 681.30 [M+1]

[1000] Example 41

[1001] (Z)-N-(3-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[c]pyrazole-3-carboxamide Compound 41

[1002] (Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-vl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide

[1003] Compound 40g (80 mg, 0.27 mmol) was synthesized by referring to the method of compound 30 to obtain compound 41 (yellow solid, 20 mg, yield: 13%).

[1004] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.2 0(m, 2H), 6.92-6.87(m, 4H), 6.83(dd, 1H), 5.04-4.98(m, 1H), 3.58(t, 2H), 3 .31(dd, 2H), 3.27(d, 2H), 3.14(dt, 2H), 3.04-3.00(m, 2H), 2.75-2.60(m, 3H ), 2.52-2.45(m, 3H), 2.33-2.31(m, 1H), 2.18-2.05(m, 4H), 1.74-1.7(m, 2H).

[1005] LC-MS m / z (ESI) = 628.30 [M+1]

[1006] Example 42

[1007] first step:

[1008] tert-Butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate 42b

[1009] tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

[1010] Compound 42a (3 g, 11 mmol) was added to N,N-dimethylformamide (30 ml), and NaH (0.36 g, 15 mmol) was added under ice bath and stirred for 30 minutes. After 30 minutes, 3-bromopiperidine-2,6-dione (1.71 g, 9 mmol) was added. The reaction flask was replaced with nitrogen and placed under ice bath for reaction. After 2 hours of reaction, saturated ammonium chloride (50 mL) was added to quench the reaction. Ethyl acetate (3×35 mL) was added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The dried organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane: methanol = 8:1) to obtain 42b (yellow solid, 2.7 g, yield 65%).

[1011] LCMS m / s=392.34[M+1].

[1012] Step 2:

[1013] 5-3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione 42c

[1014] 3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione

[1015] Compound 42b (2.7 g, 7 mol) was dissolved in dichloromethane:trifluoroacetic acid = 4:1 (25 mL). The reaction flask was purged with nitrogen and then allowed to react at 25°C. After 1.5 hours of reaction, N,N-diisopropylethylamine (20 mL) was added to adjust the pH to about 8. The reaction was concentrated under reduced pressure to obtain a crude product to obtain compound 42c as a yellow solid (1.6 g).

[1016] LCMS m / s=292.52[M+1].

[1017] Step 3:

[1018] tert-Butyl (3-(4-(5-((2,6-dioxopyrimidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate 42d

[1019] tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate

[1020] Compound 42c (1.6 g, 6 mmol), N-Boc-3-aminopropyl bromide (1.2 g, 5 mmol), potassium iodide (830 mg, 5 mmol), and potassium carbonate (0.83 g, 6 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction flask was replaced with nitrogen and then placed at 25°C for reaction. After reacting for 3 hours, water (40 mL) was added to dilute the mixture, and ethyl acetate (3×30 mL) was added to extract the mixture. After extraction, the organic phase was washed with saturated brine (3×30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 15:1) to obtain compound 42d as a yellow solid, 270 mg.

[1021] LCMS m / s=449.42[M+1].

[1022] Step 4:

[1023] 4-((2-(4-(3-aminopropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione 42e

[1024] 3-((2-(4-(3-aminopropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione

[1025] Compound 42d (270 mg 0.6 mmol) was dissolved in dichloromethane: trifluoroacetic acid = 4:1 (5 mL). The reaction flask was purged with nitrogen and then allowed to react at 25°C. After 1.5 hours of reaction, N,N-diisopropylethylamine (5 mL) was added to adjust the pH to about 8. The crude product was concentrated under reduced pressure to obtain compound 42e (yellow solid, 200 mg

[1026] LCMS m / s=349.38[M+1].

[1027] Step 5:

[1028] (Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 42

[1029] (Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[1030] Compound 42e (187 mg, 0.6 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (226 mg, 0.6 mmol), and N,N-diisopropylethylamine (78 mg, 0.6 mmol) were added to N,N-dimethylformamide (5 mL). The reaction flask was replaced with nitrogen and then placed at 25°C to react for 30 minutes. After 30 minutes, intermediate 1 (200 mg, 0.6 mmol) was added to the reaction solution. The reaction flask was replaced with nitrogen and then placed at 25°C to react. Water (20 mL) was added after the reaction for 3 hours, and the mixture was filtered to obtain a filter cake. The filter cake was washed with ethanol (5 mL) to obtain compound 42 (yellow solid, 192 mg, yield 50%).

[1031] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.20 (m , 2H), 6.92-6.87(m, 2H), 6.83(dd, 1H), 5.01-4.98(m, 1H), 3.58(t, 2H), 3.31(dd , 2H), 3.25(d, 2H), 3.14(dt, 2H), 3.04-3.00(m, 2H), 2.75-2.60(m, 3H), 2.55(s, 3H), 2.52-2.45(m, 3H), 2.34-2.31(m, 1H), 2.15-2.03(m, 4H), 1.74-1.71(m, 2H).

[1032] LCMS m / s=643.23[M+1].

[1033] Example 43

[1034] first step:

[1035] tert-Butyl (3-(4-(4-(((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate 43b

[1036] (4-tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate

[1037] Compound 43a (700 mg) was prepared according to the synthetic method of compound 42d to obtain compound 43b (brown solid, 609 mg, yield 47%).

[1038] LCMS m / s=465.42[M+1].

[1039] Step 2:

[1040] 4-(4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione 43c

[1041] 5-3-(4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione

[1042] According to the synthesis method of compound 42e, compound 43c was obtained as a white solid, 400 mg.

[1043] LCMS m / s=365.42[M+1].

[1044] Step 3:

[1045] (Z)-N-(3-(4-(4-(((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentyl[b]pyrrole-3-carboxamide Compound 43

[1046] (Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[1047] According to the synthesis method of compound 39, compound 43 (yellow solid, 100 mg, yield 23%) was obtained.

[1048] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.20 (m , 2H), 6.92-6.87(m, 3H), 6.83(dd, 1H), 5.01-4.98(m, 1H), 3.58(t, 2H), 3.31(dd , 2H), 3.27(d, 2H), 3.14(dt, 2H), 3.04-3.00(m, 2H), 2.75-2.60(m, 3H), 2.55(s, 3H), 2.52-2.45(m, 3H), 2.34-2.31(m, 1H), 2.18-2.05(m, 4H), 1.74-1.72(m, 2H).

[1049] LCMS m / s=659.47[M+1].

[1050] Example 45

[1051] first step:

[1052] tert-Butyl (3-(4-(5-nitropyridin-2-yl)piperazin-1-yl)propyl)carbamate 45b

[1053] tert-butyl(3-(4-(5-nitropyridin-2-yl)piperazin-1-yl)propyl)carbamate

[1054] Compound 45a (300 mg) was prepared according to the synthetic method of compound 44b to obtain compound 45b (yellow solid, 350 mg, yield 73%).

[1055] LCMS m / s=366.40[M+1].

[1056] Step 2:

[1057] tert-Butyl (3-(4-(5-aminopyridin-2-yl)piperazin-1-yl)propyl)carbamate 45c

[1058] tert-butyl(3-(4-(5-aminopyridin-2-yl)piperazin-1-yl)propyl)carbamate

[1059] According to the synthesis method of compound 33c, compound 45c (yellow solid, 260 mg) was obtained.

[1060] LCMS m / s=336.20[M+1].

[1061] Step 3:

[1062] tert-Butyl (3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)carbamate 45d

[1063] tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)carbamate

[1064] According to the synthesis method of compound 33d, compound 45d (brown solid, 407 mg) was obtained.

[1065] LCMS m / s=447.32[M+1].

[1066] Step 4:

[1067] 3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione 45e

[1068] 3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione

[1069] According to the synthesis method of compound 33e, compound 45e was obtained as a yellow solid, 315 mg.

[1070] LCMS m / s=347.39[M+1].

[1071] Step 5:

[1072] (Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 45

[1073] (Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide

[1074] According to the synthesis method of compound 33, compound 45 (yellow solid, 76 mg, yield 13%) was obtained.

[1075] 1 H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 10.90 (s, 1H), 10.60 (s, 1H), 7.27-7.20 (m , 2H), 6.92-6.87(m, 4H), 6.83(dd, 1H), 5.01-4.98(m, 1H), 3.58(t, 2H), 3.31(dd , 2H), 3.27(d, 2H), 3.14(dt, 2H), 3.04-3.00(m, 2H), 2.75-2.60(m, 3H), 2.55(s, 3H), 2.52-2.45(m, 3H), 2.34-2.31(m, 1H), 2.18-2.05(m, 4H), 1.74-1.72(m, 2H).

[1076] LCMS m / s=641.56[M+1].

[1077] Biological test cases

[1078] 1. Jurkat Cell Culture

[1079] Human acute T lymphoblastic leukemia Jurkat cells (Beina Biotechnology, BNCC338495) were cultured in RPMI-1640 medium containing 10% FBS and 1% double antibody at 37° C. and 5% CO 2 .

[1080] 2. HPK1, GLK, and HGK protein degradation test

[1081] On the first day, Jurkat cells in the exponential growth phase were collected and seeded in 6-well plates at a seeding density of 4 × 10 5Cells were plated in a 37°C, 5% CO2 incubator. The next day, test compounds were added to the wells at final concentrations of 50 and 500 nM and incubated in the incubator for another 48 hours. Following incubation, cells were harvested and 40 μL of cell lysis buffer was added to each tube. The cells were lysed on ice for 30 minutes, centrifuged at 13,000 rpm for 15 minutes at 4°C, and the supernatant was collected and stored at low temperatures. Protein was quantified using a BCA kit and protein samples were prepared. Protein samples were denatured in a 95°C metal bath for 10 minutes. Protein detection was performed according to the western blot protocol, with the HPK1 antibody (CST, 4472s), GLK antibody (CST, 92427S), HGK antibody (CST, 3485S), and β-Actin antibody (CST, 4970S) all diluted 1:1000. The results are shown in Table 1.

[1082] Table 1 Results of degradation of HPK1, GLK and HGK proteins by the compounds of the present invention

[1083] Conclusion: The compounds of the present invention have significant degradation activity on HPK1 protein, but relatively low degradation activity on GLK and HGK proteins.

[1084] 3. HPK1 Kinase Assay

[1085] HPK1 kinase activity of the compounds was assayed using the ADP-Glo ​​Kinase Assay (Promega, V9102). Test compounds were prepared in DMSO to final concentrations of 10,000, 2,500, 625, 156.3, 39.1, 9.8, 2.4, 0.6, 0.15, and 0.04 nM. A positive control (10,000 nM Sunitinib) and a negative control (0.5% DMSO) were also set up. Using an Echo assay, 20 nL of compound was added to a 384-well plate according to the plate layout, with two replicates per well for each concentration. 2 μL of 2× HPK1 kinase & metal solution (Thermo Fisher, 2230140) was added to each well and incubated at 25°C for 10 minutes. After 10 minutes, 2 μL of 2× substrate & ATP solution was added to each well and incubated at 25°C for 60 minutes. After 60 minutes, 4 μL of ADP-Glo ​​Reagent (ADP-Glo ​​Kinase Assay, Promega, V9102) was added to each well and incubated at 25°C for 40 minutes. After 40 minutes, 8 μL of Kinase Detection Reagent was added to each well and incubated at 25°C for 30 minutes. Chemiluminescence values ​​were read using a plate reader (BMG, PHERAstar FSX). The inhibition rate was calculated according to the formula: 100-(compound reading - positive control reading) / (negative control reading - positive control reading)*100%. The inhibition rate value was substituted into GraphPad 8.0 to calculate the fitted IC 50 , the results are shown in Table 2.

[1086] Table 2 Test results of the HPK1 kinase activity of the compounds of the present invention

[1087] Conclusion: The compounds of the present invention have a significant degradation effect on HPK1 protein.

[1088] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound of formula (I), or any stereoisomer, solvate, prodrug, metabolite, deuterated form, pharmaceutically acceptable salt, or cocrystal thereof: PTM-L-ULM (I); in, The L is Said R2 does not exist; or said R2 is selected from The A ring and the B ring are each independently selected from a 3-12 membered carbocyclylene group and a 3-12 membered heterocyclylene group; The PTM is: The ULM is: The R1, R3, R9, R 11 are independently selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -NHR 1b -, -C(=O)NH-, -NHC(=O)-, -C(=O)NHR 1b -、-NHC(=O)R 1b -、 -OC(=O)R 1b -、-C(=O)OR 1b -、-C(=O)R 1b -、-SO2R 1b -、-OR 1b -、-O- or -S-; The R 1b Selected from C 1-6 Alkylene, C 1-6 a haloalkylene or imino group; X1, X2, X3, X6, X7, X8, X9, X 10 are independently selected from C, N, O, S, -C(O)NH-; Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl; Said R4, R6, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl, C 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-8-membered aryl or 5-8-membered heteroaryl; The a, b, c, h, and k are independently selected from 0, 1, 2, 3, 4, 5, or 6.

2. The compound according to claim 1, or any stereoisomers, solvates, prodrugs, metabolites, deuterated forms, pharmaceutically acceptable salts or cocrystals thereof, wherein the compound is selected from the group consisting of compounds represented by the general formula (II): PTM-R1-R2-ULM (II); in, The R1 is selected from carbonyl, C 1-6 Alkylene, imino, -NHR 1b -, -C(=O)NH-, -NHC(=O)-, -C(=O)NHR 1b -or-NHC(=O)R 1b -; The R 1b Selected from C 1-6 Alkylene or C 1-6 halogenated alkylene; Said R2 does not exist; or said R2 is selected from The A ring and the B ring are each independently selected from a 3-8 membered monocyclic carbocyclylene, a 6-12 membered bicyclic carbocyclylene, a 3-8 membered monocyclic heterocyclylene, a 6-12 membered bicyclic heterocyclylene; the 6-12 membered bicyclic carbocyclylene and the 6-12 membered bicyclic heterocyclylene are selected from a fused bicyclic, a bridged bicyclic or a spiro-connected bicyclic; The e is selected from 0, 1, 2, 3, 4, 5 or 6; The definitions of PTM and ULM are the same as those in claim 1.

3. The compound according to claim 2, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: The R1 is selected from carbonyl, C 1-6 Alkylene, imino, -NHR 1b -, -C(=O)NH-, or -C(=O)NHR 1b -; The R 1b Selected from C 1-6 Straight chain alkylene or C 1-6 branched chain alkylene; Said R2 does not exist; or said R2 is selected from The A ring and the B ring are each independently selected from 3-8 membered monocyclic cycloalkylene, 6-12 membered bicyclic cycloalkylene, 3-8 membered monocyclic heterocycloalkylene, 6-12 membered bicyclic heterocycloalkylene; the 6-12 membered bicyclic cycloalkylene and 6-12 membered bicyclic heterocycloalkylene are selected from fused bicyclic, bridged bicyclic or spiro bicyclic; The e is selected from 0, 1, 2, 3, 4, 5 or 6.

4. The compound according to any one of claims 1 to 3, or any stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, wherein: The PTM is The definitions of X1, R5, a, R6, and h are the same as those in claim 1.

5. The compound according to claim 4, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: The PTM is Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl; Said R6 is selected from halogen, C 1-6 Alkyl, C 1-6 alkyl halide; The a's are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

6. The compound according to any one of claims 1 to 3, or any stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, wherein: The ULM is The R3 is selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -O-, or -S-; Said X2, X6, X7, X8 are each independently selected from C, N, O; The X3 is selected from -C(=O)-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 1-6 Haloalkylene-, -NH-, -O-, -S-, or -C(O)NH-; Said R4, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl; The b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

7. The compound according to claim 6, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: The ULM is The R3 is selected from -C(=O)-, -C 1-3 Alkylene-, -C 1-3 Haloalkylene-, -NH-, -O-, or -S-; Said X2, X6, X7, X8 are each independently selected from C, N, O; The X3 is selected from -C 1-3 Alkylene-, -NH-, -O-, -S- or -C(O)NH-; Said R4, R7, R8 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl; The b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

8. The compound according to claim 1, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: in, The PTM is The L is The ULM is Said X1, X2, X3 are each independently selected from C, N or O; The R1 is independently selected from carbonyl, methylene, imino, -NHR 1b -、-C(=O)NHR 1b -or-NHC(=O)R 1b -; The R 1b Independently selected from C 1-6 Alkylene or C 1-6 halogenated alkylene; The R2 is selected from The A ring and the B ring are each independently selected from a 3-10 membered carbocyclic group and a 3-10 membered heterocyclic group; Said R3 is selected from carbonyl, methylene or imino; Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl; Said R4, R6, R7 are independently selected from halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group, a cyano group, or a hydroxy group; Said a, b, c, d, e are each independently selected from 0, 1, 2, 3, 4, 5 or 6; The h is selected from 0 or 1.

9. The compound according to any one of claims 1 to 3, or any stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals thereof, wherein: The PTM is Said R5 is selected from hydrogen, F, Br, cyano, trifluoromethyl; Said R6 is selected from halogen, C 1-3 Alkyl, C 1-3 alkyl halide; Said a is selected from 0, 1, 2, 3 or 4; The ULM is Said R3 is selected from carbonyl or methylene; Said R4 and R7 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl; Said b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6; The L is The R1 is selected from -C(=O)NH- or -C(=O)NH-C 1-6 Alkylene-; Said R2 does not exist; or said R2 is selected from The A ring and the B ring are each independently selected from X4, X5, X 11 are each independently selected from C, N or O; The e, f, g, i, and j are each independently selected from 0, 1, 2, 3, or 4.

10. The compound according to any one of claims 1 to 9, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: The R2 is selected from 11. A compound represented by formula (I'), or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in, W is selected from R1 is selected from carbonyl, methylene or amino; R2 is selected from Wherein, n is an integer from 1 to 4; R3 is selected from methylene or carbonyl; R 10 is selected from H or halogen.

12. The compound according to any one of claims 1 to 11, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising: (1) The compound according to any one of claims 1 to 12, or its stereoisomers, solvates, prodrugs, metabolites, deuterated form, pharmaceutically acceptable salt or cocrystal; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

14. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 13 in the preparation of an anti-tumor drug.