WO2024188282A1

WO2024188282A1 - Indolone derivative and use thereof in medicine

Info

Publication number: WO2024188282A1
Application number: PCT/CN2024/081511
Authority: WO
Inventors: 张靖; 魏用刚; 楚洪柱; 孙毅
Original assignee: 康百达（四川）生物医药科技有限公司
Priority date: 2023-03-14
Filing date: 2024-03-13
Publication date: 2024-09-19

Abstract

The present invention relates to an indolone derivative represented by general formula (I) or all stereoisomers thereof, a pharmaceutical composition comprising same, and a use thereof in preparation of an anti-tumor drug.

Description

Indolinone derivatives and their medical applications

Technical Field

The present invention relates to an indolinone derivative or a stereoisomer thereof and application thereof in medicine.

Background Art

HPK1 (hematopoietic progenitor kinase 1), also known as MAP4K1, belongs to the MAP4K family and is a serine/threonine kinase that is mainly expressed in hematopoietic cells. HPK1 negatively regulates the immune response of T cells and B cells through the AP-1, NF-κB, Erk2, and Fos pathways. For example, in T cells, HPK1 can phosphorylate the T cell receptor adaptor protein SLP-76. The activation of SLP-76 leads to the downregulation of the AP-1 and Erk2 signaling pathways, thereby reducing T cell proliferation. In addition, in B cells, HPK1 downregulates the transduction of B cell receptor (BCR) signals by phosphorylating the paralog of SLP-76, BLINK.

Therefore, HPK1 is a potential therapeutic target. Studies have found that inhibiting the activity of HPK1 can enhance the activity of T cells and B cells, thereby improving anti-tumor immunity. For example, the loss of HPK1 can increase the production of Th1 cytokines in T cells; T cells with HPK1 loss proliferate faster and have a stronger inhibitory effect on tumor growth. In addition, researchers have found that simultaneously inhibiting the activity of HPK1 and PD-L1 can significantly enhance the anti-tumor effect of T cells. Therefore, HPK1 inhibitors are expected to become innovative treatments for cancer, or be used in combination with existing cancer immunotherapies to improve the effectiveness of cancer treatment.

So far, the main challenge faced by the development of HPK1 inhibitor drugs is that the selectivity is not high enough. Small molecule inhibitors of HPK1 will also inhibit other T cell kinases or other members of the MAP4K family, including MAP3K2, MAP4K3, MAP4K4, MAP4K5 and MAP4K6. Among them, MAP4K3 is also called GLK kinase, and its biological effect is exactly the opposite of HPK1. GLK can promote the activation of the TCR pathway by binding to downstream adaptor proteins. Therefore, researchers are in urgent need of screening for more selective HPK1 inhibitors to better meet clinical needs.

Summary of the invention

The purpose of the present invention is to provide novel indole one derivatives or all stereoisomers thereof, pharmaceutical compositions thereof and uses thereof in the preparation of antitumor drugs.

One or more embodiments of the present invention provide a compound represented by general formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:

in:

R ₁ , R ₂ , and R ₃ are each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, _5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl, -(CO)N(R ₄ ) ₂ , -NH(CO)R ₄ ; the 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl optionally contain 1 to 3 heteroaryls selected from N, O or S. atom; the C _1-6 alkyl, C _2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl is optionally further substituted by one or more substituents selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkylene-OH, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

Or, any two R ₂ and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

R ₄ is each independently selected from H, halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy is optionally further substituted with a substituent selected from NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

a, b, d are selected from 0, 1, 2, 3 or 4; c is selected from 0, 1 or 2.

One or more embodiments of the present invention provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compound represented by the general formula (II):

in:

R _2A , R _2B are each independently selected from H, halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl, -(CO)N(R ₄ ) ₂ , -NH(CO)R ₄ ; the 5-12 membered heteroaryl, 5-12 membered heterocycloalkyl optionally contain 1 to 3 heteroatoms selected from N, O or S; the C _1-6 alkyl, C _2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl optionally further substituted by one or more selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C 2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl is substituted by _{a C 1-6} alkoxy group, a C _1-6 haloalkyl group or a C _1-6 haloalkoxy group;

Or, R _2A , R _2B and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

R ₁ , R ₃ , a and c have the same definitions as those in the general formula (I).

One or more embodiments of the present invention provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compound represented by the general formula (III):

in:

R _3A is selected from -(CO)N(R ₄ ) ₂ , -NH(CO)R ₄ ; R ₄ are _each independently selected from H, halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _{1-6 haloalkoxy; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6} _haloalkoxy _is _optionally _further _substituted with a substituent selected from NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

R _3B is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6} _alkoxy _, _C _1-6 _haloalkyl _, _C _1-6 haloalkoxy is optionally further substituted with one or more substituents selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

R ₁ , a, and are defined as in the general formula (I).

One or more embodiments of the present invention provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

R ₁ is independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl is optionally further substituted by a substituent selected from C _1-4 alkyl, -C _1-6 alkylene-OH;

R _2A and R _2B are each independently selected from H, C _1-4 alkyl, 5-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by a substituent selected from C _1-3 alkyl and halogen;

Or, R _2A , R _2B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R _3A is selected from -(CO)N(R ₄ ) ₂ , -NH(CO)R ₄ ; R ₄ are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl; the C _1-6 alkyl, C _1-6 haloalkyl are optionally further substituted by a substituent selected from NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ;

R _3B is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl;

a is selected from 0, 1, 2, 3 or 4.

R _2A and R _2B are each independently selected from H, C _1-4 alkyl, 6-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by one or more substituents selected from C _1-4 alkyl and halogen;

R ₁ is independently selected from halogen, 6-10 membered heterocycloalkyl; the 6-10 membered heterocycloalkyl optionally contains 1 to 3 selected from N, O or S heteroatom; the 6-10 membered heterocycloalkyl is optionally further substituted by one or more substituents selected from C _1-4 alkyl, -C _1-6 alkylene-OH;

R _3A is selected from -(CO)N(R ₄ ); R ₄ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl; the C _1-6 alkyl, C _1-6 haloalkyl is optionally further substituted by a substituent selected from -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ;

R _3B is selected from C _1-6 alkyl, C _1-6 haloalkyl;

a is selected from 0, 1, 2, 3 or 4.

R _2A , R _2B are selected from H;

R ₁ is each independently selected from 6-10 membered heterocycloalkyl; the 6-10 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 6-10 membered heterocycloalkyl is optionally further substituted by one or more substituents selected from C _1-4 alkyl, -C _1-6 alkylene-OH;

R _3B is selected from C _1-6 alkyl, C _1-6 haloalkyl;

a is selected from 0, 1, 2, 3 or 4.

Preferably, R ₁ is independently selected from Said Optionally further substituted by one or more substituents selected from C _1-4 alkyl, -C _1-6 alkylene-OH.

One or more embodiments of the present invention provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

One or more embodiments of the present invention provide a compound represented by formula (IV) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compound represented by general formula (IV):
PTM—L—ULM (IV);

Wherein, the PTM is

R ₅ , R ₆ , and R ₇ are each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 5-12 _- membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, and 5-12-membered heterocycloalkyl; the 5-12-membered heteroaryl and 5-12-membered heterocycloalkyl optionally contain 1 to 3 heteroatoms selected from N, O or S; the C _1-6 alkyl, C _2-6 alkenyl, 5-12-membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, and 5-12-membered heterocycloalkyl optionally further substituted by one or more selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkylene-OH, C _1-6 alkoxy, C substituted by a _{C 1-6} haloalkyl or C _1-6 haloalkoxy substituent;

Or, any two R ₆ and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

m, n, r are each independently selected from 0, 1, 2, 3 or 4;

The ULM is selected from

The A ring is selected from 3-12-membered carbocyclylene and 3-12-membered heterocyclylene; the 3-12-membered carbocyclylene and 3-12-membered heterocyclylene are optionally further substituted by one or more substituents selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkylene-OH, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

The B rings are each independently selected from 3-12 membered carbocyclic groups and 3-12 membered heterocyclic groups; the 3-12 membered carbocyclic groups and 3-12 membered heterocyclic groups are optionally further substituted by one or more substituents selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkylene-OH, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;

The X ₁ is selected from -C(=O)-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)-, -C(=O)O-, -SO ₂ -, -O- or -S-;

The L is

The R ₈ is selected from -C _1-6 alkylene-, -C _2-6 alkenylene-, -C _2-6 alkynylene-, -C _1-6 haloalkylene-, -NHR _1b -, -C(═O)NHR _1b -, -NHC(═O)R _1b -, -OC(═O)R 1b -, -C(═O)OR _1b -, -C(═O)R _1b -, -SO ₂ R _1b _- or -OR _1b -;

The R _1b is selected from -C _1-6 alkylene-, -C _2-6 alkenylene-, -C _2-6 alkynylene-, -C _1-6 haloalkylene- or imino; the C ring is selected from 3-12 membered carbocyclylene and 3-12 membered heterocyclylene; the 3-12 membered carbocyclylene and 3-12 membered heterocyclylene are optionally further substituted by one or more substituents selected from NH ₂ , carbonyl, halogen, C _1-6 alkyl, C _1-6 alkylene-OH, C _{1-6 alkoxy, C 1-6 haloalkyl or C 1-6} _haloalkoxy _.

The PTM is

R _6A and R _6B are each independently selected from H, C _1-4 alkyl, 5-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by a substituent selected from C _1-3 alkyl and halogen;

R ₅ is each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl is optionally further substituted by a substituent selected from C _1-4 alkyl, -C _1-6 alkylene-OH;

_R7 is selected from _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-6 haloalkyl;

m is selected from 0, 1, 2, 3 or 4;

The ULM is selected from

R ₉ is each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 alkoxy, C 1-6} _haloalkyl , C _1-6 haloalkoxy;

p is selected from 0, 1, 2, 3 or 4;

The L is

The R ₈ is selected from -NHR _1b -, -C(=O)NHR _1b -, -NHC(=O)R _1b -, -OC(=O)R _1b -, -C(=O)OR _1b -, -C(=O)R _1b -, -SO ₂ R _1b - or -OR _1b -;

The R _1b is selected from -C _1-6 alkylene-, -C _2-6 alkenylene-, -C _2-6 alkynylene- or -C _1-6 haloalkylene;

The C ring is selected from 6-8 membered heterocycloalkylene; the 6-8 membered heterocycloalkylene optionally contains 1 to 3 heteroatoms selected from N, O or S.

The PTM is

R _6A and R _6B are each independently selected from H, C _1-4 alkyl, and 3-6 membered cycloalkyl;

Or, R _6A , R _6B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R ₅ is each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy or 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl optionally is further substituted by one or more substituents selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy;

_R7 is selected from _C1-4 alkyl;

m is selected from 0, 1, 2, 3 or 4;

The ULM is selected from

R ₉ are each independently selected from halogen, cyano, NH ₂ , C _1-6 alkyl;

p is selected from 0, 1, 2, 3 or 4;

The _X1 is selected from -C(=O)-, -NH-, -C(=O)NH-, -NHC(=O)-, -O- or -S-;

The L is

The R ₈ is selected from -C(=O)NHR _1b -, -NHC(=O)R _1b -, -OC(=O)R _1b - or -C(=O)OR _1b -;

The C ring is selected from 6-8 membered heterocycloalkylene, and the C ring optionally contains 1 to 3 heteroatoms selected from N.

R _6A and R _6B are each independently selected from H;

R ₅ is each independently selected from 6-8 membered heterocycloalkyl; the 6-8 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 6-8 membered heterocycloalkyl is optionally further substituted by one or more substituents selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, -C _1-6 alkylene-OH;

_R7 is selected from _C1-4 alkyl;

m is selected from 0, 1, 2, 3 or 4.

Preferably, R ₅ is each independently selected from a 6-membered heterocycloalkyl group; the 6-membered heterocycloalkyl group optionally contains 1 to 3 heteroatoms selected from N, O or S; the 6-membered heterocycloalkyl group is optionally further substituted by one or more substituents selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy.

Preferably, _R5 is selected from Said Optionally further substituted by one or more substituents selected from C _1-4 alkyl, -C _1-6 alkylene-OH.

One or more embodiments of the present invention provide a pharmaceutical composition, comprising:

(1) the above compounds or their stereoisomers or pharmaceutically acceptable salts;

(2) Pharmaceutically acceptable carriers and/or excipients.

Use of the pharmaceutical composition or compound or its stereoisomers or pharmaceutically acceptable salts provided by one or more embodiments of the present invention in the preparation of anti-tumor drugs

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" refers to a straight 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 further preferably an alkyl group of 1, 2, 3 or 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 chain isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

"Aryl" refers to a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, which may be a bridged ring or a spirocyclic ring, and non-limiting examples include phenyl and naphthyl.

"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated heteroaromatic ring or a non-heteroaromatic ring. When selected from heteroaromatic rings, "heteroaromatic ring" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system. and contains 1 to 6 heteroatoms selected from N, O or S; when selected from non-heteroaromatic rings, it can be a 3-10-membered monocyclic ring, a 4-12-membered bicyclic ring or a 10-15-membered tricyclic ring system, and contains 1 to 4 heteroatoms selected from N, O or S. The selectively substituted N and S in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. The "heterocyclyl" or "heterocycle" can be optionally further substituted by 0 or more substituents.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, 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, 2 or 3 heteroatoms selected from N, O or S, preferably a 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" may be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom; "heterocycloalkyl" may be a bridged ring or a spiro ring. Non-limiting examples of “heterocycloalkyl” include oxirane, aziridine, 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.

"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, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to a mixture of one or more compounds described herein, 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.

"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.

"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.

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

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

DETAILED DESCRIPTION

The following embodiments 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.

The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are expressed as The unit of 10-6 (ppm) is given. NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard;

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

Example 1

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2,4-dimethyl-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxamide compound 1

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2,4-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole -3-carboxamide

first step

2-Methyl-1-tolyl-1H-pyrrole-3-carboxylic acid ethyl ester 1b

ethyl 2-methyl-1-tosyl-1H-pyrrole-3-carboxylate

Sodium hydroxide (13 g, 326.8 mmol) was dissolved in water (50 mL), and added to ethyl 2-methylpyrrole-3-carboxylate (5 g, 32.68 mmol) and p-toluenesulfonyl chloride (6.85 g, 35.95 mmol) dissolved in toluene (50 mL) in batches at room temperature, and reacted at room temperature for 10 minutes. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to quench, and the mixture was extracted with ethyl acetate (50 mL*3), dried, and all organic phases were combined, concentrated under reduced pressure, and then column chromatography was performed to obtain compound 1b (9.5 g, white solid, 95%).

¹ H NMR (400MHz, DMSO-d6) δ7.89–7.75(m,2H),7.53–7.45(m,2H),7.42(d,1H),6.57(d,1H),4.16(d,2H) ,2.56(s,3H),2.39(s,3H),1.22(t,3H).

LC-MS m/z(ESI)＝308.10[M+1]

Step 2

2,4-Dimethyl-6-oxo-1-tolyl-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxylic acid ethyl ester 1c

ethyl 2,4-dimethyl-6-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate

Compound 1b (9.5 g, 30.94 mmol), crotonic acid (5.32 g, 61.89 mmol), and anhydrous aluminum chloride (2.06 g, 15.47 mmol) were dissolved in chloroform (100 mL), and trifluoroacetic anhydride (26 g, 123.7 mmol) was added under nitrogen protection and refluxed for 4 hours. After the reaction, sodium bicarbonate aqueous solution (100 mL) was added to quench, and the mixture was extracted with dichloromethane (50 mL*3), dried, and the organic phases were combined for column chromatography to obtain compound 1c (6 g, white solid, 52%).

LC-MS m/z(ESI)＝376.10[M+1]

Step 3

2,4-Dimethyl-6-oxo-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxylic acid ethyl ester 1d

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

Compound 1c (6 g, 16 mmol) was dissolved in methanol (60 mL), and cesium carbonate (15.64 g, 48 mmol) was added at room temperature to react overnight. After the reaction, the mixture was concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL*3), dried, concentrated under reduced pressure, and subjected to column chromatography to obtain compound 1d (3.5 g, white solid, 98%).

¹ H NMR(400MHz,DMSO-d6)δ12.21(s,1H),4.31–4.08(m,2H),3.27(td,1H),2.98(dd,1H),2.46(s,3H),2.24 (dd,1H),1.34–1.22(m,6H).

LC-MS m/z(ESI)＝222.10[M+1]

Step 4

(Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2,4-dimethyl-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxylic acid ethyl ester 1e

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

Compound 1d (3.5 g, 15.8 mmol) and 5-fluoroindole oxide (4.77 g, 31.6 mmol) were dissolved in piperidine (35 mL) and reacted at 110°C for 16 hours. After the reaction was completed and returned to room temperature, water (70 mL) was added and stirred for 30 minutes, filtered, and the filter cake was slurried with ethanol (20 mL) and filtered to obtain crude compound 1e (3 g, yellow-brown solid, 54%).

¹ H NMR (400MHz, DMSO-d6) δ11.74(s,1H),10.63(s,1H),7.22(dd,1H),6.92(dd,1H),6.83(dd,1H),4.32–4.12 (m,2H),3.80(dd,1H),3.44(t,1H),3.08(d,1H),2.61(s,3H),1.35(d,3H),1.30(t,3H).

LC-MS m/z(ESI)＝355.10[M+1]

Step 5

(Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2,4-dimethyl-1,4,5,6-tetrahydrocyclopentane[b]pyrrole-3-carboxylic acid 1f

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

Compound 1e (3 g, 8.45 mmol) was dissolved in dioxane (20 mL), water (10 mL), dimethyl sulfoxide (1 To a mixed solution of 1 mL of 4-nitropropene (2-nitropropene) and 1 mL of methanol (1 mL), lithium hydroxide (0.6 g, 25.35 mmol) was added at room temperature, and the mixture was reacted at 100 ° C for 8 hours. After the reaction was completed, the pH was adjusted to 2-3 with 1N dilute hydrochloric acid after returning to room temperature. The mixture was stirred for 30 minutes and then filtered. After drying, compound 1f (2 g, yellow solid, 73%) was obtained.

LC-MS m/z(ESI)＝327.10[M+1]

Step 6

Compound 1f (100 mg, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (140 mg, 0.36 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 30 minutes, and then N,N-diethylethylenediamine (42 mg, 0.36 mmol) was added, and the mixture was allowed to stand overnight at room temperature. After the reaction, water (10 mL) was added and stirred for 30 minutes, filtered, and the filter cake was slurried with ethanol (2 mL), filtered, and the filter cake was compressed to prepare compound 1 (20 mg, yellow solid, 15%).

1H NMR(400MHz,DMSO)δ11.65(s,1H),10.59(s,1H),7.22(dd,1H),6.99(t,1H),6.94-6.88(m,1H),6.82(dd, 1H),3.59(d,2H),3.27(dd,2H),3.10(m,1H),2.59(s,3H),2.56-2.51(m,6H),1.29-1.27(d,3H),0.98 (t,,6H).

LC-MS m/z(ESI)＝425.20[M+1]

Example 2

(Z)-4-cyclopropyl-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide compound 2

(Z)-4-cyclopropyl-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b ]pyrrole-3-carboxamide

first step:

4-Cyclopropyl-2-methyl-6-oxo-1-toluenesulfonyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 2b

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

According to the method for compound 1c, 1b (12.5 g, 40.72 mmol) and 2a (9.12 g, 81.42 mmol) gave compound 2b (brown oil, 3.5 g).

LCMS m/s＝402.23[M+1].

Step 2:

4-Cyclopropyl-2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 2c

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

According to the method of compound 1d, 4b (3.5 g, 8.73 mmol) gave compound 2c (yellow oil, 860 mg).

LCMS m/s＝248.36[M+1].

Step 3:

(Z)-4-Cyclopropyl-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 2d

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

According to the method of compound 1e, 2c (860 mg, 3.48 mmol) gave compound 2d (yellow oil, 700 mg).

LCMS m/s＝381.72[M+1].

Step 4:

(Z)-4-Cyclopropyl-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid 2e

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

According to the method of compound 1f, 2d (730 mg, 1.92 mmol) gave compound 2e (yellow oil, 520 mg).

LCMS m/s＝353.72[M+1].

Step 5:

According to the method of compound 1, 2e (100 mg, 0.28 mmol) gave compound 2 (yellow solid, 80 mg, yield 38.8%).

LCMS m/s＝451.30[M+1].

Example 3

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2,4,4-trimethyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide Compound 3

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2,4,4-trimethyl-1,4,5,6-tetrahydrocyclopenta[b ]pyrrole-3-carboxamide

first step:

2,4,4-Trimethyl-6-oxo-1-toluenesulfonyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 3b

ethyl 2,4,4-trimethyl-6-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate

According to the method of compound 1c, 1b (7.89 g, 25.69 mmol) and 3a (5.86 g, 51.38 mmol) gave compound 3b (yellow solid, 4.0 g).

LCMS m/s＝390.38[M+1].

Step 2:

2,4,4-Trimethyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 3c

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

According to the method for compound 1d, compound 3c (brown solid, 470 mg) was obtained.

LCMS m/s＝236.57[M+1].

Step 3:

(Z)-6-(5-Fluoro-2-oxoindole-3-ylidene)-2,4,4-trimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 3d

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

According to the method for compound 1e, compound 3d (brown oil, 200 mg) was obtained.

LCMS m/s＝369.26[M+1].

Step 4:

(Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2,4,4-trimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid 3e

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

According to the method of compound 1f, compound 3e (brown oil, 160 mg) was obtained.

LCMS m/s＝341.26[M+1].

Step 5:

According to the method of compound 1, compound 3 (brown solid, 20 mg, yield 78%) was obtained.

1H NMR(400MHz,DMSO)δ11.45(s,1H),10.55(s,1H),7.91(dd,1H),7.17(dd,1H),6.90-6.72(m,2H),3.50(d, 2H),3.12(m,2H),2.59(s,3H),2.56-2.51(m,6H),1.41(s,6H),0.98(t,,6H).

LC-MS m/z(ESI)＝425.20[M+1]

Example 4

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-4-phenyl-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide compound 4

(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-4-phenyl-1,4,5,6-tetrahydrocyclopenta[b ]pyrrole-3-carboxamide

first step:

2-Methyl-6-oxo-4-phenyl-1-toluenesulfonyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 4b

Ethyl 2-methyl-6-oxo-4-phenyl-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate

According to the method of compound 1c, 1b (3.6 g, 11.72 mmol) and 4a (3.47 g, 23.44 mmol) were used to obtain compound 4b (yellow solid, 2 g).

LCMS m/s＝438.20[M+1].

Step 2:

2-Methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 4c

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

According to the method for compound 1d, compound 4c (brown solid, 1.2 g) was obtained.

LCMS m/s＝284.30[M+1].

Step 3:

(Z)-6-(5-Fluoro-2-oxoindole-3-ylidene)-2-methyl-4-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester 4d

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

According to the method of compound 1e, compound 4d (brown oil, 600 mg) was obtained.

LCMS m/s＝417.28[M+1].

Step 4:

(Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-4-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid 4e

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

According to the method for compound 1f, compound 4e (yellow oil, 250 mg) was obtained.

LCMS m/s＝389.20[M+1].

Step 5:

According to the synthesis method of compound 1, compound 4 (yellow solid, 23 mg, yield 60%) was obtained.

LCMS m/s＝487.23[M+1].

Example 5

(Z)-N-(2-(diethylamino)ethyl)-6'-(5-fluoro-2-oxoindole-3-ylidene)-2'-methyl-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopentadienyl[b]pyrrole]-3'-carboxamide compound 5

(Z)-N-(2-(diethylamino)ethyl)-6'-(5-fluoro-2-oxoindolin-3-ylidene)-2'-methyl-5',6'-dihydro-1'H-spiro [cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide

first step:

2'-Methyl-6'-oxo-1'-tosyl-5'-, 6'-dihydro-1'-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylic acid ethyl ester 5b

Ethyl 2'-methyl-6'-oxo-1'-tosyl-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylate

According to the method of compound 1c, 1b (8.95 g, 29.1 mmol) and 5a (4.90 g, 43.7 mmol) were used to obtain compound 5b (yellow solid, 4.1 g)

LCMS m/s＝402.13[M+1].

Step 2:

2'-Methyl-6'-oxo-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylic acid ethyl ester 5c

Ethyl 2'-methyl-6'-oxo-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylate

According to the method of compound 1d, 5b (1.86 g, 4.64 mmol) gave compound 5c (white solid, 630 mg).

LCMS m/s＝248.23[M+1].

¹ H NMR(400MHz,Chloroform-d)δ11.71–11.37(m,1H),4.38(q,2H),3.17(s,2H),3.13–3.00(m,2H),2.68(s,3H) ,2.17–2.08(m,1H),2.00(ddd,3H),1.44(t,3H).

Step 3:

(Z)-6'-(5-fluoro-2-oxoindole-3-ylidene)-5'-6'-dihydro-1'-H-pyrrolo[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylic acid ethyl ester 5d

Ethyl(Z)-6'-(5-fluoro-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]- 3'-carboxylate

According to the method of compound 1e, 5c (630 mg, 2.55 mmol) gave compound 5d (yellow solid, 511 mg).

LCMS m/s＝381.21[M+1].

Step 4:

(Z)-6'-(5-fluoro-2-oxoindole-3-ylidene)-5'-,6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopentadienyl[b]pyrrole]-3'-carboxylic acid 5e

(Z)-6'-(5-fluoro-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3 '-carboxylic acid

According to the method of compound 1f, 5d (511 mg, 1.35 mmol) gave compound 5e (yellow oil, 390 mg).

LCMS m/s＝338.22[M+1].

Step 5:

According to the synthesis method of compound 1, 5e (200 mg, 0.74 mmol) gave compound 5 (yellow solid, 81 mg, 32%).

LCMS m/z(ESI)＝451.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.44(s,1H),10.59(s,1H),7.45(t,1H),7.32(dd,2.6Hz,1H),6.92(td,1H) ,6.83(dd,1H),3.78(s,2H),2.88–2.77(m,2H),2.55(dd,4H),2.50(d,4H),2.12(s,3H),1.89(d,1H ),1.23(s,3H),0.97(t,6H).

Example 6

(Z)-N-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)-6'-(5-fluoro-2-oxoindole-3-ylidene)-2'-methyl-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide Compound 6

(Z)-N-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)-6'-(5-fluoro -2-oxoindolin-3-ylidene)-2'-methyl-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide

first step:

Methyl 5-(4-(3-(tert-Butyloxycarbonyl)amino)propyl)piperazin-1-yl)-2-fluorobenzoate 6b

Methyl 5-(4-(3-((tert-butoxycarbonyl)amino)propyl)piperazin-1-yl)-2-fluorobenzoate

In a 250 mL three-necked flask, 6a (7 g, 30 mmol), tert-butyl (3-(piperazin-1-yl)propyl)carbamate (11 g, 45 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (2.5 g, 0.3 mmol) and cesium carbonate (29.2 g, 90 mmol) were dissolved in 1,4-dioxane (90 mL), and the temperature was raised to 100 ° C under the protection of inert gas for 8 h. The reaction was monitored by TLC, the solid was removed by filtration, and the solvent was concentrated to obtain a crude product, which was purified by column chromatography (PE:EA=5:1) to obtain compound 6b (white solid 10.3 g, 87%).

LCMS m/z(ESI)＝396.2[M+1]

Step 2:

5-(4-(3-(tert-Butyloxycarbonyl)amino)propyl)piperazin-1-yl)-2-fluorobenzoic acid 6c

5-(4-(3-((tert-butoxycarbonyl)amino)propyl)piperazin-1-yl)-2-fluorobenzoic acid

In a 250 mL single-mouth bottle, compound 6b (10.3 g, 26 mmol) and NaOH (5.2 g, 130 mmol) were dissolved in methanol (90 mL) and water (9 mL), and the temperature was raised to 40°C for reaction for 2 h after the addition was completed. The reaction was monitored by TLC, and the mixture was concentrated under reduced pressure to remove MeOH, diluted with water, and the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and water, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by reverse phase preparative chromatography to obtain compound 6c (light red solid, 5.4 g, 55%).

LCMS m/z(ESI)＝382.0[M+1]

Step 3:

Tert-butyl (3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)carbamate 6d

Tert-butyl(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)carbamate

In a 250 mL single-mouth bottle, compound 6c (5.4 g, 14.2 mmol), 3-aminopiperidine-2,6-dione (3.64 g, 28.4 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.8 g, 28.4 mmol) and N,N-diisopropylethylamine (5.5 g, 42.6 mmol) were dissolved in N,N-dimethylformamide (50 mL) and reacted at 50° C. for 3 h. After TLC monitoring, the reaction was completed, diluted with water, extracted with ethyl acetate and water, and the organic phase was collected, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin layer chromatography (DCM:MeOH=20:1) to obtain compound 6d (brown solid, 1.818 g, 26%).

LCMS m/z(ESI)＝492.23[M+1].

Step 4:

5-(4-(3-aminopropyl)piperazin-1-yl)-N-(2,6-dioxohesperidin-3-yl)-2-fluorobenzamide 6e

5-(4-(3-aminopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

In a 50 mL single-necked bottle, compound 6d (1.818 g, 3.7 mmol) was dissolved in HCl·EA (10 mL) and reacted at room temperature for 2 h. The reaction was completed after monitoring by LC-MS. The solution was concentrated under reduced pressure to obtain compound 6e (brown solid, 1.315 g, 91%).

LCMS m/z(ESI)＝392.2[M+1].

Step 5:

In a 50 mL single-necked bottle, compound 5e (52 mg, 0.15 mmol) and compound 6e (88 mg, 0.225 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.3 mmol) and N,N-diisopropylethylamine were added. (58 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL), and heated to 50°C for 4 h after the addition. TLC monitored the completion of the reaction, added water for dilution, extracted with ethyl acetate and water, and the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (DCM: MeOH = 30: 1) to obtain compound 6 (yellow solid, 12 mg, 11%).

LCMS m/z(ESI)＝726.3[M+1].

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.41(s,1H),10.88(s,1H),10.58(s,1H),8.57–8.44(m,1H),7.74(t,1H),7.31(dd,1H),7.13(dd,3H),6.92(td,1H),6.82(dd,1H),4.75(ddd,1H), 3.77(s,2H),3.34–3.25(m,4H),3.12(s,4H),2.77(dt,3H),2.54(s,4H),2.43(s,2H),2.20–2.05(m,4H),2.00(dd,1H),1.90(d,1H),1.74(s,2H), 1.36–1.20(m,2H).

Example 7

(R)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-methylmorpholinyl)-2-oxoindolyl-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 7

(R)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b ]pyrrole-3-carboxamide

first step:

(R)-2-(5-(3-methylmorpholinyl)-2-nitrophenyl)acetate 7b

Methyl(R)-2-(5-(3-methylmorpholino)-2-nitrophenyl)acetate

In a 250 mL single-mouth bottle, 7a (2.9 g, 10.58 mmol) and (R)-3-methylmorpholine (1.28 g, 12.7 mml) were dissolved in 50 mL 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (885 mg, 1.06 mmol) and cesium carbonate (8.62 g, 26.50 mmol) were added, nitrogen was replaced, and the reaction was carried out at 110 ° C for 8 h. The reaction was monitored by TLC, the reaction solution was filtered and dried, the organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA = 10: 1-3: 1) to obtain 7b (brown oil, 2.5 g, 80.4%)

LCMS m/z(ESI)＝295.2[M+1].

Step 2:

(R)-5-(3-Methylmorpholinyl)indolin-2-one 7c

(R)-5-(3-methylmorpholino)indolin-2-one

In a 150 mL single-necked bottle, 7b (2.5 g, 8.5 mmol) was dissolved in 40 mL of acetic acid, and iron powder (3.81 g, 68.03 mmol) was added, and the mixture was reacted at 50° C. for 3 h. The reaction was completed after LC-MS monitoring, and the reaction solution was filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by medium-pressure preparative reverse phase chromatography (ACN/H ₂ O) to obtain 7c (brown solid, 1.6 g, 80.4%).

LCMS m/z(ESI)＝232.2[M+1].

Step 3:

Ethyl(R)-2-methyl-6-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate 7d

(R)-2-Methyl-6-(5-(3-methylmorpholinyl)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester

In a 50 mL single-mouth bottle, 7c (600 mg, 2.59 mmol) and ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[B]pyrrole-3-carboxylate (482 mg, 2.33 mmol) were dissolved in 10 mL of hexahydropyridine and reacted at 100° C. for 8 h. The reaction was monitored by LC-MS, the reaction solution was filtered, quenched with water, extracted with EA twice, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=10:1-1:1) to obtain 7d (brown oil, 200 mg, 18.3%).

LCMS m/z(ESI)＝422.3[M+1].

Step 4:

(R)-2-Methyl-6-(5-(3-methylmorpholinyl)-2-oxoindolyl-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid 7e

(R)-2-methyl-6-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid

In a 50 mL single-mouth bottle, 7d (200 mg, 0.48 mmol) was dissolved in 3 mL of dimethyl sulfoxide, 1 ml of methanol and 1 ml of water, and reacted at 100 °C for 4 h. After LC-MS monitoring, the reaction was completed, most of the organic solvent was removed under reduced pressure, and water was added to dilute, and the pH was adjusted to about 7 with 1 mmol/L HCl. Solids precipitated and were collected by filtration to obtain 7e (yellow solid, 70 mg, 37.5%).

LCMS m/z(ESI)＝394.3[M+1].

Step 5:

In a 50 mL single-necked bottle, 7e (40 mg, 0.13 mmol) and N,N-diethylethylenediamine (22 mg, 0.19 mmol) were dissolved in 3 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were added to mL N,N-dimethylformamide, and the mixture was reacted at 50°C for 2 h. The reaction was completed after LC-MS monitoring, and the reaction solution was purified by medium pressure preparative reverse phase chromatography (ACN/H ₂ O) to obtain compound 7 (yellow solid, 10 mg, 18.3%)

LCMS m/z(ESI)＝492.4[M+1].

¹ H NMR (400MHz, DMSO-d6) δ11.69(s,1H),10.41(s,1H),7.06(s,1H),6.95(t,1H),6.78(s,2H),3.84–3.75 (m,2H),3.66(ddd,1H),3.62–3.55(m,2H),3.54–3.46(m,2H),3.36(s,6H),3.28(q,2H),3.13–3.06(m ,2H),2.98(pd,2H),2.58(s,3H),0.99(t,6H),0.87(d,3H).

Example 8

N-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)-2-methyl-6-((Z)-5-((R)-3-methylmorpholinyl)-2-oxoindol-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 8

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

first step:

In a 50 mL single-mouth bottle, 7e (30 mg, 0.08 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90 mg, 0.23 mmol) were dissolved in 3 mL N,N-dimethylformamide, and 6e (58 mg, 0.15 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol) were added, and the mixture was reacted at 50°C for 2 h. The reaction was completed after LC-MS monitoring, and the reaction solution was purified by medium pressure preparative reverse phase chromatography (ACN/H ₂ O) to obtain compound 8 (yellow solid, 4 mg, 6.9%)

LCMS m/z(ESI)＝767.4[M+1].

¹ H NMR (400MHz, DMSO-d6) δ11.71(s,1H),10.88(s,1H),10.46(s,1H),8.54(dd,1H),7.68(s,1H),7.29(s ,2H),7.17(s,2H),7.04(s,2H),4.75(dt,1H),3.81(s,3H),3.57(s,4H),3.18(d,6H),3.01(s, 3H),2.59(s,3H),2.54(s,3H),2.05–1.91(m,4H),1.62(dd,1H),1.52(s,2H),1.23(s,2H),0.86(t ,4H).

Example 9

(S, Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide compound 9

(S,Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta [b]pyrrole-3-carboxamide

first step:

(S)-2-(5-(3-methylmorpholinyl)-2-nitrophenyl)acetate 9b

Methyl(S)-2-(5-(3-methylmorpholino)-2-nitrophenyl)acetate

In a 100 mL round-bottom flask, 9a (1000 mg, 3.65 mmol), cesium carbonate (2973.24 mg, 9.13 mmol), 3-(S)-3-methylmorpholine 442.88 mg, 4.38 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (305.28 mg, 0.37 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was heated and refluxed under nitrogen for 8 h. The reaction was monitored by LCMS, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE/EA=20:1) to obtain 9b (yellow solid, 670 mg, 62.44%).

LC-MS m/z(ESI)=295.75[M+1].

Step 2:

(S)-5-(3-Methylmorpholinyl)indol-2-one 9c

(S)-5-(3-methylmorpholino)indolin-2-one

In a 100 mL round-bottom flask, 9b (670 mg, 2.28 mmol) and reduced iron powder (638.09 mg, 11.39 mmol) were dissolved in acetic acid (20 mL) and reacted at 50 °C for 4 h. The reaction was monitored by LCMS, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and filtered. Column chromatography (PE/EA=10:1) gave 9c (light yellow solid, 400 mg, 75%).

LC-MS m/z(ESI)=233.13[M+1].

Step 3:

(S,Z)-2-Methyl-6-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxylic acid ethyl ester 9d

Ethyl(S,Z)-2-methyl-6-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate

In a 100 mL round-bottom flask, 9c (300 mg, 1.29 mmol) and ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[B]pyrrole-3-carboxylate (294.77 mg, 1.42 mmol) were dissolved in piperidine (15 mL) and the temperature was raised to 100° C. for 16 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 9d (yellow solid, 240 mg, 93%).

LC-MS m/z(ESI)＝421.25[M+1].

Step 4:

(S,Z)-2-Methyl-6-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxylic acid 9e

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

In a 100 mL round-bottom flask, 9d (240 mg, 0.57 mmol) and sodium hydroxide (114.29 mg, 2.86 mmol) were dissolved in dimethyl sulfoxide, methanol and water (2:6:1 mL), and the temperature was raised to 100°C for 8 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The pH was adjusted to neutral with 6N dilute hydrochloric acid, and the solid was precipitated. The filter cake was collected by suction to obtain compound 9e (yellow solid, 100 mg, 44%).

LC-MS m/z(ESI)=395.03[M+1].

Step 5:

In a 50 mL round-bottom flask, 9e (50 mg, 0.13 mmol), N,N-diethylethylenediamine (22.18 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69.2 mg, 0.18 mmol) and N,N-diisopropylethylamine (50.31 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (7 mL) and reacted at 50° C. for 3 h. The reaction was completed after LCMS monitoring, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and purified by column chromatography to obtain compound 9 (yellow solid, 15 mg, 23%).

LC-MS m/z(ESI)＝492.53[M+1].

¹ H NMR(DMSO-d ₆ )δ11.76(s,1H),10.43(s,1H),9.11(s,1H),7.37(s,1H),7.06(d,1H),6.79(d, 1H),3.80(dd,2H),3.66(dd,1H),3.62–3.52(m,4H),3.52–3.46(m,2H),3.25-3.11(m,7H),3.02–2.89(m, 3H),2.60(s,3H),1.22(t,6H).

Example 10

(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindol-5-yl)piperazin-1-yl)propyl)-6'-(5-fluoro-2-oxoindol-3-ylidene)-2'-methyl-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopentadienyl[b]pyrrole]-3'-carboxamide Compound 10

(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-5',6'-dihydro-1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide

first step:

Tert-butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate (10b)

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

In a 100 mL round-bottom flask, 10a (3.1 g, 9.06 mmol), potassium carbonate (3.75 g, 27.18 mmol), N-Boc-3-aminopropyl bromide (2.8 g, 11.78 mmol) and potassium iodide (1.5 g, 9.06 mmol) were dissolved in N,N-dimethylformamide (30 mL). The reaction was carried out at room temperature for 4 h. The reaction was completed after LCMS monitoring. The product was extracted with ethyl acetate and water, and the residue was purified by column chromatography to obtain 10b (yellow solid, 1.82 g, 40%).

LC-MS m/z(ESI)=734.24[M+1].

Step 2:

(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)amino Tert-Butyl Formate 10c

In a 100 mL round-bottom flask, 10b (3.1 g, 9.06 mmol), potassium carbonate (3.75 g, 27.18 mmol), N-Boc-3-aminopropyl bromide (2.8 g, 11.78 mmol) and potassium iodide (1.5 g, 9.06 mmol) were dissolved in DMF (30 mL) and reacted at room temperature for 4 h. The reaction was completed after LCMS monitoring. The product was extracted with ethyl acetate and water, and the residue was purified by column chromatography (DCM/MeOH=30:1) to obtain 10c (yellow solid, 1.82 g, 40%).

LC-MS m/z(ESI)＝500.24[M+1].

Step 3:

In a 50 mL round-bottom flask, 10c (34 mg, 0.09 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31.94 mg, 0.08 mmol), 5e (20 mg, 0.06 mmol) and N,N-diisopropylethylamine (23.22 mg, 129 mmol) were dissolved in N,N-dimethylformamide (7 mL) and reacted at room temperature for 4 h. The reaction was completed after LCMS monitoring. The product was extracted with ethyl acetate and water, and the residue was purified by column chromatography to obtain compound 10 (yellow solid, 20 mg, 34%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.41 (s, 1H), 11.09 (s, 1H), 10.58 (s, 1H), 7.75 (t, J = 5.6Hz, 1H), 7.67 (d, J＝8.5Hz,1H),7.37–7.29(m,2H),7.26(d,J＝8.6Hz,1H),6.96–6.88(m,1H),6.83(dd,J＝8.5,4.7Hz,1H ),5.07(d d,J＝12.9,5.4Hz,1H),3.77(s,2H),3.32(d,J＝6.8Hz,5H),3.20(s,2H),2.86(dd,J＝28.4,15.4Hz,4H ),2.56(s,4H),2.13(s,3H),1.99(q,J＝7.8Hz,3H),1.90(d,J＝7.3Hz,2H),1.74(s,3H).

LC-MS m/z(ESI)=734.55[M+1].

Embodiment 11

N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)propyl)-2-methyl-6-((Z)-5-((S)-3-methylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadien[b]pyrrole-3-carboxamide Compound 11

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

first step:

In a 50 mL round-bottom flask, 10c (60 mg, 0.16 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69.21 mg, 0.18 mmol), 9e (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (50.34 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (7 mL) and reacted at room temperature for 4 h. The reaction was completed after LCMS monitoring. The product was extracted with ethyl acetate and water, and the residue was purified by column chromatography to obtain compound 11 (yellow solid, 20 mg, 31%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.67(s,1H),11.09(s,1H),10.40(s,1H),7.67(d,1H),7.35(d,1H),7.29–7.17(m,2H),7.05(s,1H),6.77(s,2H),5.17–5.02(m,1H),3.79(t,2 H),3.70–3.63(m,1H),3.55(s,2H),3.54–3.42(m,6H),3.28(t,3H),3.16(d,3H),2.99(d,2H),2.57(s,6H),2.40(t,2H),2.00(d,2H),1.77–1.67( m,2H).

LC-MS m/z(ESI)=775.54[M+1].

Example 12

(R, Z)-N-(2-(diethylamino)ethyl)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide Compound 12

(R,Z)-N-(2-(diethylamino)ethyl)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro -1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide

first step:

(R,Z)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-,6'-dihydro-1'-cyclobutane-1,4'-cyclopentadienyl[b]pyrrole]-3'-carboxylic acid ethyl ester 12a

Ethyl(R,Z)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1 ,4'-cyclopenta[b]pyrrole]-3'-carboxylate

In a 100 mL round-bottom flask, 7c (138.08 mg, 0.6 mmol) and 5c (140 mg, 0.57 mmol) were dissolved in piperidine (15 mL) and the temperature was raised to 100° C. for 8 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=30:1) to give compound 12a (yellow solid, 100 mg, 38%).

LC-MS m/z(ESI)=462.25[M+1].

Step 2:

(R,Z)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-,6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylic acid 12b

(R,Z)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1, 4'-cyclopenta[b]pyrrole]-3'-carboxylic acid

In a 100 mL round-bottom flask, 12a (40 mg, 0.09 mmol) and sodium hydroxide (17.35 mg, 0.44 mmol) were dissolved in dimethyl sulfoxide, methanol and water (2:5:1 mL), and the temperature was raised to 100°C for 8 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The pH was adjusted to neutral with 6N dilute hydrochloric acid, and the solid was precipitated. The filter cake was collected by suction to obtain compound 12b (yellow solid, 20 mg, 51%).

LC-MS m/z(ESI)＝434.03[M+1].

Step 3:

((R, Z)-N-(2-(diethylamino)ethyl)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide Compound 12

In a 50 mL round-bottom flask, 12b (20 mg, 0.05 mmol), N,N-diethylethylenediamine (8.05 mg, 0.07 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (26.62 mg, 0.07 mmol) and N,N-diisopropylethylamine (19.35 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 50° C. for 3 h. The reaction was completed after LCMS monitoring, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and purified by column chromatography (DCM/MeOH=20:1) to obtain compound 12 (yellow solid, 20 mg, 81%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.54(s,1H),10.44(s,1H),7.89(s,1H),7.14–7.06(m,1H),6.84–6.76(m,2H ),3.86–3.77(m,2H),3.74(s,2H),3.70–3.61(m,2H),3.48(dd,2H),3.20(s,6H),3.04–2.92(m,2H), 2.85(d,2H),2.56(s,3H),2.17–2.09(m,3H),1.93(t,1H),1.24(t,6H).

LC-MS m/z(ESI)＝532.53[M+1].

Example 13

((S, Z)-N-(2-(diethylamino)ethyl)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-, 6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide Compound 13

(S,Z)-N-(2-(diethylamino)ethyl)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro -1'H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxamide

first step:

(S,Z)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-,6'-dihydro-1'-cyclobutane-1,4'-cyclopentadienyl[b]pyrrole]-3'-carboxylic acid ethyl ester 13a

Ethyl(S,Z)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1 ,4'-cyclopenta[b]pyrrole]-3'-carboxylate

In a 100 mL round-bottom flask, 9c (138.08 mg, 0.6 mmol) and 5c (140 mg, 0.57 mmol) were dissolved in piperidine (15 mL) and the temperature was raised to 100° C. for 8 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=30:1) to give compound 13a (yellow solid, 120 mg, 43%).

LC-MS m/z(ESI)=462.25[M+1].

Step 2:

(S,Z)-2'-methyl-6'-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-5'-,6'-dihydro-1'-H-spiro[cyclobutane-1,4'-cyclopenta[b]pyrrole]-3'-carboxylic acid 13b

(S,Z)-2'-methyl-6'-(5-(3-methylmorpholino)-2-oxoindolin-3-ylidene)-5',6'-dihydro-1'H-spiro[cyclobutane-1, 4'-cyclopenta[b]pyrrole]-3'-carboxylic acid

In a 100 mL round-bottom flask, 13a (40 mg, 0.09 mmol) and sodium hydroxide (17.35 mg, 0.44 mmol) were dissolved in dimethyl sulfoxide, methanol and water (2:5:1 mL), and the temperature was raised to 100 °C for 8 h. The reaction was complete as monitored by LCMS, and the mixture was concentrated under reduced pressure. The pH was adjusted to neutral with 6N dilute hydrochloric acid to precipitate a solid, which was filtered and the filter cake was collected to obtain compound 13b (yellow solid, 20 mg, 5 1%).

LC-MS m/z(ESI)=434.03[M+1].

Step 3:

In a 50 mL round-bottom flask, 13b (20 mg, 0.05 mmol), N,N-diethylethylenediamine (8.05 mg, 0.07 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (26.62 mg, 0.07 mmol) and N,N-diisopropylethylamine (19.35 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 50° C. for 3 h. The reaction was completed after LCMS monitoring, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and purified by column chromatography (DCM/MeOH=20:1) to obtain compound 13 (yellow solid, 10 mg, 40%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.51(s,1H),10.42(s,1H),7.62(s,1H),7.09(s,1H),6.78(p,2H),3.89– 3.63(m,6H),3.54–3.42(m,8H),2.99(dd,3H),2.92–2.71(m,5H),2.52(s,3H),2.13(s,3H),1.92(d, 2H),1.08(s,6H).

LC-MS m/z(ESI)＝532.53[M+1].

Embodiment 14

(S, Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-methylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide compound 14

first step:

(S)-2-(5-(3-ethylmorpholinyl)-2-nitrophenyl)acetate 14b

Methyl(S)-2-(5-(3-ethylmorpholino)-2-nitrophenyl)acetate

In a 100 mL round-bottom flask, 7a (1000 mg, 3.65 mmol), cesium carbonate (2973.24 mg, 9.13 mmol), 3-(S)-3-ethylmorpholine (546.29 mg, 4.74 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (305.28 mg, 0.37 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was heated and refluxed under nitrogen for 8 h. The reaction was completed by LCMS monitoring, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE/EA=20:1) to obtain 14b (yellow solid, 862 mg, 76%).

LC-MS m/z(ESI)=309.75[M+1].

Step 2:

(S)-5-(3-Ethylmorpholinyl)indol-2-one 14c

(S)-5-(3-ethylmorpholino)indolin-2-one

In a 100 mL round-bottom flask, 14b (862 mg, 2.8 mmol) and reduced iron powder (1097 mg, 19.59 mmol) were dissolved in acetic acid (30 mL) and reacted at 50° C. for 4 h. The reaction was monitored by LCMS, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and purified by column chromatography (PE/EA=10:1) to obtain 14c (brown oil, 450 mg, 65%).

LC-MS m/z(ESI)=247.13[M+1].

Step 3:

(S, Z)-2-methyl-6-(5-(3-ethylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxylic acid ethyl ester Compound 14d

Ethyl(S,Z)-2-methyl-6-(5-(3-ethylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate

In a 100 mL round-bottom flask, 14c (450 mg, 1.83 mmol) and ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[B]pyrrole-3-carboxylate (361.03 mg, 1.74 mmol) were dissolved in piperidine (20 mL) and the temperature was raised to 100 °C for 16 h. The reaction was completed as monitored by MS, and the product was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 14d (yellow solid, 160 mg, 20%).

LC-MS m/z(ESI)=436.25[M+1].

Step 4:

(S,Z)-2-methyl-6-(5-(3-ethylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxylic acid 14e

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

In a 100 mL round-bottom flask, 14d (160 mg, 0.37 mmol) and sodium hydroxide (73.57 mg, 1.84 mmol) were dissolved in dimethyl sulfoxide, methanol and water (5:5:3 mL), and the temperature was raised to 100°C for 8 h. The reaction was complete after LCMS monitoring, and the mixture was concentrated under reduced pressure. The pH was adjusted to neutral with 6N dilute hydrochloric acid, and the solid was precipitated. The filter cake was collected by suction to obtain compound 14e (yellow solid, 100 mg, 66%).

LC-MS m/z(ESI)＝408.03[M+1].

Step 5:

(S, Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-ethylmorpholinyl)-2-oxoindole-3-ylidene)-1,4,5,6-tetrahydrocyclopentadienyl[b]pyrrole-3-carboxamide compound 14

(S,Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(5-(3-ethylmorpholino)-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta [b]pyrrole-3-carboxamide

In a 50 mL round-bottom flask, 14e (90 mg, 0.22 mmol), N,N-diethylethylenediamine (33.41 mg, 0.29 mmol), N,N-diisopropylethylamine (85.14 mg, 0.66 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.12 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (7 mL) and reacted at 50° C. for 3 h. The reaction was completed after LCMS monitoring, and the mixture was extracted with ethyl acetate and water. The organic phase was collected and purified by column chromatography (DCM/MeOH=10:1) to obtain compound 14 (yellow solid, 18 mg, 13%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.73(s,1H),10.39(s,1H),7.02(s,1H),6.80–6.72(m,2H),3.83(dt,1H), 3.72(qd,2H),3.64(dq,1H),3.58(p,2H),3.29(s,2H),3.13(s,2H),3.02(q,2H),2.59(s,3H),1.53 (ddd,1H),1.32–1.23(m,3H),1.09(s,6H),0.79(t,3H).

LC-MS m/z(ESI)＝506.53[M+1].

Embodiment 15

4-Cyclopropyl-N-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindol-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound 15

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

first step:

In a 50 mL single-mouth bottle, 2e (100 mg, 0.28 mmol) and 6e (333 mg, 0.85 mmol) were dissolved in 3 mL N, N-dimethylformamide, and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (324 mg, 0.85 mmol) and N, N-diisopropylethylamine (110 mg, 0.85 mmol) were added, and the mixture was reacted at 50 ° C for 2 h. The reaction was monitored by LC-MS, and the reaction solution was purified by medium pressure preparative reverse phase chromatography (ACN/H2O) to obtain compound 15 (yellow solid, 80 mg, 38.8%)

LCMS m/z(ESI)＝726.4[M+1].

Biological test cases

1. Jurkat cell culture

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 .

2. HPK1 protein degradation and GLK, HGK protein degradation test

On the first day, Jurkat cells in the exponential growth phase were collected and inoculated in 6-well plates at a density of 4×10 ⁵ cells/well and placed in a 37°C, 5% CO ₂ incubator. On the second day, test compounds were added to the wells at a final concentration of 50 and 500 nM and placed in an incubator for 48 hours. After the incubation, the cells were collected, 30 μL of cell lysis buffer was added to each tube, lysed on ice for 30 minutes, centrifuged at 4°C 13000 rpm for 15 minutes, and the supernatant was collected and stored at low temperature. The BCA kit was used for protein quantification and protein samples were prepared. The protein samples were denatured in a 95°C metal bath for 10 minutes. Protein detection was performed according to the western blot experimental steps, and the dilution ratio of HPK1 antibody (CST, 4472s), GLK antibody (CST, 92427S), HGK antibody (CST, 3485S) and β-Actin antibody (CST, 4970S) was 1:1000. The results are shown in Table 1.

Table 1 The degradation activity of the compounds of the present invention on HPK1 protein

Conclusion: This patented compound has good degradation activity on HPK1.

3. HPK1 kinase assay

use Eu Kinase Binding Assay was used to detect the HPK1 kinase activity of the compound. The test compounds were prepared using 1×Kinase buffer D (Thermo Fisher, PV3189) (1×Kinase buffer A+2% DMSO) to a final concentration of 1250, 312.5, 78.1, 19.5, 4.9, 1.2, 0.3, 0.076, 0.019, 0.005, 0.001, and 0.0003. 4 μL/well of the test compound was added to a 384-well plate, with 2 replicates for each concentration. 2×HPK1/Antibody Mix was prepared, with a final concentration of 10 nM for HPK1 enzyme (Thermo Fisher, PV6355) and a final concentration of 4 nM for Eu-Antibody (Thermo Fisher, PV5594). 4×Tracer Mix solution was prepared, with a final concentration of 40 nM for Tracer (Thermo Fisher, PV6121). After the preparation, 8 μL/well 2×HPK1/Antibody Mix and 4 μL/well 4×Tracer Mix were added to the 384-well plate. At the same time, 4 μL/well 1×Kinase buffer D, 8 μL/well 2×HPK1/Antibody Mix and 4 μL/well 4×Tracer Mix were added to the quality control group. 12 μL/well 1×Kinase buffer D and 4 μL/well 4×Tracer Mix were added to the blank control group. After the addition of the sample, the 384-well plate was placed in a centrifuge at 1000 rpm for 60 seconds. After the centrifugation, it was incubated at 25°C for 60 minutes. After the incubation, the value was read using an ELISA reader (Thermo Fisher, Varioskan LUX). Reading value = (experimental well _665nm - blank group _665nm ) / (experimental well _615nm - blank group _615nm ), the reading value was substituted into GraphPad8.0, and the fitting _IC50 was calculated. The results are shown in Table 2.

Table 2 HPK1 kinase inhibitory activity of the compounds of the present invention

The results showed that the compounds of the present invention had significant inhibitory activity on HPK1.

4. GLK kinase activity inhibition assay

ADP-Glo Kinase Assay (Promega, V9101) was used to detect the GLK kinase activity of the compound. The test compound was prepared using 1×reaction buffer D (1×reaction buffer + 5% DMSO) to a final concentration of 25000, 6250, 1562.5, 390.6, 97.7, 24.4, 6.1, 1.53, 0.38, and 0.096 nM. 1 μL/well of the test compound was added to a 384-well plate, with 2 replicates for each concentration. Next, add 2 μL/well 2.5×GLK Kinase Mix (Promega, VA7177) to the 384-well plate, where the final concentration of GLK kinase is 6 μg and the final concentration of DTT is 25 μM. Subsequently, add 2 μL/well 2.5×Substrate&ATP Mix to the 384-well plate, where the final concentration of ATP is 12.5 μM and the final concentration of PKA substrate is 0.5 mg/mL. Add 3 μL/well 1×reaction buffer D and 2 μL/well 2.5×GLK Kinase Mix to the quality control control group. Add 3 μL/well 1×reaction buffer D and 2 μL/well 2.5×Substrate&ATP Mix to the blank control group. After the addition of the sample, place the 384-well plate in a centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 60 minutes. After the incubation, add 5 μL/well ADP-Glo Reagent, place the 384-well plate in a centrifuge, centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 40 minutes. After the incubation, add 10 μL/well ADP-Glo detection Reagent, place the 384-well plate in a centrifuge, centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 30 minutes. Read the chemiluminescence value using an enzyme reader (Thermo Fisher, Varioskan LUX). Substitute the value into GraphPad8.0 to calculate the fitted IC ₅₀ .

5. HGK kinase inhibitory activity assay

ADP-Glo Kinase Assay (Promega, V9101) was used to detect the HGK kinase activity of the compound. The test compound was prepared using 1×reaction buffer D (1×reaction buffer+5% DMSO) to a final concentration of 25000, 6250, 1562.5, 390.6, 97.7, 24.4, 6.1, 1.53, 0.38, and 0.096 nM. 1 μL/well of the test compound was added to a 384-well plate, with 2 replicates for each concentration. Next, 2 μL/well of 2.5×HGK Kinase Mix (Promega, VA7471) was added to the 384-well plate, where the final concentration of HGK kinase was 3 μg and the final concentration of DTT was 25 μM. Subsequently, 2 μL/well 2.5×Substrate&ATP Mix was added to the 384-well plate, where the final concentration of ATP was 2.5 μM and the final concentration of MBP Protein was 0.25 mg/mL. 3 μL/well 1×reaction buffer D and 2 μL/well 2.5×HGK Kinase Mix were added to the quality control group. 3 μL/well 1×reaction buffer D and 2 μL/well 2.5×Substrate&ATP Mix were added to the blank control group. After the addition of the sample, the 384-well plate was placed in a centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 60 minutes. After the incubation, 5 μL/well ADP-Glo Reagent was added, and the 384-well plate was placed in a centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 40 minutes. After the incubation, add 10 μL/well ADP-Glo detection reagent, place the 384 plate in a centrifuge, centrifuge at 1000 rpm for 60 seconds. After the centrifugation, incubate at 25°C for 30 minutes. Read the chemiluminescence value with an enzyme reader (Thermo Fisher, Varioskan LUX). Substitute the value into GraphPad8.0 to calculate the fitted IC ₅₀ .

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 principle 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

The compound represented by general formula (I), or its stereoisomer, pharmaceutically acceptable salt:

in:

R 1 , R 2 , and R 3 are each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 - membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, -(CO)N(R 4 ) 2 , -NH(CO)R 4 ; the 5-12-membered heteroaryl and 5-12-membered heterocycloalkyl optionally contain 1 to 3 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 2-6 alkenyl, 5-12-membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, 5-12-membered heterocycloalkyl optionally further substituted by one or more selected from NH 2 , carbonyl, halogen, C 2-6 substituted by a C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy substituent;

Or, any two R 2 and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

R 4 is each independently selected from H, halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted with a substituent selected from NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

a, b, d are each independently selected from 0, 1, 2, 3 or 4;

c is selected from 0, 1 or 2.
The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein the compound is selected from the compound represented by general formula (II):

in:

R 2A , R 2B are each independently selected from H, halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl, -(CO)N(R 4 ) 2 , -NH(CO)R 4 ; the 5-12 membered heteroaryl, 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl Optionally further substituted with one or more substituents selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

Or, R 2A , R 2B and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

R 1 , R 3 , a and c have the same definitions as those in the general formula (I).
The compound according to claim 2, or its stereoisomer, or pharmaceutically acceptable salt, wherein the compound is selected from the compounds represented by general formula (III):

in:

R 2A , R 2B are each independently selected from H, halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl, -(CO)N(R 4 ) 2 , -NH(CO)R 4 ; the 5-12 membered heteroaryl, 5-12 membered heterocycloalkyl optionally contain 1 to 3 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl optionally further substituted by one or more selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 2-6 alkenyl, 5-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 5-12 membered heterocycloalkyl is substituted by a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group;

Or, R 2A , R 2B and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

R 3A is selected from -(CO)N(R 4 ) 2 , -NH(CO)R 4 ; R 4 are each independently selected from H, halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted with a substituent selected from NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

R 3B is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkyl , C 1-6 haloalkoxy is optionally further substituted with one or more substituents selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

R 1 , a, and are defined as in the general formula (I).
The compound according to claim 3, or its stereoisomer, or pharmaceutically acceptable salt, wherein:

R 1 is independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl is optionally further substituted by a substituent selected from C 1-4 alkyl, -C 1-6 alkylene-OH;

R 2A and R 2B are each independently selected from H, C 1-4 alkyl, 5-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by a substituent selected from C 1-3 alkyl and halogen;

Or, R 2A , R 2B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R 3A is selected from -(CO)N(R 4 ) 2 , -NH(CO)R 4 ; R 4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl; the C 1-6 alkyl, C 1-6 haloalkyl are optionally further substituted by a substituent selected from NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 ;

R 3B is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl;

a is selected from 0, 1, 2, 3 or 4.
The compound according to claim 4, or its stereoisomer, or pharmaceutically acceptable salt, wherein:

R 2A and R 2B are each independently selected from H, C 1-4 alkyl, 6-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by one or more substituents selected from C 1-4 alkyl and halogen;

Or, R 2A , R 2B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R 1 is independently selected from halogen, 6-10 membered heterocycloalkyl; the 6-10 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 6-10 membered heterocycloalkyl is optionally further substituted by one or more substituents selected from C 1-4 alkyl, -C 1-6 alkylene-OH;

R 3A is selected from -(CO)N(R 4 ); R 4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl; the C 1-6 alkyl, C 1-6 haloalkyl is optionally further substituted by a substituent selected from -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 ;

R 3B is selected from C 1-6 alkyl, C 1-6 haloalkyl;

a is selected from 0, 1, 2, 3 or 4.
The compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
A compound represented by formula (IV) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds represented by general formula (IV):
PTM—L—ULM (IV);

Wherein, the PTM is

R 5 , R 6 , and R 7 are each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 - membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, and 5-12-membered heterocycloalkyl; the 5-12-membered heteroaryl and 5-12-membered heterocycloalkyl optionally contain 1 to 3 heteroatoms selected from N, O or S; the C 1-6 alkyl, C 2-6 alkenyl, 5-12-membered aryl, 5-12-membered heteroaryl, 3-12-membered cycloalkyl, and 5-12-membered heterocycloalkyl optionally further substituted by one or more selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkoxy, C substituted by a C 1-6 haloalkyl or C 1-6 haloalkoxy substituent;

Or, any two R 6 and the carbon atoms to which they are connected form a 3- to 8-membered cyclic group;

m, n, r are each independently selected from 0, 1, 2, 3 or 4;

The ULM is selected from

The A ring is selected from 3-12-membered carbocyclylene and 3-12-membered heterocyclylene; the 3-12-membered carbocyclylene and 3-12-membered heterocyclylene are optionally further substituted by one or more substituents selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

The B rings are each independently selected from 3-12 membered carbocyclic groups and 3-12 membered heterocyclic groups; the 3-12 membered carbocyclic groups and 3-12 membered heterocyclic groups are optionally further substituted by one or more substituents selected from NH 2 , carbonyl, halogen, C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;

The X 1 is selected from -C(=O)-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)-, -C(=O)O-, -SO 2 -, -O- or -S-;

The L is

The R 8 is selected from -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 2-6 alkynylene-, -C 1-6 haloalkylene-, -NHR 1b -, -C(═O)NHR 1b -, -NHC(═O)R 1b -, -OC(═O)R 1b -, -C(═O)OR 1b -, -C(═O)R 1b -, -SO 2 R 1b - or -OR 1b -;

The R 1b is selected from -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 2-6 alkynylene-, -C 1-6 haloalkylene- or imino;

The C ring is selected from 3-12 membered carbocyclylene and 3-12 membered heterocyclylene; the 3-12 membered carbocyclylene and 3-12 membered heterocyclylene are optionally further substituted by one or more substituents selected from NH2 , carbonyl, halogen, C1-6 alkyl, C1-6 alkylene-OH, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
The compound according to claim 7, or its stereoisomer, or pharmaceutically acceptable salt, wherein:

The PTM is

R 6A and R 6B are each independently selected from H, C 1-4 alkyl, 5-8 membered aryl, 3-6 membered cycloalkyl; the 3-6 membered cycloalkyl is optionally further substituted by a substituent selected from C 1-3 alkyl and halogen;

Or, R 2A , R 2B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R 5 is each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl is optionally further substituted by a substituent selected from C 1-4 alkyl, -C 1-6 alkylene-OH;

R7 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl;

m is selected from 0, 1, 2, 3 or 4;

The ULM is selected from

R 9 is each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 haloalkoxy;

p is selected from 0, 1, 2, 3 or 4;

The X 1 is selected from -C(=O)-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)-, -C(=O)O-, -SO 2 -, -O- or -S-;

The L is

The R 8 is selected from -NHR 1b -, -C(=O)NHR 1b -, -NHC(=O)R 1b -, -OC(=O)R 1b -, -C(=O)OR 1b -, -C(=O)R 1b -, -SO 2 R 1b - or -OR 1b -;

The R 1b is selected from -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 2-6 alkynylene- or -C 1-6 haloalkylene;

The C ring is selected from 6-8 membered heterocycloalkylene; the 6-8 membered heterocycloalkylene optionally contains 1 to 3 heteroatoms selected from N, O or S.
The compound according to claim 8, or its stereoisomer, or pharmaceutically acceptable salt, wherein:

The PTM is

R 6A and R 6B are each independently selected from H, C 1-4 alkyl, and 3-6 membered cycloalkyl;

Or, R 6A , R 6B and the carbon atoms to which they are connected form a 3- to 6-membered cycloalkyl group;

R 5 is each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or 5-12 membered heterocycloalkyl; the 5-12 membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N, O or S; the 5-12 membered heterocycloalkyl optionally is further substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

R7 is selected from C1-4 alkyl;

m is selected from 0, 1, 2, 3 or 4;

The ULM is selected from

R 9 are each independently selected from halogen, cyano, NH 2 , C 1-6 alkyl;

p is selected from 0, 1, 2, 3 or 4;

The X1 is selected from -C(=O)-, -NH-, -C(=O)NH-, -NHC(=O)-, -O- or -S-;

The L is

The R 8 is selected from -C(=O)NHR 1b -; the R 1b is selected from -C 1-6 alkylene- or -C 1-6 haloalkylene;

The C ring is selected from 6-8 membered heterocycloalkylene, and the C ring optionally contains 1 to 3 heteroatoms selected from N.
The compound according to claim 9 or its stereoisomers or pharmaceutically acceptable salts, wherein the compound is selected from:
A pharmaceutical composition, comprising:

(1) The compound according to any one of claims 1 to 10 or a stereoisomer or a pharmaceutically acceptable salt thereof;

(2) Pharmaceutically acceptable carriers and/or excipients.
Use of the pharmaceutical composition of claim 11 or the compound or its stereoisomers or pharmaceutically acceptable salts according to any one of claims 1 to 10 in the preparation of anti-tumor drugs.