CN118290446A

CN118290446A - Compound for inhibiting and degrading c-MYC and medical application thereof

Info

Publication number: CN118290446A
Application number: CN202311853785.2A
Authority: CN
Inventors: 张晨; 王健民; 黄正刚; 黄安邦; 余彦; 李瑶; 严庞科
Original assignee: Tibet Haisike Pharmaceutical Co ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2023-01-05
Filing date: 2023-12-29
Publication date: 2024-07-05

Abstract

The present invention relates to a compound of formula (I) or formula (I-A) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and intermediates thereof, and use thereof in the inhibition or degradation of c-MYC related diseases such as cancer.

Description

Compound for inhibiting and degrading c-MYC and medical application thereof

Technical Field

The present invention relates to a compound of general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and uses thereof in c-MYC related diseases such as cancer diseases.

Background

MYC oncogenes are a "major driver" of human cancers, and are abnormally activated in various hematological malignancies such as leukemia, lymphoma and multiple myeloma, and various solid tumors such as Pancreatic Ductal Adenocarcinoma (PDAC), brain cancer, non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC), liver cancer, and prostate cancer (adv. Sci.2022,9,2104344). MYC genes are the most studied types of nucleoprotein oncogenes at present, and comprise c-MYC, N-MYC, L-MYC and R-MYC 4 types. The c-MYC protooncogene is one of the most common activated protooncogenes, and the cancers involved in the regulation of c-MYC account for about 20% of cancers affected by human beings, and cancer patients which are fatally affected by the c-MYC protooncogene can reach hundreds of thousands each year. But at the same time the c-MYC protein is considered "non-patentable" because its helix-helix topology lacks a pharmaceutically acceptable domain and nuclear localization within cancer cells, making direct targeting of c-MYC with traditional small molecule inhibitors difficult (CANCER CELL,2014,26:414;CANCER DISCOVERY,2015,5:768.). In the field of developing drugs for the treatment of c-MYC over-expressed tumors, great efforts have been made by humans, but no c-MYC inhibitors of a drug-like nature have been developed for over three decades (Nat. Biotechnol,2021, 39:754).

PROTAC (proteolysis TARGETING CHIMERA) is a bifunctional compound capable of simultaneously combining a target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding to different targeting proteins at PROTAC molecules, the PROTAC technology has become possible for use in the treatment of various diseases, which has received extensive attention in recent years (Drug Discovery Today technology.2019, 31:15-27;Nat.Rev.Drug Discovery,2022,21:181-200.).

Ubiquitin ligases such as Cereblon (CRBN) promote ubiquitination of different proteins in vivo, contributing to the precise regulation of the ubiquitination system. After the target protein is identified, ubiquitin ligase mediates ligation of the ubiquitin moiety to the target protein. Small molecule degradation agents that hijack E3 ubiquitin ligases to target disease kinesin for degradation are becoming a promising therapeutic approach. The development of immunomodulatory (IMiD) drugs, next generation cereblon E3 ligase modulating (CELMoD) drugs, and numerous heterobifunctional proteolytically targeted chimeras reflects a significant advance in the art. As a "molecular gel", the cereblon-modulator reuses ubiquitin ligase to promote ubiquitination and proteasome degradation of different substrates of CRBN for the treatment of various diseases (Blood, 2021,137 (5): 661-677). For example, lenalidomide and pomalidomide can induce CRBN to degrade transcription factors Ikaros (IKZF 1) and Aiolos (IKZF 3) for the treatment of multiple myeloma, and lenalidomide can also induce CRBN to degrade ck1α for the clinical treatment of myelodysplastic syndrome with chromosome 5q deletion; CC-90009 promotes GSPT1 degradation for treatment of Acute Myelogenous Leukemia (AML).

In addition to the target proteins mentioned above, more and more other proteins such as SALL4, DCAF, ZFP91, etc. are degraded target proteins of immunomodulators or molecular gums for the treatment of diseases. Immunomodulators or molecular adhesives with different structures have different action mechanisms, clinical treatment effects and toxic and side effects. Therefore, there is a need to develop new immunomodulators or molecular gels to meet different clinical needs.

Development of novel c-MYC protein degradation agents for treating diseases related to c-MYC proteins would be promising in application.

Disclosure of Invention

The invention aims to provide a compound which has novel structure, good drug effect, high bioavailability and safer property and can inhibit or degrade c-MYC, and is used for treating diseases related to c-MYC such as autoimmune diseases, inflammatory diseases or cancers.

The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),

In some embodiments involving formula (I), B is selected from C _6-12 carbocyclyl or 4-to 12-membered heterocyclyl, optionally substituted with 1 to 4R ^b;

In some embodiments involving formula (I), B is selected from phenyl, 5 to 6 membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered fused ring heteroaryl, 9 to 12 membered tri-fused ring heteroaryl, said B being optionally substituted with 1 to 4R ^b;

In some embodiments involving formula (I), B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolopyridinyl thiazolopyrrolyl, thiazolopyrimidinyl, oxazolopyridinyl, oxazolopyrrolyl, oxazolopyrrol oxazolopyrimidinyl, pyrazolopyridinyl, pyrazolophenyl, pyrazolopyrimidinyl, and, Said B is optionally substituted with 1 to 4R ^b;

in some embodiments involving formula (I), B is selected from Said B is optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, methyl or ethyl;

In some embodiments involving formula (I), each of B ₁ or B ₂ is independently selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl;

in some embodiments involving formula (I), the compound of formula (I) is selected from formula (II)

In some embodiments involving formula (I), each R ^k10 is independently selected from C (CH ₃)₂、CO、CH₂;

In some embodiments involving formula (I), Y ₅ is selected from one of the following groups optionally substituted with 1 to 4R ^y3: benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered benzocyclic heteroaryl, preferably one of the following groups optionally substituted with 1 to 4R ^y3:

In some embodiments involving formula (I), Y ₁ is selected from the group consisting of a bond, -N (R ^y1)C(＝O)-、-NHCH₂-、-OCH₂ -or-C (=o) N (R ^y1) -;

In some embodiments involving formula (I), Y ₁ is selected from-N (R ^y1)C(＝O)-、-NHCH₂-、-OCH₂ -or-C (=o) N (R ^y1) -;

In some embodiments involving formula (I), Y ₁ is selected from-NHC (=o) -or-C (=o) NH-, attached to the right to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I), Y ₂ is selected from C _1-4 alkylene, said Y ₂ optionally substituted with 1 to 4R ^y2;

In some embodiments involving formula (I), Y ₂ is selected from-CH ₂ -or-CH ₂CH₂ -, said Y ₂ being optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I), -Y ₂-Y₁ -selected from-CH ₂ -C (=o) NH-or-CH ₂ -NHC (=o) -, the left side is directly linked to Y ₃;

In some embodiments involving formula (I), Y ₃ is selected from C _3-10 carbocyclyl or 4 to 10 membered heterocyclyl, optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₃ is selected from phenyl, 5-to 6-membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4-to 6-membered heterocyclyl, 8-to 10-membered benzocyclic heteroaryl, said Y ₃ being optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₃ is selected from phenyl, 5-to 6-membered heteroaryl, Y ₅, said Y ₃ optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₃ is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, thiophenyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and, Said Y ₃ is optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₃ is selected from phenyl, pyridine, Said Y ₃ is optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₅ is selected from The left side of the compound is directly connected with Y ₅, and Y ₃ is optionally substituted by 1 to 4R ^y3;

In some embodiments involving formula (I), Y ₄ is selected from C _1-4 alkylene or C _1-4 heteroalkylene, said alkylene or heteroalkylene optionally substituted with 1 to 8R ^y4;

In some embodiments involving formula (I), Y ₄ is selected from the group consisting of-CH ₂ described in -CH₂CH₂CH₂-、-CH₂CH₂-、-CH₂-NR^y4C(＝O)-CH₂-、-CH₂-C(＝O)NR^y4、-CH₂CH₂-NR^y4-、-CH₂-C(＝O)-、-CH₂-C(＝O)NR^y4-CH₂-、-CH₂CH₂-NR^y4-CH₂-、-CH₂CH₂-O-CH₂-、-CH₂CH₂-S-CH₂-, -optionally substituted with 1 to 2R ^y4;

In some embodiments involving formula (I), Y ₄ is selected from -CH₂-C(＝O)-、-CH₂-C(＝O)NH-、-CH₂-NHC(＝O)-CH₂-、-CH₂-C(＝O)NH-CH₂-、-CH₂CH₂-NH-CH₂-, and is linked to Y ₃ to the right, said-CH ₂ -is optionally substituted with 1 to 2 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said NH is optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I), Selected from the group consisting of

The left side is directly connected with B;

In some embodiments involving formula (I), R ^y1 is selected from H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I), R ^y1 is selected from H, deuterium, C _1-4 alkyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 6 membered heterocyclyl, said alkyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I), each R ^y2、R^y3、R^y4、R^b is independently selected from deuterium, halogen, =o, OH, NH ₂、NHC_1-6 alkyl, N (C _1-6 alkyl) ₂、CN、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I), each R ^y2、R^y3、R^y4、R^b is independently selected from deuterium, halogen, =o, OH, NH ₂、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、CN、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-7 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I), R ^y2、R^y3、R^y4、R^b are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN, or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I), R ^y3 is selected from F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, methyl or ethyl;

In some embodiments involving formula (I), ring F is selected from C _4-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl;

In some embodiments involving formula (I), ring F is selected from the group consisting of C _3-7 Shan Tanhuan, C _4-10 carbocyclyl, C _5-12 spirocarbocyclyl, C _5-10 carbocyclyl, 4-7 membered heteromonocyclic group, 4-10 membered heterobicyclic group, 8-15 membered tricyclic heterobicyclic group, 12-17 membered tetracyclic heterobicyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclic group, C _6-14 aryl group, 5-10 membered heteroaryl group, Represents a ring selected from aromatic or non-aromatic rings;

In some embodiments involving formula (I), F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrimidyl, pyri pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, pyrido-yl, pyrido-pyrazinyl, pyrido-pyrrolyl, and pyrido-pyrrolyl,

The left side of the main body is directly connected with Y ₁;

In some embodiments involving formula (I), X ₁ is selected from N or CR ^k3;

In some embodiments involving formula (I), X ₁ is selected from N or CH;

In some embodiments involving formula (I), Q is selected from the group consisting of a bond, -O-, -S-, -CH ₂-、-NR^q-、-CO-、-NR^qCO-、-CONR^q -, or a 3-12 membered heterocyclyl, said heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z;

in some embodiments involving formula (I), Q is selected from the group consisting of a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

In some embodiments involving formula (I), Q is selected from Q ₁ or Q ₂;

In some embodiments involving formula (I), R ^q is selected from H, deuterium, or C _1-4 alkyl;

In some embodiments involving formula (I), R ^q is selected from H or C _1-4 alkyl;

In some embodiments involving formula (I), R ^q is selected from H, methyl, ethylisopropyl;

In some embodiments involving formula (I), Q ₁ is selected from a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

In some embodiments involving formula (I), Q ₂ is selected from a bond, CH ₂、O、S、C(＝O)、NHC(＝O)、N(CH₃) C (=o);

in some embodiments involving formula (I), each F ₁ or F ₂ is independently selected from phenyl, Pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl;

In some embodiments involving formula (I), each F ₃ or F ₄ is independently selected from phenyl, 5to 6 membered heteroaryl, benzoc _4-6 membered carbocyclyl, or benzo4 to 6 membered heterocyclyl;

In some embodiments involving formula (I), each F ₃ or F ₄ is independently selected from phenyl or pyridinyl;

In some embodiments involving formula (I), F ₅ is selected from 5-membered heteroaryl;

In some embodiments involving formula (I), F ₅ is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl, or pyrazolyl;

In some embodiments involving formula (I), E is selected from 5 to 6 membered heteroaryl;

In some embodiments involving formula (I), E is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;

in some embodiments involving formula (I), E ₁ is selected from 5-to 6-membered heteroaryl, benzoc _4-6 -membered carbocyclyl, or benzo4-to 6-membered heterocyclyl;

in some embodiments involving formula (I), E ₁ is selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl,

In some embodiments involving formula (I), each R ^k1 is independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, c _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z; In some embodiments involving formula (I), each R ^k1 is independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, c _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z; In some embodiments involving formula (I), R ^k1 are each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CF₃、CN、COOH、CONH₂, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 groups selected from F, cl, br, I, A substituent of OH or NH ₂;

In some embodiments involving formula (I), R ^k2 is each independently selected from the group consisting of a bond, -CO-, -SO ₂ -, -SO-, or-C (R ^k3)₂ -;

In some embodiments involving formula (I), each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 3 to 8 membered heterocyclyl, Said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from R ^z; In some embodiments involving formula (I), each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl, Said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from R ^z; In some embodiments involving formula (I), R ^k3 are each independently selected from H, deuterium, F, cl, br, I, OH, = O, CF ₃, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 groups selected from F, cl, br, I, A substituent of OH or NH ₂; In some embodiments involving formula (I), R ^k4 is each independently selected from H, deuterium, C _1-6 alkyl, -C _0-2 alkylene-C _3-8 cycloalkyl, or-C _0-2 alkylene-3 to 8 membered heterocyclyl, Said alkyl, alkylene, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I), R ^k4 are each independently selected from H, deuterium, CF ₃, or C _1-4 alkyl; in some embodiments involving formula (I), R ^k4 are each independently selected from H, deuterium, CF ₃, methyl;

In some embodiments involving formula (I), R ^k5 are each independently selected from C(CH₃)₂、CO、CH₂、CH₂CH₂、SO₂、

In some embodiments involving formula (I), R ^k5a are each independently selected fromCH₂CH₂、SO₂、

In some embodiments involving formula (I), each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

in some embodiments involving formula (I), R ^k7 are each independently selected from C(CH₃)₂、CO、CH、N、CH₂、O、S、NR^k7a；

In some embodiments involving formula (I), each R ^k8 is independently selected from C, N or CH;

In some embodiments involving formula (I), R ^k9 are each independently selected from the group consisting of a bond, C (CH ₃)₂、CO、CH₂、CH₂CH₂ or SO ₂;

in some embodiments involving formula (I), R ^ka is selected from O, S or NH;

In some embodiments involving formula (I), R ^k7a is selected from H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I), R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF ₃、C_1-4 alkyl, C _1-4 alkoxy, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl;

In some embodiments involving formula (I), Selected from one of the structures shown in Table K:

In some embodiments involving formula (I), R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form a C _3-8 carbocyclyl or a 3 to 8 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I), R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form a C _3-6 carbocyclyl or a 4 to 6 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I), R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, said cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl being optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I), R ^z are each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-4 alkylene-C _3-6 cycloalkyl, said alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments involving formula (I), R ^z are each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

in some embodiments involving formula (I), n1 is selected from 0,1, 2, or 3;

In some embodiments involving formula (I), p1 or p2 are each independently selected from 0,1, 2,3,4, 5, or 6;

In some embodiments involving formula (I), p1 or p2 are each independently selected from 0,1, 2, or 3;

In some embodiments involving formula (I), p3 are each independently selected from 0, 1,2, 3, or 4;

Optionally, compounds of formula (I) are contemplated when Y ₃ is selected from one of the following groups optionally substituted with 1 to 4R ^y3: c ₆ -membered carbocyclyl, 5-to 6-membered heteroaryl,

Not optionally substituted

The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I-A),

In some embodiments involving formula (I-a), B is selected from C _6-12 carbocyclyl or 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^b;

In some embodiments involving formula (I-a), B is selected from phenyl, 5 to 6 membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered fused-ring heteroaryl, 9 to 12 membered tri-fused-ring heteroaryl, said B being optionally substituted with 1 to 4R ^b;

in some embodiments involving formula (I-A), B is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolopyridinyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridinyl, pyrazolopyrimidinyl, pyrazolophenyl, pyrazolopyrimidinyl, imidazolyl, pyrrolopyrimidinyl, thiazolopyridinyl, imidazolyl, pyrrolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, and oxazolopyridinyl, Said B is optionally substituted with 1 to 4R ^b;

in some embodiments involving formula (I-A), B is selected from Said B is optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, methyl or ethyl;

In some embodiments involving formula (I-A), each of B ₁ or B ₂ is independently selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl;

In some embodiments involving general formula (I-a), Y ₁ is selected from-N (R ^y1)C(＝O)-、-NHCH₂-、-OCH₂ -or-C (=o) N (R ^y1) -, the right side is attached to ring F;

In some embodiments involving formula (I-a), Y ₁ is selected from-NHC (=o) -or-C (=o) NH-, attached to the right to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I-a), each Y ₂、Y₄ is independently selected from C _1-4 alkylene, said Y ₂ is optionally substituted with 1 to 8R ^y2, said Y ₄ is optionally substituted with 1 to 8R ^y4;

In some embodiments involving formula (I-a), each Y ₂、Y₄ is independently selected from-CH ₂CH₂CH₂-、-CH₂CH₂-、-CH₂ -, said Y ₂ is optionally substituted with 1 to 4R ^y2, said Y ₄ is optionally substituted with 1 to 4R ^y4;

In some embodiments involving formula (I-a), each Y ₂、Y₄ is independently selected from-CH ₂ -or-CH ₂CH₂ -, said Y ₂、Y₄ being optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I-a), -Y ₂-Y₁ -selected from-CH ₂ -C (=o) NH-or-CH ₂ -NHC (=o) -, the left side is directly linked to Y ₃;

In some embodiments involving formula (I-a), Y ₃ is selected from phenyl, 5-to 6-membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4-to 6-membered heterocyclyl, 8-to 10-membered benzocyclic heteroaryl, said Y ₃ being optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I-A), Y ₃ is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, thiophenyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and, Said Y ₃ is optionally substituted with 1 to 4R ^y3; in some embodiments involving formula (I-A), Y ₃ is selected from phenyl, pyridine,Said Y ₃ is optionally substituted with 1 to 4R ^y3;

In some embodiments involving formula (I-a), Y ₅ is selected from C _3-10 cycloalkyl, C _3-10 cycloalkenyl, 4 to 10 membered heterocycloalkenyl, or 4 to 10 membered heterocycloalkyl, said Y ₅ being optionally substituted with 1 to 4R ^y5;

In some embodiments involving formula (I-a), Y ₅ is selected from C _3-7 monocycloalkyl, C _3-7 monocycloalkenyl, C _4-10 and cycloalkyl, C _5-12 spirocycloalkyl, C _5-10 bridged cycloalkyl, 4-7 membered heteromonocycloalkyl, 4-7 membered heteromonocycloalkenyl, 4-10 membered heterocycloalkyl, 5-10 membered heterospirocycloalkyl, 5-10 membered heterobridged cycloalkyl, said Y ₅ being optionally substituted with 1 to 4R ^y5;

In some embodiments involving formula (I-a), Y ₅ is selected from the group consisting of azetidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydroimidazolyl, 2-imidazolidinone, cyclohexenyl, azepinyl, piperidinyl, piperazinyl, said Y ₅ being optionally substituted with 1 to 3R ^y5;

In some embodiments involving formula (I-A), Y ₅ is selected from The Y ₅ is optionally substituted with 1 to 2R ^y5;

in some embodiments involving formula (I-A), Selected from the group consisting of

The left side is directly connected with B;

In some embodiments involving formula (I-a), R ^b、R^y5 are each independently selected from R ^z;

In some embodiments involving formula (I-a), R ^y1 is selected from H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), R ^y1 is selected from H, deuterium, C _1-4 alkyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 6 membered heterocyclyl, said alkyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), R ^y1 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl, said R ^y1 being optionally substituted with 1 to 3R ^z;

In some embodiments, R ^y2、R^y3、R^y4 is each independently selected from deuterium, halogen, =o, OH, NH ₂、NHC_1-6 alkyl, N (C _1-6 alkyl) ₂、CN、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally being substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), R ^y2、R^y3、R^y4、R^b are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、CN、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-7 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), R ^y2、R^y3、R^y4 are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN, or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

In some embodiments involving formula (I-a), R ^y3 is selected from F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, methyl or ethyl;

In some embodiments involving formula (I-A), ring F is selected from C _4-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl;

In some embodiments involving formula (I-A), ring F is selected from the group consisting of C _3-7 Shan Tanhuan-membered, C _4-10 -membered carbocyclyl, C _5-12 -membered spirocarbocyclyl, C _5-10 -bridged carbocyclyl, 4-7-membered heteromonocyclic group, 4-10-membered heterobicyclic group, 8-15-membered tricyclic heterobicyclic group, 12-17-membered tetracyclic heterobicyclic group, 5-17-membered heterospirocyclic group, 5-10-membered heterobridged cyclic group, C _6-14 aryl, 5-10-membered heteroaryl group, Represents a ring selected from aromatic or non-aromatic rings;

In some embodiments involving formula (I-A), F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrimidyl, pyri pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, pyrido-yl, pyrido-pyrazinyl, pyrido-pyrrolyl, and pyrido-pyrrolyl,

The left side of the main body is directly connected with Y ₁;

In some embodiments involving formula (I-A), X ₁ is selected from N or CR ^k3;

In some embodiments involving formula (I-A), X ₁ is selected from N or CH;

In some embodiments involving formula (I-A), Q is selected from the group consisting of a bond, -O-, -S-, -CH ₂-、-NR^q-、-CO-、-NR^qCO-、-CONR^q -, or a 3-12 membered heterocyclyl, said heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I-A), Q is selected from the group consisting of a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

In some embodiments involving formula (I-A), Q is selected from Q ₁ or Q ₂;

In some embodiments involving formula (I-a), R ^q is selected from H, deuterium, or C _1-4 alkyl;

in some embodiments involving formula (I-A), R ^q is selected from H or C _1-4 alkyl;

In some embodiments involving formula (I-A), R ^q is selected from H, methyl, ethyl isopropyl;

in some embodiments involving formula (I-A), Q ₁ is selected from a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

In some embodiments involving formula (I-a), Q ₂ is selected from a bond, CH ₂、O、S、C(＝O)、NHC(＝O)、N(CH₃) C (=o);

in some embodiments involving formula (I-A), each F ₁ or F ₂ is independently selected from phenyl, Pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl;

In some embodiments involving formula (I-a), each F ₃ or F ₄ is independently selected from phenyl, 5-to 6-membered heteroaryl, benzoc _4-6 -membered carbocyclyl, or benzo4-to 6-membered heterocyclyl; in some embodiments involving formula (I-a), each F ₃ or F ₄ is independently selected from phenyl or pyridinyl;

In some embodiments involving formula (I-A), F ₅ is selected from 5-membered heteroaryl;

in some embodiments involving formula (I-A), F ₅ is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl, or pyrazolyl; in some embodiments involving formula (I-a), E is selected from 5 to 6 membered heteroaryl;

in some embodiments involving formula (I-A), E is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;

In some embodiments involving formula (I-a), E ₁ is selected from 5-to 6-membered heteroaryl, benzoc _4-6 -membered carbocyclyl, or benzo4-to 6-membered heterocyclyl; in some embodiments involving formula (I-A), E ₁ is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl,

In some embodiments involving formula (I-a), each R ^k1 is independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), each R ^k1 is independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z;

In some embodiments involving formula (I-a), R ^k1 are each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CF₃、CN、COOH、CONH₂, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂;

In some embodiments involving formula (I-A), R ^k2 are each independently selected from the group consisting of a bond, -CO-, -SO ₂ -, -SO-, or-C (R ^k3)₂ -;

In some embodiments involving formula (I-a), each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, or a 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z; in some embodiments involving formula (I-a), each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or a4 to 6 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z; in some embodiments involving formula (I-a), R ^k3 are each independently selected from H, deuterium, F, cl, br, I, OH, = O, CF ₃, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂;

In some embodiments involving formula (I-a), each R ^k4 is independently selected from H, deuterium, C _1-6 alkyl, -C _0-2 alkylene-C _3-8 cycloalkyl, or-C _0-2 alkylene-3 to 8 membered heterocyclyl, said alkyl, alkylene, cycloalkyl, or heterocyclyl optionally being substituted with 1 to 4R ^z; in some embodiments involving formula (I-a), R ^k4 are each independently selected from H, deuterium, CF ₃, or C _1-4 alkyl; in some embodiments involving formula (I-a), R ^k4 are each independently selected from H, deuterium, CF ₃, methyl;

in some embodiments involving formula (I-A), R ^k5 are each independently selected from C(CH₃)₂、CO、CH₂、CH₂CH₂、SO₂、

In some embodiments involving formula (I-A), R ^k5a are each independently selected fromCH₂CH₂、SO₂、

In some embodiments involving formula (I-a), each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

In some embodiments involving formula (I-A), R ^k7 are each independently selected from C(CH₃)₂、CO、CH、N、CH₂、O、S、NR^k7a；

In some embodiments involving formula (I-a), each R ^k8 is independently selected from C, N or CH;

in some embodiments involving formula (I-A), R ^k9 are each independently selected from the group consisting of a bond, C (CH ₃)₂、CO、CH₂、CH₂CH₂ or SO ₂;

in some embodiments involving formula (I-A), R ^ka is selected from O, S or NH;

In some embodiments involving formula (I-a), R ^k7a is selected from H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from R ^z;

in some embodiments involving formula (I-a), R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF ₃、C_1-4 alkyl, C _1-4 alkoxy, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl;

in some embodiments involving formula (I-A), Selected from one of the structures shown in Table K-A:

in some embodiments involving formula (I-a), R ^k3 and R ^k3、R^k1 are directly linked to R ^k1 to form a C _3-8 carbocyclyl or a 3-to 8-membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I-a), R ^k3 and R ^k3、R^k1 are directly linked to R ^k1 to form a C _3-6 carbocyclyl or a 4 to 6 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I-a), R ^k3 and R ^k3、R^k1 are directly linked to R ^k1 to form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, said cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl being optionally substituted with 1 to 4 substituents selected from R ^z;

In some embodiments involving formula (I-a), R ^z are each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-4 alkylene-C _3-6 cycloalkyl, said alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments involving formula (I-a), R ^z are each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

in some embodiments involving formula (I-A), n1 is selected from 0, 1, 2, or 3;

in some embodiments involving formula (I-A), p1 or p2 are each independently selected from 0,1, 2, 3, 4, 5 or 6;

In some embodiments involving formula (I-A), p1 or p2 are each independently selected from 0,1, 2, or 3;

In some embodiments involving formula (I-A), p3 are each independently selected from 0, 1, 2,3, or 4;

Optionally, the composition may be used in combination with, Not optionally substituted

As a first embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Y ₁ is selected from the group consisting of bond, -N (R ^y1)C(＝O)-、-NHCH₂-、-OCH₂ -or-C (=O) N (R ^y1) -;

y ₂ is selected from C _1-4 alkylene, said Y ₂ optionally substituted with 1 to 4R ^y2;

Y ₃ is selected from C _3-10 carbocyclyl or 4 to 10 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted with 1 to 4R ^y3;

Y ₄ is selected from C _1-4 alkylene or C _1-4 heteroalkylene, said alkylene or heteroalkylene optionally substituted with 1 to 8R ^y4;

b is selected from C _6-12 carbocyclyl or 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^b;

R ^y1 is selected from H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

R ^y2、R^y3、R^y4、R^b is each independently selected from deuterium, halogen, =O, OH, NH ₂、NHC_1-6 alkyl, N (C _1-6 alkyl) ₂、CN、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

X ₁ is selected from N or CR ^k3;

Q is selected from the group consisting of bond, -O-, -S-, -CH ₂-、-NR^q-、-CO-、-NR^qCO-、-CONR^q -, or 3-12 membered heterocyclyl, said heterocyclyl optionally substituted with 1 to 4 substituents selected from R ^z;

R ^q is selected from H, deuterium, or C _1-4 alkyl;

Ring F is selected from C _4-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

R ^k2 is each independently selected from the group consisting of bond, -CO-, -SO ₂ -, -SO-, or-C (R ^k3)₂ -;

R ^k1 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z;

Each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or a 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z;

Alternatively, R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form a C _3-8 carbocyclyl or a 3 to 8 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted with 1 to 4 substituents selected from R ^z;

R ^k4 is each independently selected from H, deuterium, C _1-6 alkyl, -C _0-2 alkylene-C _3-8 cycloalkyl, or-C _0-2 alkylene-3 to 8 membered heterocyclyl, said alkyl, alkylene, cycloalkyl, or heterocyclyl optionally substituted with 1to 4R ^z;

R ^z is each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-4 alkylene-C _3-6 cycloalkyl, said alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

n1 is selected from 0,1,2 or 3;

p1 or p2 are each independently selected from 0, 1,2, 3, 4, 5 or 6;

provided that when Y ₃ is selected from one of the following groups optionally substituted with 1 to 4R ^y3: c ₆ -membered carbocyclyl, 5-to 6-membered heteroaryl,

Not optionally substituted

As a second embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Y ₃ is selected from phenyl, 5 to 6 membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered benzocyclic heteroaryl, said Y ₃ optionally substituted with 1 to 4R ^y3;

Y ₄ is selected from the group consisting of-CH ₂ -described in -CH₂CH₂CH₂-、-CH₂CH₂-、-CH₂-NR^y4C(＝O)-CH₂-、-CH₂-C(＝O)NR^y4-CH₂-、-CH₂-C(＝O)NR^y4、-CH₂CH₂-NR^y4-、-CH₂-C(＝O)-、-CH₂CH₂-NR^y4-CH₂-、-CH₂CH₂-O-CH₂-、-CH₂CH₂-S-CH₂-, -optionally substituted with 1 to 2R ^y4;

B is selected from phenyl, 5 to 6 membered heteroaryl, benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered fused ring heteroaryl, 9 to 12 membered tri fused ring heteroaryl, said B optionally substituted with 1 to 4R ^b;

R ^y1 is selected from H, deuterium, C _1-4 alkyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 6 membered heterocyclyl, said alkyl, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

R ^y2、R^y3、R^y4、R^b is each independently selected from deuterium, halogen, =O, OH, NH ₂、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、CN、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-7 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

Ring F is selected from the group consisting of C _3-7 Shan Tanhuan, C _4-10 carbocyclyl, C _5-12 spiro carbocyclyl, C _5-10 bridged carbocyclyl, 4-7 membered heteromonocyclic group, 4-10 membered heterofused cyclic group, 8-15 membered tricyclic heterofused cyclic group, 12-17 membered tetracyclic heterofused cyclic group, 5-17 membered heterospiro group, 5-10 membered heterobridged cyclic group, C _6-14 aryl group, 5-10 membered heteroaryl group,

Represents a ring selected from aromatic or non-aromatic rings;

Ring E is each independently selected from phenyl, 5 to 6 membered heteroaryl;

Each Q is independently selected from the group consisting of a bond, -O-, -S-, -CH ₂-、-NR^q-、-C(＝O)-、-NR^qC(＝O)-、-C(＝O)NR^q -, or a 4-7 membered heterocyclyl, said heterocyclyl optionally substituted with 1 to 4R ^z;

R ^q is selected from H or C _1-4 alkyl;

R ^k1 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CN、COOH、CONH₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4R ^z;

Each R ^k3 is independently selected from H, deuterium, F, cl, br, I, OH, = O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or a 4 to 6 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from R ^z;

Alternatively, R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form a C _3-6 carbocyclyl or a 4 to 6 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted with 1 to 4 substituents selected from R ^z;

R ^k4 is independently selected from H, deuterium, CF ₃ or C _1-4 alkyl;

R ^k5 are each independently selected from C(CH₃)₂、CO、CH₂、CH₂CH₂、SO₂、

Each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

R ^k7 are each independently selected from C(CH₃)₂、CO、CH、N、CH₂、O、S、NR^k7a；

Each R ^k8 is independently selected from C, N or CH;

R ^k9 are each independently selected from the group consisting of a bond, C (CH ₃)₂、CO、CH₂、CH₂CH₂ or SO ₂;

R ^ka is selected from O, S or NH;

R ^k7a is selected from H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from R ^z;

the remaining definitions are the same as in the first embodiment of the invention.

As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Y ₁ is selected from-NHC (=O) -or-C (=O) NH-, the right side of which is attached to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Y ₂ is selected from-CH ₂ -or-CH ₂CH₂ -, the Y ₂ is optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Y ₃ is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and combinations thereof, Said Y ₃ is optionally substituted with 1 to 4R ^y3;

y ₄ is selected from -CH₂-C(＝O)-、-CH₂-C(＝O)NH-、-CH₂-NHC(＝O)-CH₂-、-CH₂-C(＝O)NH-CH₂-、-CH₂CH₂-NH-CH₂-, and is linked to Y ₃, said-CH ₂ -being optionally substituted with 1 to 2 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolopyridinyl thiazolopyrrolyl, thiazolopyrimidinyl, oxazolopyridinyl, oxazolopyrrolyl, oxazolopyrrol oxazolopyrimidinyl, pyrazolopyridinyl, pyrazolophenyl, pyrazolopyrimidinyl, and, Said B is optionally substituted with 1 to 4R ^b;

B ₁ or B ₂ are each independently selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl;

R ^y2、R^y3、R^y4、R^b are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

q is selected from the group consisting of a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridinyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, and pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, pyridopyrazinyl, and pyridopyrazinyl,

The left side of the main body is directly connected with Y ₁;

E is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;

F ₃ or F ₄ are each independently selected from phenyl, 5 to 6 membered heteroaryl, benzoc _4-6 membered carbocyclyl or benzo4 to 6 membered heterocyclyl;

F ₅ is selected from 5 membered heteroaryl;

E ₁ is selected from 5-to 6-membered heteroaryl, benzoC _4-6 -membered carbocyclyl, or benzo4-to 6-membered heterocyclyl;

r ^k5a are each independently selected from CH₂CH₂、SO₂、

R ^ka is selected from O, S or NH;

R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF ₃、C_1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl;

R ^z is each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

p1 or p2 are each independently selected from 0, 1,2 or 3;

the remaining definitions are the same as in the first or second embodiment of the invention.

As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from the group consisting of

Q ₁ is selected from the group consisting of a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

Q ₂ is selected from a bond, CH ₂、O、S、C(＝O)、NHC(＝O)、N(CH₃) C (=o);

F ₁ or F ₂ are each independently selected from phenyl, Pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl;

f ₃ or F ₄ are each independently selected from phenyl or pyridinyl;

F ₅ is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl or pyrazolyl;

e ₁ is selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, and,

R ^k1 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CF₃、CN、COOH、CONH₂, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂;

r ^k3 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, CF ₃, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂;

R ^k4 is independently selected from H, deuterium, CF ₃ and methyl;

The remaining definitions are the same as in the first, second or third embodiments of the invention.

As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from one of the structures shown in Table K;

B is selected from Said B is optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, methyl or ethyl;

-Y ₂-Y₁ -selected from-CH ₂ -C (=o) NH-or-CH ₂ -NHC (=o) -, the left side being directly linked to Y ₃;

y ₃ is selected from phenyl, pyridine, Said Y ₃ is optionally substituted with 1 to 4R ^y3;

The remaining definitions are the same as in the first, second, third or fourth embodiments of the invention.

As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from the group consisting of

The left side is directly connected with B;

R ^y3 is selected from F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, methyl or ethyl;

p3 are each independently selected from 0,1, 2, 3 or 4;

the remaining definitions are the same as in the first, second, third, fourth or fifth embodiments of the invention.

As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the general formula (I) is selected from the group consisting of general formula (II),

Each R ^k10 is independently selected from C (CH ₃)₂、CO、CH₂;

Y ₅ is selected from one of the following groups optionally substituted with 1 to 4R ^y3: benzoc _4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 8 to 10 membered benzocyclic heteroaryl, preferably one of the following groups optionally substituted with 1 to 4R ^y3:

The remaining definitions are the same as in any of the embodiments of the present invention.

As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I-A) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

Y ₁ is selected from-N (R ^y1)C(＝O)-、-NHCH₂-、-OCH₂ -or-C (=O) N (R ^y1) -, the right side is connected with a ring F;

y ₂、Y₄ are each independently selected from C _1-4 alkylene, said Y ₂ optionally substituted with 1 to 8R ^y2, said Y ₄ optionally substituted with 1 to 8R ^y4;

Y ₅ is selected from C _3-10 cycloalkyl, C _3-10 cycloalkenyl, 4 to 10 membered heterocycloalkenyl, or 4 to 10 membered heterocycloalkyl, said Y ₅ being optionally substituted with 1 to 4R ^y5;

r ^b、R^y5 are each independently selected from R ^z;

R ^y2、R^y3、R^y4 is each independently selected from deuterium, halogen, =O, OH, NH ₂、NHC_1-6 alkyl, N (C _1-6 alkyl) ₂、CN、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -O-C _0-4 alkylene-C _3-10 carbocyclyl, -O-C _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-10 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

X ₁ is selected from N or CR ^k3;

R ^q is selected from H, deuterium, or C _1-4 alkyl;

Alternatively, R ^k3 and R ^k3、R^k1 are directly linked to R ^k1 to form a C _3-8 carbocyclyl or a3 to 8 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

n1 is selected from 0,1,2 or 3;

p1 or p2 are each independently selected from 0, 1,2, 3, 4, 5 or 6;

Provided that the conditions are that, Not optionally substituted

As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula (I-A) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Y ₂、Y₄ are each independently selected from-CH ₂CH₂CH₂-、-CH₂CH₂-、-CH₂ -, said Y ₂ being optionally substituted with 1 to 4R ^y2, said Y ₄ being optionally substituted with 1 to 4R ^y4;

Y ₅ is selected from the group consisting of C _3-7 monocycloalkyl, C _3-7 monocycloalkenyl, C _4-10 cycloalkyl, C _5-12 spirocycloalkyl, C _5-10 bridged cycloalkyl, 4-7 membered heteromonocycloalkyl, 4-7 membered heteromonocycloalkenyl, 4-10 membered heteroacenyl, 5-10 membered heterospirocycloalkyl, 5-10 membered heterobridged cycloalkyl, said Y ₅ being optionally substituted with 1 to 4R ^y5;

R ^y2、R^y3、R^y4 is each independently selected from deuterium, halogen, =O, OH, NH ₂、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、CN、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -O-C _0-2 alkylene-C _3-6 carbocyclyl, -O-C _0-2 alkylene-4 to 7 membered heterocyclyl, -NH-C _0-2 alkylene-C _3-6 carbocyclyl, -NH-C _0-2 alkylene-4 to 7 membered heterocyclyl, -C _0-2 alkylene-C _3-7 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl optionally substituted with 1 to 4R ^z;

Represents a ring selected from aromatic or non-aromatic rings;

Ring E is each independently selected from phenyl, 5 to 6 membered heteroaryl;

R ^q is selected from H or C _1-4 alkyl;

Alternatively, R ^k3 and R ^k3、R^k1 are directly linked to R ^k1 to form a C _3-6 carbocyclyl or a4 to 6 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from R ^z;

R ^k4 is independently selected from H, deuterium, CF ₃ or C _1-4 alkyl;

Each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

Each R ^k8 is independently selected from C, N or CH;

R ^ka is selected from O, S or NH;

The remaining definitions are the same as in the eighth embodiment of the invention.

As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula (I-A) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Y ₁ is selected from-NHC (=O) -or-C (=O) NH-, the right side of which is connected to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

y ₂、Y₄ is each independently selected from-CH ₂ -or-CH ₂CH₂ -, the Y ₂、Y₄ is optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Y ₅ is selected from the group consisting of azetidinyl, pyrrolidinone, pyrrolidinyl, tetrahydroimidazolyl, 2-imidazolidinone, piperidinyl, cyclohexenyl, azepanyl, piperazinyl, said Y ₅ being optionally substituted with 1 to 3R ^y5;

R ^y2、R^y3、R^y4 are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

The left side of the main body is directly connected with Y ₁;

F ₅ is selected from 5 membered heteroaryl;

r ^k5a are each independently selected from CH₂CH₂、SO₂、

R ^ka is selected from O, S or NH;

p1 or p2 are each independently selected from 0, 1,2 or 3;

the remaining definitions are the same as in the eighth or ninth embodiment of the invention.

As an eleventh embodiment of the present invention, the compound represented by the aforementioned general formula (I-A) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from the group consisting of

f ₃ or F ₄ are each independently selected from phenyl or pyridinyl;

R ^k4 is independently selected from H, deuterium, CF ₃ and methyl;

The remaining definitions are the same as in the eighth, ninth or tenth embodiment of the invention.

As a twelfth embodiment of the present invention, the compound represented by the aforementioned general formula (I-A) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from one of the structures shown in Table K-A;

y ₅ is selected from The Y ₅ is optionally substituted with 1 to 2R ^y5;

the remaining definitions are the same as for the eighth, ninth, tenth or eleventh embodiment of the invention.

As a thirteenth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

Selected from the group consisting of

The left side is directly connected with B;

p3 are each independently selected from 0,1, 2, 3 or 4;

The present invention relates to a compound selected from one of the structures of table E below, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition preferably contains 1-1500 mg of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof.

The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic or pharmaceutical composition thereof in preparing medicaments for treating diseases related to c-MYC activity or expression level.

The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic or pharmaceutical composition thereof in preparing medicaments for treating and inhibiting or degrading c-MYC related diseases.

The disease related to inhibiting or degrading c-MYC is cancer.

The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in unit dosage form (the amount of the main drug in a unit dosage form is also referred to as "formulation specification").

The present invention also provides a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal of the present invention comprises a human.

By "effective amount" or "therapeutically effective amount" in the present application is meant that a sufficient amount of a compound of the present disclosure is administered that will alleviate to some extent one or more symptoms of the disease or disorder being treated (e.g., cancer). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound of the present disclosure that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to 1-1500mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1500mg、80-1000mg、80-800mg;

In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500mg、1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg、1000mg a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or pharmaceutical composition thereof, preferably 1-1500mg, said disease preferably being autoimmune disease, inflammatory disease or cancer.

A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof to a subject at a daily dose of 1-1500 mg/day, which may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 600 mg/day, 1000 mg/day, 480 mg/day.

The present invention relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to the amount of the compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

The amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the present invention is in each case converted in the form of the free base.

The synthesis method comprises the following steps:

PG is selected from amino protecting groups;

the definition of the rest groups is consistent with the specification;

The compound of the general formula (Ia-1) and the compound of the general formula (Ia-2) are subjected to condensation reaction or substitution reaction to obtain a compound of the general formula (Ia-3);

removing amino protecting groups from the compound of the general formula (Ia-3) to obtain a compound of the general formula (Ia-4);

The compound of the general formula (Ia-4) and the compound of the general formula (Ia-5) are subjected to condensation reaction or substitution reaction to obtain the compound of the general formula (I).

For the purpose of the present invention, the compounds used in the reactions described herein are prepared starting from commercially available chemicals and/or compounds described in the chemical literature according to organic synthesis techniques known to the person skilled in the art. "commercially available chemicals" are obtained from standard commercial sources, including Shanghai Alasdine Biotechnology Co., ltd., shanghai Michelin Biotechnology Co., sigma-Aldrich, afforesa (China) chemical Co., ltd., boschia (Shanghai) chemical industry development Co., an Naiji chemical, shanghai Teitan technology Co., ltd., kelong chemical, balanwei technology Co., etc.

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

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

"CN" refers to cyano.

"Halogen" means F, cl, br or I.

"Halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, and 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".

"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups 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; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.

"Alkylene" refers to substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radicals including- (CH ₂)_v - (v being an integer from 1 to 10), with alkylene embodiments including but not limited to methylene, ethylene, propylene, butylene, and the like.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. The heterocycloalkyl group may be attached to a heteroatom or carbon atom, the heterocycloalkyl group may be attached to an aromatic ring or to a non-aromatic ring, and the heterocycloalkyl group may be attached to a bridged or spiro ring, non-limiting examples include epoxy ethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocyclylalkyl can be monovalent, divalent, trivalent, or tetravalent

"Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1,2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1,2 or 3 carbon-carbon triple bonds, the backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 1-4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.

"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, 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, to which carbocyclyl may be attached, optionally in the form of a monocyclic, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,"Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and N, S optionally substituted in the heterocyclyl ring may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic or non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include an oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydropyranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzo [ 3.5. 5. Aza ] benzo [3. 5. Aza ] cyclopropyl, 3. 5. Aza ] benzo [3. 5. Cyano, 3. Aza ] pyrrolyl, 3. Aza ] benzo [3. 5. Aza ] pyrrolyl, 5 "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.

"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S (=o) _n. Non-limiting embodiments include:

"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"Fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) _n or O, n being 0, 1, or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

"fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.

"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.

"Carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms.

"Carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms.

"Carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic group" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system.

"Heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom.

"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms.

"Heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.

"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n, n being 0,1, 2), the number of ring atoms in the heteroaryl ring including but not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which includeHeteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.

"Substituted" or "substituted" means substituted with 1 or more (including but not limited to 2,3,4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate 、-(CH₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m- alkenyl-R ^a、OR^d, or- (CH ₂)_m -alkynyl-R ^a (where m, n is 0,1, or 2), arylthio, thiocarbonyl, silane, or-NR ^bR^c, where R ^b and R ^c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively R ^b and R ^c may form a five-or six-membered cycloalkyl or heterocyclyl, each independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, heterocyclyl, cycloalkyl, bridged ring, or spirocyclic.

"1 To X substituents selected from … …" means substituted with 1, 2, 3, … X substituents selected from … …, X being selected from any integer between 1 and 10. For example, "1 to 4 substituents R ^z substituted" means substituted with 1, 2, 3, or 4R ^z. By "the hetero-bridged ring is optionally substituted with 1 to 4 substituents selected from deuterium or F" is meant that the hetero-bridged ring is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium or F.

The X-Y membered ring (X is selected from an integer of 3 or less and Y is selected from any integer of 4 to 12) includes X, X +1, X+2, X+3, X+4 … Y membered rings. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.

"Optional" 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 or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

"Formulation specification" refers to the weight of the principal drug contained in each individual, tablet or other unit of formulation.

By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

"Stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.

"Tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.

Detailed Description

The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using a (Bruker AVANCE III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and an internal standard of Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;

Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.

Reagent abbreviations:

DMF: CAS number: 68-12-2, N-dimethylformamide; NMP: CAS number: 872-50-4, n-methylpyrrolidone;

example 1: preparation of Compound 1

The first step: preparation of Compound 1B

Sodium hydride (1g,25mmol,60%dispersion in mineral oil) was added to a solution of compound 1A (3 g,18 mmol) in DMF (20 mL) in portions, stirred at room temperature for 0.5h, then ethyl bromoacetate (3 g,18 mmol) was added and reacted at room temperature for 2h, then saturated aqueous ammonium chloride solution (50 mL) was added to quench, ethyl acetate (80 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/1) to give compound 1B (4 g, yield 87%)

LCMS m/z＝255.1[M+H]⁺

And a second step of: preparation of Compound 1C

Compound 1B (4 g,15.7 mmol) and NaOH (1.89 g,47.3 mmol) were dissolved with 30mL of water and 30mL of ethanol, the reaction was warmed to 100℃for 2 hours, the reaction solution was cooled to room temperature after TLC detection of completion of the reaction of the starting materials, the solvent was distilled off under reduced pressure, white solid was precipitated when the pH was adjusted to 6-7 with 1M diluted hydrochloric acid, filtered, and dried in a vacuum oven to give Compound 1C (3.2 g, yield 90%) as a white solid

LCMS m/z＝227.1[M+H]⁺

And a third step of: preparation of Compound 1E

Nitric acid (3 g,47.7 mmol) is added dropwise to a solution of compound 1C (5, 29.4 mmol) in glacial acetic acid (60 mL) at 0deg.C, the mixture is stirred for 1h at 50deg.C, cooled to room temperature, filtered with suction, the filter cake is washed with 50% acetic acid, and then recrystallized from methanol to give compound 1E (5.2 g, yield 82%)

LCMS m/z＝213.0[M-H]^-

Fourth step: preparation of Compound 1F

Sodium hydride (230mg,6mmol,60%dispersion in mineral oil) was added in portions to a solution of compound 1E (1.2 g,5.6 mmol) in tetrahydrofuran (50 mL), after stirring at room temperature for 0.5h, 3-bromopiperidine-2, 6-dione (1.08 g,5.6 mmol) was added, warmed to 60℃and reacted for 5h, saturated aqueous ammonium chloride solution (60 mL) was added to quench, ethyl acetate (80 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =1/100-1/10) to give compound 1F (0.8 g, yield 44%).

Fifth step: preparation of Compound 1G

In a 50mL reaction flask, compound 1F (0.8G, 2.46 mmol) was added and dissolved in methanol (20 mL), palladium on carbon (wt% = 10%,80 mg) was added, 1atm hydrogen was displaced 3 times, the reaction was stirred at room temperature overnight, celite was filtered, the filter cake was washed with dichloromethane/methanol (V/v=10/1), and the filtrate was concentrated under reduced pressure to give crude compound 1G (0.65G) which was directly used in the next step.

LCMS m/z＝296.2[M+H]⁺

Sixth step: preparation of Compound 1H

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (770 mg,2.03 mmol) was added to compound 1G (0.5G, 1.69 mmol) and 2- (4- (((t-butoxycarbonyl) amino) methyl) phenyl) acetic acid (0.45G, 1.69 mmol) N, N-dimethylformamide (18 mL), stirred at room temperature for 5min, N, N-diisopropylethylamine (0.66G, 5.07 mmol) was added, stirred at room temperature overnight, 100mL ethyl acetate and 50mL water were added and the layers were separated, and the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) =1/100-1/5) to give compound 1H (0.5G, yield 54.5%).

LCMS m/z＝443.5[M-99]⁺

Seventh step: preparation of hydrochloride of Compound 1I

Compound 1H (0.2 g,0.37 mmol) was dissolved in hydrochloric acid-dioxane solution (15 mL, 4N) and stirred at room temperature for 3H. After completion of the reaction, the mixture was concentrated under reduced pressure to give hydrochloride (0.16 g) of Compound 1I. Directly used in the next step.

LCMS m/z＝443.2[M+H]⁺

Eighth step: preparation of Compound 1

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.17 g,0.44 mmol) was added to hydrochloride of Compound 1I (0.16 g,0.37 mmol) and N, N-dimethylformamide (5 mL) of Compound 1C (83 mg,0.37 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.14 g,1.08 mmol) was added, stirring at room temperature for 2 hours, and after adding 5mL of water, a solid was precipitated, and the obtained crude product was subjected to preparative HPLC (instrument: waters 2767 for preparing a liquid phase; column: XB ridge@PrepC18 (30 mm. Times.150 mm), mobile phase: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) was purified, and the preparation was collected and lyophilized to give trifluoroacetate of Compound 1 (100 mg).

LCMS m/z＝651.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.21–10.99(m,1H),10.32–10.17(m,1H),8.81–8.66(m,1H),8.61–8.50(m,1H),8.50–8.40(m,1H),8.39–8.28(m,1H),8.25–8.17(m,1H),8.17–8.07(m,1H),7.93–7.79(m,1H),7.78–7.66(m,1H),7.63–7.44(m,2H),7.43–7.19(m,6H),7.17–7.05(m,1H),5.53–5.37(m,1H),5.17(s,2H),4.40–4.20(m,2H),3.79(s,2H),3.05–2.87(m,1H),2.85–2.58(m,2H),2.19–2.02(m,1H).

Example 2: preparation of Compound 2

The first step: preparation of Compound 2B

To a single flask, 2A (1 g,3.93 mmol) and 2,6-bis (benzyloxy) -4- (4, 5-tetramethyl-1,3, 2-dioxaborane-2-yl) pyridine (2, 6-bis (benzyloxy) -4- (4, 5-tetramethy-1, 3, 2-dioxaborolan-2-yl) were added under nitrogen protection, dissolved in 50mL dioxane and 10mL water, then 0.32g,0.39 mmol) of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (1.36 g,9.83 mmol) and anhydrous potassium carbonate (1.36 mmol) were added thereto, nitrogen was replaced three times, the temperature was lowered to room temperature, the reaction solution was poured into water (60 mL) and ethyl acetate (60 mL. Times 3) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol V/V) =100/1-100/3) to give compound 2B (1.2 g, yield 73%)

LCMS m/z＝419.1[M+H]⁺

And a second step of: preparation of Compound 2C

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.03 g,2.71 mmol) was added to N, N-dimethylformamide (10 mL) of compound 2B (0.95 g,2.26 mmol) and 2- (4- (((t-butoxycarbonyl) amino) methyl) phenyl) acetic acid (0.6 g,2.26 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.87 g,6.76 mmol) was added, the reaction was carried out at room temperature overnight, 60mL ethyl acetate and 30mL water were added and the layers were separated, and the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) =1/100-1/5) to give compound 2C (1.2 g, yield 80%).

And a third step of: preparation of Compound 2D

In a 50mL reaction flask, compound 2C (1.2 g,0.984 mol) was added to methanol (20 mL), palladium on carbon (wt% = 10%60 mg) and 1atm hydrogen were added to replace 3 times, the reaction was stirred at room temperature overnight, celite was filtered, the filter cake was washed with dichloromethane/methanol (V/v=10/1), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) =1/100-1/5) to give compound 2D (0.45 g, yield 51%).

LCMS m/z＝388.1[M-99]⁺

Fourth step: preparation of hydrochloride salt of Compound 2E

Compound 2D (0.45 g,0.92 mmol) was dissolved in hydrochloric acid-dioxane solution (15 mL, 4N) and stirred at room temperature for 3h. After completion of the reaction, the mixture was concentrated under reduced pressure to give hydrochloride (0.36 g) of Compound 2E, which was used directly in the next step.

Fifth step: preparation of Compound 2

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.4 g,1.06 mmol) was added to hydrochloride of Compound 2E (0.34 g,0.88 mmol) and N, N-dimethylformamide (5 mL) of Compound 1C (0.2 g,0.88 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.34 g,2.63 mmol) was added, and after adding 5mL of water, a solid was precipitated, and the obtained crude product was slurried with dichloromethane (5 mL) to give Compound 2 (0.2 g, yield 38%).

LCMS m/z＝596.7[M+H]⁺

Example 3: preparation of Compound 3

The first step: preparation of Compound 3B

Potassium carbonate (4.77 g,34.5 mmol) and methyl iodide (0.98 g,6.90 mmol) were added to a solution of compound 3A (2 g,6.90 mmol) in DMF (20 mL), stirred at 60℃for 3 hours, cooled to room temperature, water (50 mL) and ethyl acetate (50 mL. Times.3) were added to extract, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/10) to give compound 3B (1.3 g, yield 62%).

LCMS m/z＝304.1[M+H]⁺

And a second step of: preparation of Compound 3C

To a 50mL single-necked flask under nitrogen atmosphere, compound 3B (1 g,3.30 mmol) and 2, 6-dimethoxypyridine-3-boronic acid (0.72 g,3.96 mmol) were added, dissolved in 18mL dioxane and 3mL water, and then [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (0.16 g,0.20 mmol) and anhydrous potassium carbonate (3.23 g,9.90 mmol) were added thereto, the mixture was replaced with nitrogen gas three times, reacted with an oil bath at 80℃for 16 hours, cooled to room temperature, the reaction solution was poured into water (60 mL) and ethyl acetate (60 mL. Times.3) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/10) to give compound 3C (0.7 g, yield 67%).

LCMS m/z＝315.1[M+H]⁺

And a third step of: preparation of Compound 3D

Concentrated hydrochloric acid (8 mL) and glacial acetic acid (8 mL) were added dropwise to compound 3C (0.8 g,2.55 mmol) at room temperature, the mixture was stirred at 140 ℃ for 4h, cooled to room temperature, the reaction mixture was concentrated, slurried with ethyl acetate, suction filtered, the filter cake washed once with ethyl acetate, and concentrated and dried to give compound 3D (0.7 g, yield 96%).

LCMS m/z＝287.1[M+H]⁺

Fourth step: preparation of Compound 3E

In a 50mL reaction flask, compound 3D (0.5 g,1.75 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), palladium on carbon (wt% = 10%,0.5 g) was added, hydrogen (hydrogen balloon) was displaced 3 times, the reaction was stirred overnight at 40 ℃, celite was filtered, the filter cake was washed with dichloromethane/methanol (V/v=10/1), and the filtrate was concentrated under reduced pressure to give compound 3E (0.36 g) which was directly used in the next step.

LCMS m/z＝259.2[M+H]⁺

Fifth step: preparation of Compound 3F

2- (7-Azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (1.06 g,2.78 mmol) was added to compound 3E (0.36 g,1.39 mmol) and 2- (4- (((t-butoxycarbonyl) amino) methyl) phenyl) acetic acid (0.41 g,1.53 mmol) N, N-dimethylformamide (10 mL), stirred at room temperature for 5min, N-diisopropylethylamine (0.54 g,4.17 mmol) was added, stirred at room temperature for 16h, ethyl acetate and 30mL water were added and the layers separated, and the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =1/100-1/20) to give compound 3F (0.4 g, yield 57%).

LCMS m/z＝450.2[M-55]⁺

Sixth step: preparation of Compound 3G hydrochloride

Compound 3F (0.4 g,0.79 mmol) was dissolved in hydrochloric acid-dioxane solution (15 mL, 4N) and stirred at room temperature for 3h. After the completion of the reaction, the mixture was concentrated under reduced pressure to give 3G hydrochloride (0.3G) which was used directly in the next step.

LCMS m/z＝406.2[M+H]⁺

Seventh step: preparation of Compound 3

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.34G, 0.89 mmol) was added to N, N-dimethylformamide (6 mL) of Compound 3G hydrochloride (0.30G, 0.74 mmol) and Compound 1C (0.17G, 0.74 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.48G, 3.69 mmol) was added, after stirring at room temperature for 1h, a solid was precipitated after adding 10mL of water, and the obtained crude product was subjected to preparative HPLC (instrument: waters 2767 for preparing a liquid phase; column: xbridge@PrepC18 (30 mm. Times.150 mm), mobile phase: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) was purified, and the preparation was collected and lyophilized to give trifluoroacetate (100 mg) of Compound 3.

LCMS m/z＝614.3[M+H]⁺

Example 4: preparation of Compound 4

The first step: preparation of Compound 4B

Palladium acetate (97 mg,0.43 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.50 g,0.87 mmol) and triethylamine (4.39 mg,43.35 mmol) were added to a solution of compound 4A (2 g,8.67 mmol) in acetonitrile (60 mL), after three carbon monoxide substitutions, the mixture was stirred for 15 hours at 80℃and cooled to room temperature, celite was filtered, the organic phase was concentrated under reduced pressure, and the residue was purified with a reverse phase column to give compound 4B (1.5 g, yield 89%).

LCMS m/z＝193.9[M-H]^-

And a second step of: preparation of Compound 4C

To a 50mL single-necked flask, compound 4B (1.5 g,7.69 mmol) was added, and the mixture was dissolved in 20mL of ethanol, then hydrazine hydrate (0.77 g,15.38 mmol) was added thereto, and after reaction in an oil bath at 80℃for 3 hours, the temperature was lowered to room temperature, the reaction solution was concentrated, water was added, the solid was separated out, and the filter cake was washed with water, and concentrated under reduced pressure and dried to give Compound 4C (1 g, yield 68%).

LCMS m/z＝190.1[M-H]^-

And a third step of: preparation of Compound 4D

Sodium hydride (280mg,7.06mmol,60%dispersion in mineral oil) was added in portions to a solution of compound 4C (0.9 g,4.71 mmol) in DMF (15 mL) under ice-bath, stirred in ice-bath for 0.5h, 3-bromopiperidine-2, 6-dione (1.36 g,7.06 mmol) in DMF (5 mL) was added, the reaction was warmed to 80 ℃ for 15h, cooled to room temperature, quenched with saturated aqueous ammonium chloride (60 mL), ethyl acetate (30 ml×3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) =1/100-1/30) to give compound 4D (0.45 g, yield 32%).

Fourth step: preparation of Compound 4E

In a 50mL reaction flask, compound 4D (0.45 g,1.49 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), palladium on carbon (wt% = 10%,0.18 g) was added, hydrogen (hydrogen balloon) was substituted 3 times, the reaction was stirred at room temperature overnight, celite was filtered, the filter cake was washed with dichloromethane/methanol (V/v=10/1), and the filtrate was concentrated under reduced pressure to give compound 4E (0.18 g) which was directly used in the next step.

LCMS m/z＝273.3[M+H]⁺

Fifth step: preparation of Compound 4F

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.50 g,1.32 mmol) was added to N, N-dimethylformamide (8 mL) of compound 4E (0.18 g,0.66 mmol) and 2- (4- (((t-butoxycarbonyl) amino) methyl) phenyl) acetic acid (0.18 g,0.66 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.26 g,1.98 mmol) was added, and after stirring at room temperature for 16h, 50mL of ethyl acetate and 30mL of water were added, and the layers were separated, and the organic layer was dried under reduced pressure, and the residue was purified by a reverse phase column to give compound 4F (0.24 g, yield 70%).

LCMS m/z＝518.5[M-H]^-

Sixth step: preparation of Compound 4G hydrochloride

Compound 4F (0.24 g,0.46 mmol) was dissolved in hydrochloric acid-dioxane solution (10 mL, 4N) and stirred at room temperature for 3h. After completion of the reaction, the mixture was concentrated under reduced pressure to give Compound 4G hydrochloride (0.19G) which was used directly in the next step.

Seventh step: preparation of Compound 4

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.21G, 0.54 mmol) was added to N, N-dimethylformamide (5 mL) of Compound 4G hydrochloride (0.19G, 0.45 mmol) and Compound 1C (0.10G, 0.45 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.29G, 2.25 mmol) was added, and after stirring at room temperature for 1h, 10mL of water was added to precipitate a solid which was dried (70 mg).

LCMS m/z＝628.3[M+H]⁺

Example 5: preparation of Compound 5

The first step: preparation of Compound 5B

N, N-diisopropylethylamine (10.35 g,80.08 mmol) and methylamine hydrochloride (2.70 g,40.04 mmol) were added to a solution of Compound 5A (3.7 g,20.02 mmol) in NMP (30 mL), and after heating to 120℃and stirring for 48 hours, cooled to room temperature, water was added, pH was adjusted to about 3 with concentrated hydrochloric acid, solids were precipitated, filtered, the cake was washed twice with water, concentrated under reduced pressure and dried to give Compound 5B (2.5 g, yield 64%).

LCMS m/z＝197.1[M+H]⁺

And a second step of: preparation of Compound 5C

In a 50mL single flask, compound 5B (2 g,10.20 mmol) was dissolved in 10mL t-butanol, then N, N-diisopropylethylamine (3.95 g,30.60 mmol) and diphenyl azide phosphate (3.37 g,12.24 mmol) were added thereto, and after an oil bath reaction at 90℃for 16 hours, the reaction solution was cooled to room temperature and filtered directly, and the cake was concentrated under reduced pressure and dried to give Compound 5C (1.6 g, yield 81%).

LCMS m/z＝194.1[M+H]⁺

And a third step of: preparation of Compound 5D

Sodium hydride (0.42g,10.56mmol,60%dispersion in mineral oil) was added in portions to a solution of compound 5C (1.7 g,8.80 mmol) in DMF (30 mL) under ice-bath stirring for 0.5h, 3-bromopiperidine-2, 6-dione (3.38 g,17.6 mmol) in DMF (10 mL) was added, the temperature was raised to 80℃and the reaction was allowed to react for 15h, cooled to room temperature, quenched with saturated aqueous ammonium chloride (80 mL), ethyl acetate (40 mL. Times.3) was added, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by slurrying with dichloromethane to give compound 5D (1.6 g, 60% yield).

Fourth step: preparation of Compound 5E

In a 100mL reaction flask, compound 5D (0.8 g,2.63 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), palladium on carbon (wt% = 10%,0.20 g) was added, hydrogen (hydrogen balloon) was displaced 3 times, the reaction was stirred at room temperature overnight, celite was filtered, the filter cake was washed with dichloromethane/methanol (V/v=10/1), and the filtrate was concentrated under reduced pressure to give crude compound 5E (0.59 g) which was directly used in the next step.

LCMS m/z＝275.2[M+H]⁺

Fifth step: preparation of Compound 5F

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.63 g,4.3 mmol) was added to N, N-dimethylformamide (10 mL) of compound 5E (0.59 g,2.15 mmol) and 2- (4- (((t-butoxycarbonyl) amino) methyl) phenyl) acetic acid (0.63 g,2.37 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.83 g,6.45 mmol) was added, and after stirring at room temperature for 16h, 50mL of ethyl acetate and 30mL of water were added and the layers were separated, and the organic layer was dried under reduced pressure, and the residue was purified by a reverse phase column to give compound 5F (0.23 g, yield 21%).

LCMS m/z＝520.5[M-H]^-

Sixth step: preparation of Compound 5G hydrochloride

Compound 5F (0.23 g,0.44 mmol) was dissolved in hydrochloric acid-dioxane solution (10 mL, 4N) and stirred at room temperature for 3h. After completion of the reaction, the mixture was concentrated under reduced pressure to give Compound 5G hydrochloride (0.18G). Directly used in the next step.

Seventh step: preparation of Compound 5

2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.20G, 0.52 mmol) was added to N, N-dimethylformamide (5 mL) of Compound 5G hydrochloride (0.18G, 0.43 mmol) and Compound 1C (0.097G, 0.43 mmol), after stirring at room temperature for 5min, N, N-diisopropylethylamine (0.28G, 2.15 mmol) was added, and after stirring at room temperature for 1h, 10mL of water was added to precipitate a solid which was dried (160 mg).

LCMS m/z＝630.60[M+H]⁺

Example 6: preparation of Compound B-1

The first step: preparation of Compound B-1B

Methyl 2-methyl-4-nitrobenzoate (4.0 g,20.49 mmol), NBS (4.81 g,27.05 mmol) and benzoyl peroxide (0.15 g,0.61 mmol) were mixed in a solution of carbon tetrachloride (80 mL), stirred at 80℃for 16h, quenched with saturated aqueous sodium chloride (80 mL), extracted with methylene chloride (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100 to 1/5) to give compound B-1B (5.86 g) which was directly taken for the next reaction.

LCMS m/z＝274.0[M+H]⁺

And a second step of: preparation of Compound B-1C

Compound B-1B (2.0 g,7.30 mmol), 3-amino-2, 6-piperidinedione hydrochloride (0.94 g,7.30 mmol) and N, N-diisopropylethylamine (2.97 g,22.99 mmol) were mixed in acetonitrile (80 mL), stirred at 80℃for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (acetonitrile/dichloromethane (v/v) =1/100 to 1/3) to give compound B-1C (1.2 g, yield: 57%).

LCMS m/z＝290.1[M+H]⁺

And a third step of: preparation of Compound B-1D

Compound B-1C (1.2 g,4.63 mmol) and palladium on carbon (0.3 g,10% wt) were mixed in a solution of N, N-dimethylformamide (20 mL), the mixture was stirred at room temperature for 16h after three times of hydrogen substitution, the reaction mixture was suction-filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) =1/100-3/100) to give compound B-1D (0.2 g, yield: 17%).

LCMS m/z＝260.2[M+H]⁺

Fourth step: preparation of Compounds B-1F

3, 4-Dichlorobromobenzene (1.13 g,4.99 mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (1.70 g,5.49 mmol), potassium phosphate (1.59 g,7.49 mmol) and tetraphenylphosphine palladium (1.13 g,4.99 mmol) were mixed in a solution of 1, 4-dioxane/water (10 mL, v/v=4/1), the mixture was stirred at 85℃for 16h after three nitrogen substitutions, the reaction solution was suction-filtered with celite, water (80 mL), ethyl acetate (100 mL×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-30/100) to give compound B-1F (1.75 g) which was directly used in the next step.

Fifth step: preparation of Compound B-1G

Compound B-1F (0.90 g,2.74 mmol) and trifluoroacetic acid (2 mL) are uniformly mixed in a solution of dichloromethane (10 mL), the mixture is stirred at room temperature for 2h after nitrogen substitution for three times, the pH of the reaction solution is regulated to be about 13 by saturated sodium bicarbonate aqueous solution, dichloromethane (100 mL multiplied by 2) is used for extraction, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate and then concentrated under reduced pressure to obtain an intermediate crude product, and the intermediate crude product is directly put into a next step for reaction.

The crude intermediate obtained above, methyl 4-formylphenylacetate (270 mg,1.52 mmol) and glacial acetic acid (90 mg,1.52 mmol) were mixed in a solution of dichloromethane (10 mL), and after three times of nitrogen substitution, the mixture was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (640 mg,3.01 mmol) was added in portions, and after the addition was completed, the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered with celite, 2N sodium hydroxide solution (10 mL) was added, dichloromethane (30 ml×2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/3) to give compound B-1G (423 mg, yield: 71%).

LCMS m/z＝390.1[M+H]⁺

Sixth step: preparation of Compound B-1H

Compound B-1G (423 mg,1.08 mmol) and lithium hydroxide monohydrate (180 mg,4.29 mmol) were mixed and stirred in a solution of tetrahydrofuran/water (10 mL, v/v=1/1) for 3 hours at room temperature after three times of nitrogen substitution, the reaction mixture was adjusted to pH 3 with a 1N diluted hydrochloric acid solution, extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound B-1H (450 mg) which was directly added to the next reaction.

LCMS m/z＝376.1[M+H]⁺

Seventh step: preparation of Compound B-1

Compound B-1H (100 mg,0.27 mmol), DIPEA (350 mg,2.71 mmol) and HATU (210 mg,0.55 mmol) were mixed and stirred at room temperature for 10 minutes in N, N-dimethylformamide (10 mL), compound B-1D (70 mg,0.27 mmol) was added, after three nitrogen substitutions, and stirred at room temperature for 16 hours, ethyl acetate (60 mL) was added to the reaction mixture, which was then washed successively with water (60 mL. Times.2) and saturated brine (60 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) =1/100-1/20) to give crude compound 1 (76 mg) which was then purified by preparative liquid phase separation (instrument: waters 2767 to prepare liquid phase; column: XB@PrepC18 (30 mm. Times.150 mm), mobile phase composition: mobile phase: acetonitrile; mobile phase B: water (0.1%) and trifluoroacetic acid) to obtain a lyophilized compound B (40 mg).

LCMS m/z＝617.2[M+H]⁺

Example 7: preparation of Compound B-2

The first step: preparation of Compound B-2B

3, 4-Dichlorobenzene (1.13 g,4.99 mmol), tert-butyl piperazine-1-carboxylate (0.93 mg,4.99 mmol), palladium acetate (45 mg,0.20 mmol), BINAP (0.19 g,0.30 mmol), sodium t-butoxide (0.72 g,7.49 mmol) were mixed in a solution of 1, 4-dioxane (15 mL), after three times of nitrogen substitution, the reaction was stirred at 85℃for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/20) to give compound B-2B (1.51 g, yield: 91%).

And a second step of: preparation of Compound B-2C

Compound B-2B (1.50 g,2.74 mmol) and trifluoroacetic acid (5 mL) were mixed and reacted in a solution of dichloromethane (15 mL) under stirring at room temperature for 2h after three times of nitrogen substitution, the reaction solution was adjusted to pH about 13 with saturated sodium bicarbonate solution, dichloromethane (100 mL. Times.2) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude intermediate for use.

The crude intermediate obtained above, methyl 4-formylphenylacetate (710 mg,3.98 mmol) and glacial acetic acid (240 mg,3.99 mmol) were mixed in a solution of dichloromethane (10 mL), and after three times of nitrogen substitution, the mixture was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (2.50 g,11.78 mmol) was added in portions, and after the addition, the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered with celite, 2N sodium hydroxide solution (10 mL) was added, dichloromethane (30 ml×2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100-1/3) to give compound B-2C (920 mg, yield: 58%).

LCMS m/z＝393.10[M+H]⁺

And a third step of: preparation of Compound B-2D

Compound B-2C (920 mg,2.34 mmol) and lithium hydroxide monohydrate (360 mg,8.58 mmol) were mixed and stirred at room temperature for 3 hours after three times of nitrogen substitution in a solution of tetrahydrofuran/water (10 mL, v/v=1/1), the pH of the reaction solution was adjusted to about 3 with a 1N diluted hydrochloric acid solution, ethyl acetate (100 mL. Times.2) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound B-2D (905 mg) which was directly cast into the next reaction.

LCMS m/z＝379.1[M+H]⁺

Fourth step: preparation of Compound B-2

Compound B-2D (110 mg,0.29 mmol), DIPEA (190 mg,1.45 mmol) and HATU (220 mg,0.58 mmol) were mixed and stirred at room temperature for 10 minutes in N, N-dimethylformamide (10 mL), compound B-1D (70 mg,0.27 mmol) was added, after three nitrogen substitutions, and stirred at room temperature for 16 hours, ethyl acetate (60 mL) was added to the reaction mixture, which was then washed with water (60 mL. Times.2) and saturated brine (60 mL. Times.1) in this order, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) =1/100-1/20) to give crude compound 2, which was prepared by preparative liquid phase separation and purification (instrument: waters 2767; column: xbridge@PrepC18 (30 mm. Times.150 mm), mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (0.1% trifluoroacetic acid)), and lyophilized to give trifluoroacetate (77 mg) of compound B-2.

LCMS m/z＝620.1[M+H]⁺

Biological test case

Test example 1: proliferation inhibitory Activity against human promyelocytic leukemia cell HL60

Human promyelocytic leukemia cells HL60 were purchased from ATCC and cultured in IMDM+20% FBS at 37deg.C in 5% CO ₂ incubator. Cells in exponential growth phase were collected on the first day, cell suspensions were plated at the corresponding concentrations with complete medium to 20000 cells/well, 80 μl per well, followed by 20 μl of different concentrations of compound, and incubated in a CO ₂ incubator for further 3 days. After the completion of the incubation, 50. Mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes at room temperature, the fluorescence signal value was measured with an enzyme-labeled instrument (PHERASTAR FSX). Chemiluminescence readings were plotted using GRAPHPAD PRIM 8.0.0 software using a four parameter nonlinear regression model to plot S-type concentration curves and calculate IC ₅₀ values. As a result, the inhibition ratios of the respective concentrations of the compounds were calculated by the treatment of the formula (1), and IC ₅₀ values of the concentrations of the compounds were calculated at a proliferation ratio of 50% using GRAPHPAD PRIM 8.0.0 software. Where RLU _compound is a readout of the drug-treated group and RLU _control is an average of the solvent control group.

Growth% = (RLU _compound/RLU_control ×100)% formula (1)

TABLE 1 results of test Compounds for proliferation inhibitory Activity on HL60 cells

Note that: in Table 1A < 0.1. Mu.M, 0.1. Mu.M.ltoreq.B < 0.5. Mu.M, 0.5. Mu.M.ltoreq.C

Conclusion: the compound has good proliferation inhibition activity on human promyelocytic leukemia cells HL 60.

Claims

1. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),

X ₁ is selected from N or CR ^k3;

R ^q is selected from H, deuterium, or C _1-4 alkyl;

n1 is selected from 0,1,2 or 3;

p1 or p2 are each independently selected from 0, 1,2, 3, 4, 5 or 6;

Not optionally substituted

2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

y ₄ is selected from -CH₂CH₂CH₂-、-CH₂CH₂-、-CH₂-NR^y4C(＝O)-CH₂-、-CH₂-C(＝O)NR^y4-CH₂-、-CH₂-C(＝O)NR^y4、

-CH₂CH₂-NR^y4-、-CH₂-C(＝O)-、-CH₂CH₂-NR^y4-CH₂-、-CH₂CH₂-O-CH₂-、-CH₂CH₂-S-CH₂-, -CH ₂ -optionally substituted with 1 to 2R ^y4;

Represents a ring selected from aromatic or non-aromatic rings;

Ring E is each independently selected from phenyl, 5 to 6 membered heteroaryl;

R ^q is selected from H or C _1-4 alkyl;

Alternatively, R ^k3 and R ^k3、R^k1 and R ^k1、R^y2 and R ^y2 or R ^y4 and R ^y4 are directly linked to form a C _3-6 carbocyclyl or a4 to 6 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted with 1 to 4 substituents selected from R ^z;

R ^k4 is independently selected from H, deuterium, CF ₃ or C _1-4 alkyl;

Each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

Each R ^k8 is independently selected from C, N or CH;

R ^ka is selected from O, S or NH;

R ^k7a is selected from H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from R ^z.

Preferably, Y ₁ is selected from-NHC (=o) -or-C (=o) NH-, attached to the right to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Preferably, Y ₂ is selected from-CH ₂ -or-CH ₂CH₂ -, the Y ₂ is optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Preferably, Y ₃ is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, Said Y ₃ is optionally substituted with 1 to 4R ^y3;

Preferably Y ₄ is selected from -CH₂-C(＝O)-、-CH₂-C(＝O)NH-、-CH₂-NHC(＝O)-CH₂-、-CH₂-C(＝O)NH-CH₂-、-CH₂CH₂-NH-CH₂-, to Y ₃, said-CH ₂ -being optionally substituted with 1 to 2 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

preferably, B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolopyridinyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridinyl, oxazolopyrimidinyl, pyrazolopyridinyl, pyrazolophenyl, pyrazolopyrimidinyl, thiazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and combinations thereof, Said B is optionally substituted with 1 to 4R ^b;

Preferably, B ₁ or B ₂ are each independently selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl;

Preferably, R ^y2、R^y3、R^y4、R^b are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN, or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

preferably, Q is selected from the group consisting of a bond, CH ₂、NH、N(CH₃)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃),

Preferably, the method comprises the steps of, F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrimidyl, pyri pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, pyridopyrazinyl, and pyridopyrazinyl, The left side of the main body is directly connected with Y ₁;

F ₅ is selected from 5 membered heteroaryl;

r ^k5a are each independently selected from CH₂CH₂、SO₂、

R ^ka is selected from O, S or NH;

Preferably, R ^z are each independently selected from deuterium, F, cl, br, I, OH, = O, CF ₃、CN、NH₂、COOH、CONH₂, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy;

preferably, p1 or p2 are each independently selected from 0, 1,2 or 3.

3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

Selected from the group consisting of

f ₃ or F ₄ are each independently selected from phenyl or pyridinyl;

R ^k4 is independently selected from H, deuterium, CF ₃ and methyl.

Preferably, the method comprises the steps of,Selected from one of the structures shown in Table K;

Table K

Preferably, B is selected fromSaid B is optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, methyl or ethyl;

Preferably, -Y ₂-Y₁ -is selected from-CH ₂ -C (=o) NH-or-CH ₂ -NHC (=o) -, the left side being directly linked to Y ₃;

preferably, Y ₃ is selected from phenyl, pyridine, The Y ₃ is optionally substituted with 1 to 4R ^y3.

4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

Selected from the group consisting of

The left side is directly connected with B;

p3 is each independently selected from 0,1, 2, 3 or 4.

5. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds represented by the general formula (I-A),

r ^b、R^y5 are each independently selected from R ^z;

X ₁ is selected from N or CR ^k3;

R ^q is selected from H, deuterium, or C _1-4 alkyl;

n1 is selected from 0,1,2 or 3;

p1 or p2 are each independently selected from 0, 1,2, 3, 4, 5 or 6;

Provided that the conditions are that, Not optionally substituted

6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

Represents a ring selected from aromatic or non-aromatic rings;

Ring E is each independently selected from phenyl, 5 to 6 membered heteroaryl;

R ^q is selected from H or C _1-4 alkyl;

R ^k4 is independently selected from H, deuterium, CF ₃ or C _1-4 alkyl;

Each R ^k6 is independently selected from CO, CH, SO, SO ₂、CH₂ or N;

Each R ^k8 is independently selected from C, N or CH;

R ^ka is selected from O, S or NH;

Preferably, Y ₁ is selected from-NHC (=o) -or-C (=o) NH-, the right side being attached to ring F, said NH being optionally substituted with 1 substituent selected from methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Preferably, Y ₂、Y₄ is each independently selected from-CH ₂ -or-CH ₂CH₂ -, the Y ₂、Y₄ is optionally substituted with 1 to 4 substituents selected from F, cl, br, methyl, CF ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Preferably, Y ₅ is selected from the group consisting of azetidinyl, pyrrolidone, pyrrolidinyl, tetrahydroimidazolyl, 2-imidazolidinone, piperidinyl, cyclohexenyl, azepinyl, piperazinyl, said Y ₅ being optionally substituted with 1 to 3R ^y5;

Preferably, R ^y2、R^y3、R^y4 are each independently selected from deuterium, halogen, =o, OH, NH ₂、NHCH₃、N(CH₃)₂, CN, or one of the following groups optionally substituted with 1 to 4R ^z: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl;

Preferably, the method comprises the steps of, F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrimidyl, pyri pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, pyridopyrazinyl, and pyridopyrazinyl,

The left side of the main body is directly connected with Y ₁;

F ₅ is selected from 5 membered heteroaryl;

r ^k5a are each independently selected from CH₂CH₂、SO₂、

R ^ka is selected from O, S or NH;

Preferably, p1 or p2 are each independently selected from 0, 1, 2 or 3;

more preferably, the process is carried out, Selected from the group consisting of

Q ₁ is selected from a bond, CH ₂、NH、N(CH₃), O, S, C (=o), NHC (=o),

C(＝O)NH、N(CH₃)C(＝O)、C(＝O)N(CH₃)、

Q ₂ is selected from a bond, CH ₂、O、S、C(＝O)、NHC(＝O)、N(CH₃)C(＝O),F₁ or F ₂ each independently selected from phenyl, Pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridothiazolyl, pyridooxazolyl, pyridofuranyl, F ₃ or F ₄ are each independently selected from phenyl or pyridyl, F ₅ is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl or pyrazolyl, E ₁ is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl,R ^k1 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, NH ₂、CF₃、CN、COOH、CONH₂, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂, R ^k3 is each independently selected from H, deuterium, F, cl, br, I, OH, = O, CF ₃, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH ₂, R ^k4 is each independently selected from H, deuterium, CF ₃, methyl.

7. The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

Selected from one of the structures shown in Table K-A;

Table K-A

B is selected fromSaid B is optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, COOH, CN, NH ₂、CF₃, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, methyl or ethyl;

y ₅ is selected from The Y ₅ is optionally substituted with 1 to 2R ^y5.

8. A compound selected from one of the structures shown in table E, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof;

9. a pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably wherein the pharmaceutical composition comprises 1 to 1500mg of a compound according to any one of claims 1 to 8 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

10. Use of a compound according to any one of claims 1-8 or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of a disease associated with c-MYC activity or expression level, preferably for the manufacture of a medicament for the treatment and inhibition or degradation of a c-MYC associated disease (e.g. cancer).