CN115340552A - Heterocyclic derivative and application thereof in medicine - Google Patents

Abstract

The present invention relates to a compound described in general formula (I) or (II) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate The body and preparation method, as well as the application in the preparation of medicines for treating diseases related to RET activity or expression.

Description

A kind of heterocyclic derivative and its application in medicine

technical field

The present invention relates to a compound described in general formula (I) or (II) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate Body and preparation method, and application in preparation of medicines for treating diseases related to RET activity or expression

Background technique

RET is a relatively rare oncogene located on the long arm of human chromosome 10, which encodes a receptor tyrosine kinase that spans both sides of the cell membrane. Receptor tyrosine kinases are the largest class of enzyme-linked receptors, which are both receptors and enzymes, capable of binding to ligands, phosphorylating tyrosine residues of target proteins, and then interacting with signaling proteins in cells Combination, amplifies information through a variety of different signal transduction pathways, activates a series of biochemical reactions in cells; or combines different information to cause a comprehensive response of cells, such as cell proliferation. Once dysregulation of receptor tyrosine kinases can cause tumorigenesis.

The activated RET protein can activate multiple downstream signaling pathways, including RAS/RAF/ERK pathway, PI3K/Akt pathway, JNK pathway, etc., resulting in cell proliferation, migration and differentiation. RET gene alteration (mutation or fusion) and abnormal expression of wild-type RET gene lead to abnormal activation of RET protein and overactive signaling pathway, which is also one of the main mechanisms of carcinogenesis. Abnormally activated RET protein participates in the proliferation and invasion of different tumor cells through various signaling pathways, thereby affecting the occurrence and development of tumors. Therefore, inhibition of RET activity has great medical value.

The present invention develops a RET inhibitor with novel structure, good efficacy and safety, which is used for treating diseases related to RET such as IBS, tumor or autoimmune system diseases.

Contents of the invention

The invention provides a RET inhibitor with novel structure, good drug efficacy and safety, which is used for treating RET-related diseases such as IBS, tumor or autoimmune system diseases.

The compound of the present invention has good pharmacokinetic performance and bioavailability, has oral performance and good safety.

The present invention provides a compound described in general formula (I) or (II) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

表示环为芳香环；

Indicates that the ring is an aromatic ring;

In some embodiments, Z ₁ , Z ₂ , Z ₃ , Z ₆ or Z ₇ are each independently selected from CR ^z , NR ^z or N;

In some embodiments, Z ₁ , Z ₃ are selected from N, Z ₆ is each independently selected from CR ^z or N, and Z ₇ is selected from NR ^z ;

In some embodiments, Z ₁ , Z ₃ are selected from N, Z ₆ are each independently selected from CH or N, and Z ₇ is selected from NR ^z ;

_In some embodiments, each Z is independently selected from CR ^z or N;

_In some embodiments, each Z is independently selected from CH or N;

_In some embodiments, Z or Z are each independently selected from C or N _;

_In some embodiments, Z or Z are each independently selected from C _;

In some embodiments, A ₁ , A ₂ , A ₃ or A ₄ are each independently selected from CR ^a or N;

In some embodiments, Ring A is selected from

In some embodiments, each ring B is independently selected from a benzene ring or a 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, each ring B is independently selected from phenyl, pyridine, pyrazine, pyrimidine;

In some embodiments, ring B is selected from phenyl;

In some embodiments, each R ^z is independently selected from H, halogen, OH, =O, cyano, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 Alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkyl, CONH ₂ , CONHC _1-6 alkyl, COC _1-6 alkyl, CON(C _{1- 6} alkyl) ₂ , said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, NH ₂ , C ₁ Substituents of _-6 alkyl, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkyl, halogen substituted C _1-6 alkyl or C _1-6 alkoxy;

In some embodiments, each R ^z is independently selected from H, C _1-4 alkyl, COC _1-6 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, CONH ₂ , CONHC _1-4 alkyl, CON(C _1-4 alkyl) ₂ , the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy replaced by substituents;

In some embodiments, each R ^z is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl, the methyl, ethyl, propyl , isopropyl, cyclopropyl, cyclobutyl and cyclopentyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _{1- 4} alkyl, cyclopropyl, cyclobutyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy substituents;

In some embodiments, each R ^z is independently selected from H, methyl, ethyl, propyl, isopropyl.

In some embodiments, each ^Rz is independently selected from H, isopropyl;

In some embodiments, each of R ¹ , R ² , R ⁵ or R ⁶ is independently selected from H, C _1-6 alkyl, halogen substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl;

In some embodiments, each of R ¹ and R ² is independently selected from H or C _1-4 alkyl;

In some embodiments, R ¹ , R ² are each independently selected from H, methyl, or ethyl;

In some embodiments, R ¹ , R ² are each independently selected from H;

^In some embodiments, each R or R is independently selected from H ^;

In some embodiments, R ³ , R ⁴ , R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alk base) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene-C _3-12 carbocyclyl or -C _0-4 alkylene-4 to 12-membered heterocyclic group, the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 Substituted by H, halogen, OH, =O, cyano, NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl or C _1-6 alkoxy;

In some embodiments, R ³ , R ⁴ are each independently selected from H;

In some embodiments, R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene -C _3-7 carbocyclyl or -C _0-2 Alkyl-4 to 7-membered heterocyclic group, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, halogen, OH, = O, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy substituent;

In some embodiments, R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl , isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, butyl, isobutyl, vinyl, Ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidyl are optionally further selected from 0 to 4 Substituted by H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy ;

In some embodiments, R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl , isobutyl, methoxy, ethoxy or cyclopropyl;

In some embodiments, R ^a or R ^b are each independently selected from H, F, CF ₃ ;

In some embodiments, X1 is selected from a bond, -CH ₂ -, -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C ( ⁼ O)N(Rx)-, -N(Rx)C( ⁼ O)-;

In some embodiments, X1 is selected from a bond, _-CH2- , -O-, -C( ⁼ O)N(Rx)-;

In some embodiments, X1 is selected from a bond, _-CH2- , -O-, -C(=O)NH-;

In some embodiments, X2 is selected from -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N(R ^x )-, -N(R ^x )C(=O)-;

In some embodiments, X2 is selected from -O-, -C(=O)N(R ^x )-;

In some embodiments, X2 is selected from -O-, -C(=O)NH-;

In some embodiments, each R ^x is independently selected from H or C _1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C Substituents of _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl;

In some embodiments, each R ^x is independently selected from H or C _1-4 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C Substituents of _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl;

In some embodiments, each R ^x is independently selected from H, methyl, ethyl, and said methyl, ethyl are optionally further selected from 0 to 4 H, F, Cl, Br, I, OH , =O, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

In some embodiments, each R ^x is independently selected from H;

In some embodiments, each R ⁷ is independently selected from C _1-6 alkyl, -C _0-4 alkylene-C _3-12 carbocyclyl, -C _0-4 alkylene-4 to 12-membered Heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted by =O or (=O) ₂ ;

In some embodiments, each R ⁷ is independently selected from C _1-4 alkyl, -C _0-4 alkylene-C _3-7 monocyclic carbocyclyl, -C _0-4 alkylene-C _{4 -11} and ring carbocyclyl, -C _0-4 alkylene-C _5-11 spirocyclic carbocyclyl, -C _0-4 alkylene-C _5-11 bridged ring carbocyclyl, -C _{0- 4} -alkylene-4 to 7-membered monocyclic heterocyclic group, -C _0-4 alkylene-5 to 11-membered ring heterocyclic group, -C _0-4 alkylene-5 to 11-membered spirocyclic heterocyclic group Cyclic group, -C _0-4 alkylene-5 to 11-member bridged ring heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic group contains 1 to 4 selected A heteroatom from O, S, N, when the heteroatom is selected from S, is optionally further replaced by =O or (=O) ₂ ;

In some embodiments, each R is independently selected from C _1-4 alkyl, C ^3-7 _monocyclic carbocyclyl, C _4-11 acyclic carbocyclyl, C _5-11 spirocyclic carbocyclyl, C _5-11 bridged ring carbocyclic group, 4 to 7 membered monocyclic heterocyclic group, 5 to 11 membered ring heterocyclic group, 5 to 11 membered spirocyclic heterocyclic group, 5 to 11 membered bridged ring heterocyclic group, -CH ₂ -C _3-7 monocyclic carbocyclyl, -CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ -C _5-11 Bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11 membered heterocyclic ring, -CH ₂ CH ₂ -5 to 11 membered spirocyclic ring Heterocyclyl, -CH ₂ CH ₂ -5 to 11-membered bridged ring heterocyclyl, -CH ₂ CH ₂ -C _3-7 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 acyclic carbocycle -CH ₂ CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7-membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11-membered ring heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered bridged ring heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted by = O or (=O) ₂ is substituted;

In some embodiments, each R ⁷ is independently selected from C _1-4 alkyl, C _3-6 monocyclic carbocyclyl, -CH ₂ -C _3-6 monocyclic carbocyclyl, -CH ₂ CH ₂ - C _3-6 monocyclic carbocyclic group, 3 to 6 membered monocyclic heterocyclic group, -CH ₂ -3 to 6 membered monocyclic heterocyclic group, -CH ₂ CH ₂ -3 to 6 membered monocyclic heterocyclic group, 3 and 4-membered carbocyclyl, 3 and 5-membered carbocyclyl, 3 and 6-membered carbocyclyl, 4 and 4-membered carbocyclyl, 4 and 5-membered carbocyclyl, 4 and 6-membered carbocyclyl, 5 and 5-membered carbocyclyl, 5-6-membered carbocyclyl, 6-6-membered carbocyclyl, 3-spiro, 4-membered carbocyclyl, 3-spiro, 5-membered carbocyclyl, 3-spiro, 6-membered carbocyclyl, 4-spiro, 4-membered Carbocyclyl, 4-spiro, 5-membered carbocyclyl, 4-spiro, 6-membered carbocyclyl, 5-spiro, 5-membered carbocyclyl, 5-spiro, 6-membered carbocyclyl, 6-spiro, 6-membered carbocyclyl, 3 and 4-membered heterocycle Base, 3 and 5-membered heterocyclic group, 3 and 6-membered heterocyclic group, 4 and 4-membered heterocyclic group, 4 and 5-membered heterocyclic group, 4 and 6-membered heterocyclic group, 5 and 5-membered heterocyclic group, 5-6 membered heterocyclyl, 6-6 membered heterocyclyl, 3-spiro 4-membered heterocyclyl, 3-spiro 5-membered heterocyclyl, 3-spiro 6-membered heterocyclyl, 4-spiro 4-membered heterocyclyl, 4-spiro 5-membered heterocyclyl, 4-spiro 6-membered heterocyclyl, 5-spiro 5-membered heterocyclyl, 5-spiro 6-membered heterocyclyl, 6-spiro 6-membered heterocyclyl, C _5-10 member bridged ring carbocyclyl, - CH ₂ -C _5-10 membered bridged ring carbocyclyl, 5 to 10 membered bridged ring heterobridged group, -CH ₂ -5 to 10 membered bridged ring heterobridged group, the R ⁷ is optionally further replaced by 0 to 4 R ^7a are substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ;

环丙基并环戊基、环丁基并环戊基、环戊基并环戊基、环戊基并环已基、环丙基螺环戊基、环丁基螺环丁基、环丁基螺环戊基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并哌啶基、环已基并氮杂环丁基、环已基并氮杂环戊基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并哌啶基、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并哌啶基、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环己基并哌啶基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺哌啶基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺哌啶基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺哌啶基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、哌啶基螺哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丙基并氧杂环丁基、环丙基并氧杂环戊基、环丙基并氧杂环己基、环丁基并氧杂环丁基、环丁基并氧杂环戊基、环丁基并氧杂环已基、环戊基并氧杂环丁基、环戊基并氧杂环戊基、环戊基并氧杂环已基、环已基并氧杂环丁基、环已基并氧杂环戊基、环已基并氧杂环已基、氮杂环丁基并氧杂环丁基、氮杂环丁基并氧杂环戊基、氮杂环丁基并氧杂环已基、哌啶并氧杂环丁基、氮杂环戊基并氧杂环丁基、氮杂环戊基并氧杂环戊基、氮杂环戊基并氧杂环已基、哌啶并氧杂环戊基、哌啶基并氧杂环丁基、哌啶基并氧杂环戊基、哌啶并氧杂环己基、环丁基螺氧杂环丁基、环丁基螺氧杂环戊基、环丁基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺氧杂环戊基、环戊基螺氧杂环已基、环已基螺氧杂环丁基、环已基螺氧杂环戊基、环已基螺氧杂环已基、氮杂环丁基螺氧杂环丁基、氮杂环丁基螺氧杂环戊基、氮杂环丁基螺氧杂环已基、氮杂环戊基螺氧杂环丁基、氮杂环戊基螺氧杂环戊基、氮杂环戊基螺氧杂环已基、氮杂环已基螺氧杂环丁基、氮杂环已基螺氧杂环戊基、氮杂环已基螺氧杂环已基、哌啶螺氧杂环丁基、哌啶螺氧杂环戊基、哌啶螺氧杂环己基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基、金刚烷基、

所述R⁷任选进一步被0至4个R^7a取代； ^In some embodiments, each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine , pyridazin-3(2H)-one, oxetanyl, oxolyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxolyl, -CH ₂ -oxo Heterocyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azetidinyl, -CH ₂ -piperidine, -CH ₂ -morpholine, -CH ₂ -piperazine, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ -oxetanyl, -CH ₂ CH ₂ -Oxolyl, -CH ₂ CH ₂ -Oxanyl, -CH ₂ CH ₂ -Azetidinyl, -CH ₂ CH ₂ -Azacyclopentyl, -CH ₂ CH ₂ -piperidine, -CH ₂ CH ₂ -morpholine, -CH ₂ CH ₂ -piperazine, -CH ₂ CH ₂ -imidazolidine, -CH ₂ CH ₂ -oxazolidine, -CH ₂ CH ₂ -pyrazole, -CH ₂ CH ₂ -pyrrole, -CH ₂ CH ₂ -imidazole, -CH ₂ CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[ 1.1.1] Pentyl, -CH ₂ -bicyclo[2.1.1]hexyl, -CH ₂ -bicyclo[2.2.1]heptyl, -CH ₂ -bicyclo[3.3.2]decyl, -CH ₂ -bicyclo[2.2.2]octyl, -CH ₂ -bicyclo[3.2.1]octyl, -CH ₂ -bicyclo[3.3.3]undecyl, -CH ₂ -adamantyl ,

Cyclopropylcyclopentyl, cyclobutylcyclopentyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutyl Spirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, Cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentyl Azacyclopentyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl Butyl, azetidinyl azetidinyl, azetidinyl piperidinyl, azetidinyl azetidinyl, azacyclopentyl azetidinyl, nitrogen Heterocyclopentylpiperidinyl, Azetiylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylpiperidinyl, Cyclobutylspiroazetidinyl Cyclobutylspiroazacyclopentyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazacyclopentyl, cyclopentylspiropiperidinyl, cyclohexane Basespiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidinylspiropiperidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiropiperidinyl, azacyclohexylspiro Azetidinyl, Azacyclohexylspiroazolyl, Piperidylspiropiperidinyl, Oxetanyl, Oxolyl, Oxanyl, Cyclopropyloxetane Butyl, Cyclopropyloxolane, Cyclopropyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl Cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclohexyl oxetanyl, cyclohexyl oxetanyl base, cyclohexyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, piperidine Azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, piperidoxetanyl Base, piperidinyl and oxetanyl, piperidinyl oxetanyl, piperidinoxanyl, cyclobutylspirooxetanyl, cyclobutylspirooxetyl, Cyclobutylspiropiperidinyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclohexylspirooxetanyl, cyclohexane Basespirooxolyl, cyclohexylspirooxanexyl, azetidinylspirooxetanyl, azetidinylspirooxolyl, azetidinylspirooxetyl Cyclohexyl, Azacyclopentylspirooxetanyl, Azacyclopentylspirooxetyl, Azacyclopentylspirooxetyl, Azepanylspirooxetanyl Base, azacyclohexylspirooxolyl, azacyclohexylspirooxanexyl, piperidinespirooxetanyl, piperidinespirooxolyl, piperidinespirooxane Hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl,

The R ⁷ is optionally further substituted by 0 to 4 R ^7a ;

所述R⁷任选进一步被0、1、2、3或4个R^7a取代； ^In some embodiments, each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, pyridazine, pyridazin-3(2H)-one, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclo Hexyl,

The R ⁷ is optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ;

In some embodiments, each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-6 Alkyl, -C _0-4 alkylene-N(C _1-6 alkyl) ₂ , -SO ₂ -C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, -SO ₂ -C _3-7 carbocyclyl, C _3-12 carbocyclyl or 4 to 12 membered heterocyclyl, the R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkyl substituted by hydroxy, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkoxy substituted by halogen, C _3-6 cycloalkyl or C _1-6 alkoxyalkyl substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally further =O or (=O) ₂ substitution;

In some embodiments, each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-4 Alkyl, -C _0-4 alkylene-N(C _1-4 alkyl) ₂ , -SO ₂ -C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _{1 -4} alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-7 carbocyclyl, 5 to 7 membered heterocyclyl, the R ^7a is optionally further selected from 0 to 4 selected from H, Halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, Hydroxyl substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxy The substituent of the alkyl group is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, it is optionally further replaced by =O or (=O) ₂ replaced;

In some embodiments, each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _1-4 alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _{3 -6} carbocyclyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a is optionally further selected from 0 to 4 selected from H, halogen, OH, =O, cyano, COOH , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxyl substituted C _1-4 alkyl, C Substituents of _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, said The heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ;

In some embodiments, each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _1-4 alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkane group, 4-7 membered heterocycloalkyl group, said R ^7a is optionally further replaced by 0 to 4 alkyl groups selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 , N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 alkane Oxygen, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl substituents, the heterocycloalkyl contains 1 to 4 selected A heteroatom from O, S, N, when the heteroatom is selected from S, is optionally further substituted by =O or (=O) ₂ ;

In some embodiments, each R ^7a is independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH ₃ , -CH ₂ CH ₂ NHCH ₂ CH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ -cyclopropyl, -SO ₂ -phenyl, methyl, ethyl, methoxy, ethoxy, propoxy , Isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetyl, Oxolyl, Oxetyl, Azetidinyl, Azetidinyl , piperidine, morpholine or piperazine, said R ^7a is optionally further 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N( C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 alkoxy , halogen-substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl substituents;

In some embodiments, each R ^7a is independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolyl, Oxycyclohexyl, azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a is optionally further selected from H, F by 0, 1, 2, 3 or 4 , Cl, Br, I, OH, =O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl are substituted by substituents;

In some embodiments, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic 4-12 membered heterocyclic ring optionally further substituted by 0 to 4 R ^7a , said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, ^R and R together with the atoms to which they are attached form a non-aromatic heterocyclic ring as follows: 4 to ⁷ membered monocyclic heterocycle, 5 to 11 membered heterocyclic ring, 5 to 11 membered spirocyclic heterocycle , 5 to 11-membered bridged ring heterocycle, said heterocycle is optionally further substituted by 0 to 4 R ^7a , said heterocycle contains 1 to 4 heteroatoms selected from O, S, N

In some embodiments, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic 4 to 7 membered monocyclic heterocycle, said heterocycle is optionally further substituted with 0 to 4 R ^7a , said heterocycle The ring contains 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, R ^x and R ⁷ form azetidinyl, azetidinyl, piperidine, morpholine or piperazine together with the atoms to which they are attached, and said azetidinyl, azeticyclic Amyl, piperidine, morpholine, piperazine are optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ;

In some embodiments, -X1- ^R7 are each independently selected from

In some embodiments, each -X2- ^R7 is independently selected from

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

In some embodiments, m is selected from 1.

As the first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

表示环为芳香环；

Indicates that the ring is an aromatic ring;

Z ₁ , Z ₂ , Z ₃ , Z ₆ or Z ₇ are each independently selected from CR ^z , NR ^z or N;

Z ₄ or Z ₅ are each independently selected from C or N;

A ₁ , A ₂ , A ₃ or A ₄ are each independently selected from CR ^a or N;

Ring B is each independently selected from a benzene ring or a 6-membered heteroaryl ring, and the heteroaryl ring contains 1 to 3 heteroatoms selected from O, S, and N;

R ^z are each independently selected from H, halogen, OH, =O, cyano, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _{1- 6} alkoxy, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkyl, CONH ₂ , CONHC _1-6 alkyl, COC _1-6 alkyl, CON(C _1-6 alkyl) ₂ , The alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-6 alkyl, C Substituted by _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, halogen-substituted C _1-6 alkyl or C _1-6 alkoxy;

R ¹ , R ² , R ⁵ or R ⁶ are each independently selected from H, C _1-6 alkyl, halogen substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, C _2-6 alkenes Base, C _2-6 alkynyl;

R ³ , R ⁴ , R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene -C _3-12 carbocyclyl or -C _0-4 alkylene Alkyl-4 to 12-membered heterocyclic group, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, halogen, OH, = O, cyano, NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl or C _1-6 alkoxy substituent;

X1 is selected from a bond, -CH ₂ -, -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N( R ^x )-, -N(R ^x )C(=O)-;

X2 is selected from -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N(R ^x )-, -N (Rx)C( ⁼ O)-;

R ^x are each independently selected from H or C _1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C _1-6 alkyl, Substituents of C _1-6 alkoxy or C _3-6 cycloalkyl;

R ⁷ are each independently selected from C _1-6 alkyl, -C _0-4 alkylene-C _3-12 carbocyclyl, -C _0-4 alkylene-4 to 12 membered heterocyclyl, said R ⁷ is optionally further substituted by 0 to 4 R ^7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted by =O Or (=O) ₂ substitution; each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _{1 -6} alkyl, -C _0-4 alkylene-N(C _1-6 alkyl) ₂ , -SO ₂ -C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -SO ₂ -C _3-7 carbocyclyl, C _3-12 carbocyclyl or 4 to 12 membered heterocyclyl, the R ^7a is optionally further By 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen Substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 ring Substituted by alkyl or C _1-6 alkoxyalkyl, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally Further replaced by =O or (=O) ₂ ;

Alternatively, R ^x and R ⁷ together with the atoms they are attached to form a non-aromatic 4-12 membered heterocyclic ring optionally further substituted by 0 to 4 R ^7a , said heterocyclic ring containing 1 to 4 a heteroatom selected from O, S, N;

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

As the second embodiment of the present invention, the compound represented by the following general formula (I-1) or (II-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically Acceptable salts or co-crystals,

Z ₆ are each independently selected from CR ^z or N;

R ¹ and R ² are each independently selected from H or C _1-4 alkyl;

The rest of the definitions are the same as the first embodiment of the present invention.

As the third embodiment of the present invention, the compound represented by the aforementioned general formula (I-1) or (II-1) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

R ^z are each independently selected from H, C _1-4 alkyl, COC _1-6 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, CONH ₂ , CONHC _1-4 alkyl, CON(C _1-4 alkyl) ₂ , the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, Substituents of NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy;

R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-7 carbocyclyl or -C _0-2 alkylene-4 to 7 A membered heterocyclyl, the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, Substituents of NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy;

R ^x are each independently selected from H or C _1-4 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C _1-4 alkyl, Substituents of C _1-4 alkoxy or C _3-6 cycloalkyl;

R ⁷ are each independently selected from C _1-4 alkyl, -C _0-4 alkylene-C _3-7 monocyclic carbocyclyl, -C _0-4 alkylene-C _{4-11 alkane} carbocycle Base, -C _0-4 alkylene -C _5-11 spiro ring carbocyclyl, -C _0-4 alkylene -C _5-11 bridged ring carbocyclyl, -C _0-4 alkylene -4 to 7-membered monocyclic heterocyclyl, -C _0-4 alkylene-5 to 11-membered and ring heterocyclyl, -C _0-4 alkylene-5 to 11-membered spirocyclic heterocyclyl, -C _{0 -4} alkylene-5 to 11-member bridged ring heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic group contains 1 to 4 members selected from O, S, N A heteroatom, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ;

R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-4 alkyl, -C _{0 -4} alkylene-N(C _1-4 alkyl) ₂ , -SO ₂ -C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-7 carbocyclyl, 5 to 7 membered heterocyclyl, the R ^7a is optionally further selected from 0 to 4 selected from H, halogen, OH, =O , cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1- Substituents of ₄ alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ ;

Alternatively, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic heterocyclic ring as follows: 4 to 7 membered monocyclic heterocyclic ring, 5 to 11 membered heterocyclic ring, 5 to 11 membered spirocyclic heterocyclic ring, 5 to 11 membered spirocyclic heterocyclic ring, 11-member bridged ring heterocycle, said heterocycle is optionally further substituted by 0 to 4 R ^7a , said heterocycle contains 1 to 4 heteroatoms selected from O, S, N;

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

As the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I-1) or (II-1) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

Ring B is each independently selected from phenyl, pyridine, pyrazine, pyrimidine;

R ¹ and R ² are each independently selected from H, methyl or ethyl;

R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl and cyclopentyl are optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, cyclopropyl Substituents of radical, cyclobutyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy;

R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl, isobutyl, ethylene radical, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl base, -CH ₂ -cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy , ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Substituted by Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy;

R ^x are each independently selected from H, methyl, and ethyl, and the methyl and ethyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, cyano , C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

R ⁷ are each independently selected from C _1-4 alkyl, C _3-7 monocyclic carbocyclyl, C _4-11 acyclic carbocyclyl, C _5-11 spirocyclic carbocyclyl, C _5-11 bridged ring Carbocyclyl, 4 to 7 membered monocyclic heterocyclic group, 5 to 11 membered heterocyclic heterocyclic group, 5 to 11 membered spirocyclic heterocyclic group, 5 to 11 membered bridged ring heterocyclic group, -CH ₂ -C _{3 -7} monocyclic carbocyclyl, -CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7-membered monocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered parallel heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5- to 11-membered bridged ring heterocyclyl, -CH ₂ CH ₂ -C _3-7 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ - 5 to 11 membered ring heterocyclic group, -CH ₂ CH ₂ -5 to 11 membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11 membered bridged ring heterocyclic group, the R ⁷ is optionally further 0 to 4 R ^7a are substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, it is optionally further replaced by =O or (=O) ₂ replaced;

R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _{1- 4} alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, R ^7a is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _{1 -4} alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _2-4 alkynyl, Substituents of C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ;

Alternatively, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic 4 to 7 membered monocyclic heterocyclic ring, said heterocyclic ring is optionally further substituted by 0 to 4 R ^7a , said heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N;

The remaining definitions are the same as the first, second or third embodiment of the present invention.

As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I-1) or (II-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

Each R ⁷ is independently selected from C _1-4 alkyl, C _3-6 monocyclic carbocyclyl, -CH ₂ -C _3-6 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _3-6 monocyclic Carbocyclyl, 3 to 6 membered monocyclic heterocyclic group, -CH ₂ -3 to 6 membered monocyclic heterocyclic group, -CH ₂ CH ₂ -3 to 6 membered monocyclic heterocyclic group, 3 to 4 membered carbocyclic group Base, 3 and 5-membered carbocyclyl, 3 and 6-membered carbocyclyl, 4 and 4-membered carbocyclyl, 4 and 5-membered carbocyclyl, 4 and 6-membered carbocyclyl, 5 and 5-membered carbocyclyl, 5 and 6-membered carbocyclyl, 6 and 6-membered carbocyclyl, 3-spiro 4-membered carbocyclyl, 3-spiro 5-membered carbocyclyl, 3-spiro 6-membered carbocyclyl, 4-spiro 4-membered carbocyclyl, 4-spiro 5-membered carbocyclyl, 4-membered 6-membered carbocyclyl, 5-membered 5-membered carbocyclyl, 5-membered 6-membered carbocyclyl, 6-membered 6-membered carbocyclyl, 3 and 4-membered heterocyclyl, 3 and 5-membered Heterocyclic group, 3 and 6-membered heterocyclic group, 4 and 4-membered heterocyclic group, 4 and 5-membered heterocyclic group, 4 and 6-membered heterocyclic group, 5 and 5-membered heterocyclic group, 5 and 6-membered heterocyclic group Base, 6 and 6-membered heterocyclyl, 3-spiro 4-membered heterocyclyl, 3-spiro 5-membered heterocyclyl, 3-spiro 6-membered heterocyclyl, 4-spiro 4-membered heterocyclyl, 4-spiro 5-membered heterocyclyl, 4-spiro 6-membered heterocyclyl, 5-spiro 5-membered heterocyclyl, 5-spiro 6-membered heterocyclyl, 6-spiro 6-membered heterocyclyl, C _5-10 member bridged ring carbocyclyl, -CH ₂ -C _{5- 10} -membered bridged ring carbocyclic group, 5-10-membered bridged ring heterobridged group, -CH ₂ -5- to 10-membered bridged ring heterobridged group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ ;

R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _{1- 4} alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-7 members Heterocycloalkyl, said R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 Alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted Substituents of C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 selected from O, S, N A heteroatom, when the heteroatom is selected from S, is optionally further substituted by =O or (=O) ₂ ;

The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I-1) or (II-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

环丙基并环戊基、环丁基并环戊基、环戊基并环戊基、环戊基并环已基、环丙基螺环戊基、环丁基螺环丁基、环丁基螺环戊基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并哌啶基、环已基并氮杂环丁基、环已基并氮杂环戊基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并哌啶基、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并哌啶基、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环己基并哌啶基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺哌啶基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺哌啶基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺哌啶基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、哌啶基螺哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丙基并氧杂环丁基、环丙基并氧杂环戊基、环丙基并氧杂环己基、环丁基并氧杂环丁基、环丁基并氧杂环戊基、环丁基并氧杂环已基、环戊基并氧杂环丁基、环戊基并氧杂环戊基、环戊基并氧杂环已基、环已基并氧杂环丁基、环已基并氧杂环戊基、环已基并氧杂环已基、氮杂环丁基并氧杂环丁基、氮杂环丁基并氧杂环戊基、氮杂环丁基并氧杂环已基、哌啶并氧杂环丁基、氮杂环戊基并氧杂环丁基、氮杂环戊基并氧杂环戊基、氮杂环戊基并氧杂环已基、哌啶并氧杂环戊基、哌啶基并氧杂环丁基、哌啶基并氧杂环戊基、哌啶并氧杂环己基、环丁基螺氧杂环丁基、环丁基螺氧杂环戊基、环丁基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺氧杂环戊基、环戊基螺氧杂环已基、环已基螺氧杂环丁基、环已基螺氧杂环戊基、环已基螺氧杂环已基、氮杂环丁基螺氧杂环丁基、氮杂环丁基螺氧杂环戊基、氮杂环丁基螺氧杂环已基、氮杂环戊基螺氧杂环丁基、氮杂环戊基螺氧杂环戊基、氮杂环戊基螺氧杂环已基、氮杂环已基螺氧杂环丁基、氮杂环已基螺氧杂环戊基、氮杂环已基螺氧杂环已基、哌啶螺氧杂环丁基、哌啶螺氧杂环戊基、哌啶螺氧杂环己基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基、金刚烷基、

所述R⁷任选进一步被0至4个R^7a取代；Each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert ^- butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine Azolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazine-3( 2H)-keto, oxetanyl, oxolyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ - Cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxolyl, -CH ₂ -oxanyl, - CH ₂ -azetidinyl, -CH ₂ -azetidinyl, -CH ₂ -piperidine, -CH ₂ -morpholine, -CH ₂ -piperazine, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ -oxetanyl, -CH ₂ CH ₂ -oxetanyl Pentyl, -CH ₂ CH ₂ -oxanyl, -CH ₂ CH ₂ -azetidinyl, -CH ₂ CH ₂ -azetidinyl, -CH ₂ CH ₂ -piperidine, -CH ₂ CH ₂ -morpholine, -CH ₂ CH ₂ -piperazine, -CH ₂ CH ₂ -imidazolidine, -CH ₂ CH ₂ -oxazolidine, -CH ₂ CH ₂ -pyrazole, -CH ₂ CH ₂ - Pyrrole, -CH ₂ CH ₂ -imidazole, -CH ₂ CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane base, -CH ₂ -bicyclo[2.1.1]hexyl, -CH ₂ -bicyclo[2.2.1]heptanyl, -CH ₂ -bicyclo[3.3.2]decyl, -CH ₂ -bicyclo[ 2.2.2] Octyl, -CH ₂ -bicyclo[3.2.1]octyl, -CH ₂ -bicyclo[3.3.3]undecyl, -CH ₂ -adamantyl,

Cyclopropylcyclopentyl, cyclobutylcyclopentyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutyl Spirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, Cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentyl Azacyclopentyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl Butyl, azetidinyl azetidinyl, azetidinyl piperidinyl, azetidinyl azetidinyl, azacyclopentyl azetidinyl, nitrogen Heterocyclopentylpiperidinyl, Azetiylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylpiperidinyl, Cyclobutylspiroazetidinyl Cyclobutylspiroazacyclopentyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazacyclopentyl, cyclopentylspiropiperidinyl, cyclohexane Basespiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidinylspiropiperidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiropiperidinyl, azacyclohexylspiro Azetidinyl, Azacyclohexylspiroazolyl, Piperidylspiropiperidinyl, Oxetanyl, Oxolyl, Oxanyl, Cyclopropyloxetane Butyl, Cyclopropyloxolane, Cyclopropyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl Cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclohexyl oxetanyl, cyclohexyl oxetanyl base, cyclohexyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, piperidine Azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, piperidoxetanyl Base, piperidinyl and oxetanyl, piperidinyl oxetanyl, piperidinoxanyl, cyclobutylspirooxetanyl, cyclobutylspirooxetyl, Cyclobutylspiropiperidinyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclohexylspirooxetanyl, cyclohexane Basespirooxolyl, cyclohexylspirooxanexyl, azetidinylspirooxetanyl, azetidinylspirooxolyl, azetidinylspirooxetyl Cyclohexyl, Azacyclopentylspirooxetanyl, Azacyclopentylspirooxetyl, Azacyclopentylspirooxetyl, Azepanylspirooxetanyl Base, azacyclohexylspirooxolyl, azacyclohexylspirooxanexyl, piperidinespirooxetanyl, piperidinespirooxolyl, piperidinespirooxane Hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl,

The R ⁷ is optionally further substituted by 0 to 4 R ^7a ;

R ^7a are each independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH _3. -CH ₂ CH ₂ NHCH ₂ CH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH _3. -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ -cyclopropyl, -SO ₂ -phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Azetidinyl, Azacyclopentyl, Piperidine, Morpholine Or piperazine, said R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl ) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 alkoxy, C ₁ substituted by halogen Substituents of _-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl;

The remaining definitions are the same as the first, second, third, fourth or fifth embodiment of the present invention.

As the seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I-1) or (II-1) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

Ring A is selected from

Ring B is selected from phenyl;

m is selected from 1;

R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl, isobutyl, methyl Oxy, ethoxy or cyclopropyl;

R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl;

X1 is selected from a bond, -CH ₂ -, -O-, -C(=O)N(R ^x )-;

X2 is selected from -O-, -C(=O)N(R ^x )-;

所述R⁷任选进一步被0、1、2、3或4个R^7a取代；Each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert ^- butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridazine, pyridyl Oxazin-3(2H)-one, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutane -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl,

The R ⁷ is optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ;

Alternatively, R ^x and R ⁷ form azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine together with the atoms they are connected to, and the azetidinyl, azetidinyl, azetidinyl, Piperidine, morpholine, piperazine are optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ;

R ^7a are each independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , methyl, ethyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetyl, Oxol, Oxetyl, Azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a is optionally further selected from H, F, Cl, Br, I by 0, 1, 2, 3 or 4 , OH, =O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl are substituted by substituents;

The remaining definitions are the same as those of the first, second, third, fourth, fifth or sixth embodiment of the present invention.

As the eighth embodiment of the present invention, the following general formula (I-1-1), (I-1-2), (II-1-1) or (II-1-2) shown The compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Z ₆ are each independently selected from CH or N;

-X1- ^R7 are each independently selected from

-X2- ^R7 are each independently selected from

The present invention relates to a compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

The present invention relates to some embodiments of general formula (I) or (II), Z ₁ , Z ₂ , Z ₃ , Z ₆ or Z ₇ are each independently selected from CR ^z , NR ^z or N.

In some embodiments of the present invention related to general formula (I) or (II), Z ₁ and Z ₃ are selected from N, Z ₆ is independently selected from CR ^z or N, and Z ₇ is selected from NR ^z .

The present invention relates to some embodiments of general formula (I) or (II), Z ₁ and Z ₃ are selected from N, Z ₆ is independently selected from CH or N, and Z ₇ is selected from NR ^z .

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), Z ₆ are each independently selected from CR ^z or N.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), Z ₆ are each independently selected from CH or N.

The present invention relates to some embodiments of general formula (I) or (II), Z ₄ or Z ₅ are each independently selected from C or N.

The present invention relates to some embodiments of general formula (I) or (II), Z ₄ or Z ₅ are each independently selected from C.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), A ₁ , A ₂ , A ₃ or A ₄ are each independently selected from CR ^a or N .

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), ring A is selected from

The present invention relates to some embodiments of the general formula (I), (II), (I-1) or (II-1), each ring B is independently selected from a benzene ring or a 6-membered heteroaromatic ring, and the hetero The aromatic ring contains 1 to 3 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), ring B is each independently selected from phenyl, pyridine, pyrazine, pyrimidine.

In some embodiments of the present invention related to general formula (I), (II), (I-1) or (II-1), ring B is selected from phenyl;

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), each R ^z is independently selected from H, halogen, OH, =O, cyano, NH _2. NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkane group, CONH ₂ , CONHC _1-6 alkyl, COC _1-6 alkyl, CON(C _1-6 alkyl) ₂ , the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally further C substituted by 0 to 4 selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-6 alkyl, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkyl, halogen Substituents of _1-6 alkyl or C _1-6 alkoxy.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^z are each independently selected from H, C _1-4 alkyl, COC _1-6 Alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, CONH ₂ , CONHC _1-4 alkyl, CON(C _1-4 alkyl) ₂ , the alkyl, alkoxy, Cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4 to Substituents of 7-membered heterocycloalkyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl base, cyclopropyl, cyclobutyl and cyclopentyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl are optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, cyclopropyl, cyclobutyl, halogen substituted C _1-4 alkyl or C _1-4 Alkoxy substituents are substituted.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl base.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^z are each independently selected from H, isopropyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ¹ , R ² , R ⁵ or R ⁶ are each independently selected from H, C _{1 -6} alkyl, C _1-6 alkyl substituted by halogen, C _1-6 alkyl substituted by hydroxy, C _2-6 alkenyl, C _2-6 alkynyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ¹ and R ² are each independently selected from H or C _1-4 alkyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ¹ and R ² are each independently selected from H, methyl or ethyl.

In some embodiments of the present invention related to general formula (I), (II), (I-1) or (II-1), R ¹ and R ² are each independently selected from H.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ⁵ or R ⁶ are each independently selected from H.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ³ , R ⁴ , R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene -C _3-12 carbocyclyl or -C _0-4 alkylene -4 to 12 membered heterocyclic group, the alkyl, alkylene, Alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further substituted by 0 to 4 C selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-6 alkyl, halogen Substituents of _1-6 alkyl or C _1-6 alkoxy.

The present invention relates to some embodiments of general formula (I) or (II), R ³ and R ⁴ are each independently selected from H.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy , -C _0-2 alkylene -C _3-7 carbocyclic group or -C _0-2 alkylene -4 to 7 membered heterocyclic group, the alkyl, alkylene, alkenyl, alkynyl, Carbocyclyl or heterocyclyl is optionally further substituted by 0 to 4 C _1-4 alkyl selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-4 alkyl, halogen or Substituents of C _1-4 alkoxy groups are substituted.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl Pyridyl, the methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl or piperidinyl is optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkane Substituents of radical, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, _NH2 , _CF3 , methyl, ethyl, propyl, butyl, isobutyl, methoxy, ethoxy, or cyclopropyl.

The present invention relates to some embodiments of general formula (I), (I-1), (I-1-1), X1 is selected from bond, -CH ₂ -, -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N(R ^x )-, -N(R ^x )C(=O)-.

The present invention relates to some embodiments of general formula (I), (I-1), (I-1-1), X1 is selected from the group consisting of bond, -CH ₂ -, -O-, -C(=O)N( R ^x )-.

The present invention relates to some embodiments of general formula (I), (I-1), (I-1-1), X1 is selected from the group consisting of bond, -CH ₂ -, -O-, -C(=O)NH- .

The present invention relates to some embodiments of general formula (II), (II-1) or (II-1-1), X2 is selected from -O-, -S-, -N(R ^x )-, -S( O) ₂ -, -C(=O)-, -C(=O)N(R ^x )-, -N(R ^x )C(=O)-.

In some embodiments of the present invention related to general formula (II), (II-1) or (II-1-1), X2 is selected from -O-, -C(=O)N(R ^x )-.

In some embodiments of the present invention related to general formula (II), (II-1) or (II-1-1), X2 is selected from -O-, -C(=O)NH-.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^x is independently is selected from H or C _1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, C _1-6 alkyl, C _1-6 Substituents of alkoxy or C _3-6 cycloalkyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^x is independently is selected from H or C _1-4 alkyl, and said alkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, C _1-4 alkyl, C _1-4 Substituents of alkoxy or C _3-6 cycloalkyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^x is independently is selected from H, methyl, ethyl, and said methyl and ethyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, cyano, C _1- Substituents of ₄ alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^x is independently ground selected from H.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from C _1-6 alkyl, -C _0-4 alkylene-C _3-12 carbocyclyl, -C _0-4 alkylene-4 to 12 membered heterocyclyl, and the R ⁷ is optionally Further substituted by 0 to 4 R ^7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted by =O or (=O ) ₂ instead.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from C _1-4 alkyl, -C _0-4 alkylene-C _3-7 monocyclic carbocyclyl, -C _0-4 alkylene-C _4-11 and ring carbocyclyl, -C _0-4 alkylene-C _5-11 spiro ring carbocyclyl, -C _0-4 alkylene-C _5-11 bridged ring carbocyclyl, -C _0-4 alkylene-4 to 7-membered unit Ring heterocyclyl, -C _0-4 alkylene-5 to 11-membered ring heterocyclyl, -C _0-4 alkylene-5 to 11-membered spirocyclic heterocyclyl, -C _0-4 alkylene Base-5 to 11-member bridged ring heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, one is optionally further substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from C _1-4 alkyl, C _3-7 monocyclic carbocyclyl, C _4-11 acyclic carbocyclyl, C _5-11 spirocyclic carbocyclyl, C _5-11 bridged ring carbocyclyl, 4 to 7 membered monocyclic heterocyclic group, 5 to 11 membered parallel ring heterocyclic group, 5 to 11 membered spirocyclic heterocyclic group, 5 to 11 membered bridged ring heterocyclic group, -CH ₂ -C _3-7 monocyclic ring Carbocyclyl, -CH ₂ -C _4-11 and ring carbocyclyl, -CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7-membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11-membered heterocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11-membered spirocyclic heterocyclyl, -CH ₂ CH ₂ - 5- to 11-membered bridged ring heterocyclyl, -CH ₂ CH ₂ -C _3-7 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ CH ₂ -C _{5 -11} spirocyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered Paracyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered bridged ring heterocyclic group, the R ⁷ is optionally further replaced by 0 to 4 R ^7a is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, one is optionally substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from C _1-4 alkyl, C _3-6 monocyclic carbocyclyl, -CH ₂ -C _3-6 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _3-6 monocyclic carbocyclyl, 3 to 6-membered monocyclic heterocyclyl, -CH ₂ -3 to 6-membered monocyclic heterocyclyl, -CH ₂ CH ₂ -3 to 6-membered monocyclic heterocyclyl, 3 and 4-membered carbocyclyl, 3 and 5-membered carbocyclyl, 3-6-membered carbocyclyl, 4-4-membered carbocyclyl, 4-5-membered carbocyclyl, 4-6-membered carbocyclyl, 5-5-membered carbocyclyl, 5-6-membered Carbocyclyl, 6 and 6-membered carbocyclyl, 3-spiro, 4-membered carbocyclyl, 3-spiro, 5-membered carbocyclyl, 3-spiro, 6-membered carbocyclyl, 4-spiro, 4-membered carbocyclyl, 4-spiro, 5-membered carbocyclyl Base, 4 spiro 6-membered carbocyclyl, 5 spiro 5-membered carbocyclyl, 5 spiro 6-membered carbocyclyl, 6 spiro 6-membered carbocyclyl, 3 and 4-membered heterocyclyl, 3 and 5-membered heterocyclyl, 3 and 6-membered heterocyclic group, 4 and 4-membered heterocyclic group, 4 and 5-membered heterocyclic group, 4 and 6-membered heterocyclic group, 5 and 5-membered heterocyclic group, 5 and 6-membered heterocyclic group, 6- and 6-membered heterocyclyl, 3-spiro 4-membered heterocyclyl, 3-spiro 5-membered heterocyclyl, 3-spiro 6-membered heterocyclyl, 4-spiro 4-membered heterocyclyl, 4-spiro 5-membered heterocyclyl, 4-spiro 6-membered Heterocyclyl, 5-spiro 5-membered heterocyclyl, 5-spiro 6-membered heterocyclyl, 6-spiro 6-membered heterocyclyl, C _5-10 -membered bridged ring carbocyclyl, -CH ₂ -C _5-10 -membered bridged ring Carbocyclyl, 5 to 10-membered bridged ring heterobridged group, -CH ₂ -5 to 10-membered bridged ring heterobridged group, said R ⁷ is optionally further substituted by 0 to 4 R ^7a , said hetero The cyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, one is optionally substituted by =O or (=O) ₂ .

环丙基并环戊基、环丁基并环戊基、环戊基并环戊基、环戊基并环已基、环丙基螺环戊基、环丁基螺环丁基、环丁基螺环戊基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并哌啶基、环已基并氮杂环丁基、环已基并氮杂环戊基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并哌啶基、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并哌啶基、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环己基并哌啶基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺哌啶基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺哌啶基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺哌啶基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、哌啶基螺哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丙基并氧杂环丁基、环丙基并氧杂环戊基、环丙基并氧杂环己基、环丁基并氧杂环丁基、环丁基并氧杂环戊基、环丁基并氧杂环已基、环戊基并氧杂环丁基、环戊基并氧杂环戊基、环戊基并氧杂环已基、环已基并氧杂环丁基、环已基并氧杂环戊基、环已基并氧杂环已基、氮杂环丁基并氧杂环丁基、氮杂环丁基并氧杂环戊基、氮杂环丁基并氧杂环已基、哌啶并氧杂环丁基、氮杂环戊基并氧杂环丁基、氮杂环戊基并氧杂环戊基、氮杂环戊基并氧杂环已基、哌啶并氧杂环戊基、哌啶基并氧杂环丁基、哌啶基并氧杂环戊基、哌啶并氧杂环己基、环丁基螺氧杂环丁基、环丁基螺氧杂环戊基、环丁基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺氧杂环戊基、环戊基螺氧杂环已基、环已基螺氧杂环丁基、环已基螺氧杂环戊基、环已基螺氧杂环已基、氮杂环丁基螺氧杂环丁基、氮杂环丁基螺氧杂环戊基、氮杂环丁基螺氧杂环已基、氮杂环戊基螺氧杂环丁基、氮杂环戊基螺氧杂环戊基、氮杂环戊基螺氧杂环已基、氮杂环已基螺氧杂环丁基、氮杂环已基螺氧杂环戊基、氮杂环已基螺氧杂环已基、哌啶螺氧杂环丁基、哌啶螺氧杂环戊基、哌啶螺氧杂环己基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.3.2]癸烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.3]十一烷基、金刚烷基、

所述R⁷任选进一步被0至4个R^7a取代。The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyrrole Base, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazin-3(2H)-one , oxetanyl, oxolyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxolyl, -CH ₂ -oxanyl, -CH ₂ -azepine Heterobutyl, -CH ₂ -azepine, -CH ₂ -piperidine, -CH ₂ -morpholine, -CH ₂ -piperazine, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ -oxetanyl, -CH ₂ CH ₂ -oxolyl, - CH ₂ CH ₂ -oxanyl, -CH ₂ CH ₂ -azetidinyl, -CH ₂ CH ₂ -azepanyl, -CH _{2 CH 2 -piperidine, -CH 2 CH 2 -} Morpholine, -CH ₂ CH ₂ -piperazine, -CH ₂ CH ₂ -imidazolidine, -CH ₂ CH ₂ -oxazolidine, -CH ₂ CH ₂ -pyrazole, -CH ₂ CH ₂ -pyrrole, -CH ₂ CH ₂ -imidazole, -CH ₂ CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentyl, -CH ₂ -bicyclo[2.1.1]hexyl, -CH ₂ -bicyclo[2.2.1]heptanyl, -CH ₂ -bicyclo[3.3.2]decyl, -CH ₂ -bicyclo[2.2.2] Octyl, -CH ₂ -bicyclo[3.2.1]octyl, -CH ₂ -bicyclo[3.3.3]undecyl, -CH ₂ -adamantyl,

Cyclopropylcyclopentyl, cyclobutylcyclopentyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutyl Spirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, Cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentyl Azacyclopentyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl Butyl, azetidinyl azetidinyl, azetidinyl piperidinyl, azetidinyl azetidinyl, azacyclopentyl azetidinyl, nitrogen Heterocyclopentylpiperidinyl, Azetiylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylpiperidinyl, Cyclobutylspiroazetidinyl Cyclobutylspiroazacyclopentyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazacyclopentyl, cyclopentylspiropiperidinyl, cyclohexane Basespiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidinylspiropiperidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiropiperidinyl, azacyclohexylspiro Azetidinyl, Azacyclohexylspiroazolyl, Piperidylspiropiperidinyl, Oxetanyl, Oxolyl, Oxanyl, Cyclopropyloxetane Butyl, Cyclopropyloxolane, Cyclopropyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl Cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclohexyl oxetanyl, cyclohexyl oxetanyl base, cyclohexyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, piperidine Azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, piperidoxetanyl Base, piperidinyl and oxetanyl, piperidinyl oxetanyl, piperidinoxanyl, cyclobutylspirooxetanyl, cyclobutylspirooxetyl, Cyclobutylspiropiperidinyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclohexylspirooxetanyl, cyclohexane Basespirooxolyl, cyclohexylspirooxanexyl, azetidinylspirooxetanyl, azetidinylspirooxolyl, azetidinylspirooxetyl Cyclohexyl, Azacyclopentylspirooxetanyl, Azacyclopentylspirooxetyl, Azacyclopentylspirooxetyl, Azepanylspirooxetanyl Base, azacyclohexylspirooxolyl, azacyclohexylspirooxanexyl, piperidinespirooxetanyl, piperidinespirooxolyl, piperidinespirooxane Hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl,

Said R ⁷ is optionally further substituted with 0 to 4 R ^7a .

所述R⁷任选进一步被0、1、2、3或4个R^7a取代。The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ⁷ are independently is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridazine, pyridazine-3 ( 2H)-keto, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl,

Said R ⁷ is optionally further substituted by 0, 1, 2, 3 or 4 R ^7a .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-6 alkyl, -C _0-4 alkylene -N(C _1-6 alkyl) ₂ , -SO ₂ -C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkane Oxygen, -SO ₂ -C _3-7 carbocyclyl, C _3-12 carbocyclyl or 4 to 12 membered heterocyclyl, the R ^7a is optionally further selected from 0 to 4 selected from H, halogen, OH , =O, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl or C _1-6 alkoxyalkyl The substituent is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-4 alkyl, -C _0-4 alkylene -N(C _1-4 alkyl) ₂ , -SO ₂ -C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ - C _3-6 carbocyclyl, C _3-7 carbocyclyl, 5-7 membered heterocyclyl, the R ^7a is optionally further selected from 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, Substituents of C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the The above-mentioned heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkane radical, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _1-4 alkyl) _2. -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a is optionally further replaced by 0 to 4 alkyls selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 , N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 Substituents of alkoxy, halogen-substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 A heteroatom selected from O, S, N, when the heteroatom is selected from S, is optionally further substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkane radical, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _1-4 alkyl) _2. -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl , said R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 substituted by halogen Substituted by alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ .

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH _3. -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH ₃ , -CH ₂ CH ₂ NHCH ₂ CH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ -cyclopropyl, -SO ₂ -phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolyl, oxetanyl, azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, The R ^7a is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy Substituents of radical, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), each R ^7a is independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ N (CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , Methyl, Ethyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetanyl, Oxolyl, Oxetyl, Azetidinyl Base, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a is optionally further selected from 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, OH, = Substituents of O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ^x and R ⁷ forms a non-aromatic 4-12 membered heterocyclic ring together with the atoms connected to it, and the heterocyclic ring is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic ring contains 1 to 4 members selected from O, S, N heteroatoms.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ^x and R ⁷ and the atoms to which it is attached form a non-aromatic heterocyclic ring as follows: 4 to 7 membered monocyclic heterocyclic ring, 5 to 11 membered heterocyclic ring, 5 to 11 membered spirocyclic heterocyclic ring, 5 to 11 membered bridged ring heterocyclic ring, The heterocycle is optionally further substituted by 0 to 4 R ^7a , and the heterocycle contains 1 to 4 heteroatoms selected from O, S, N

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ^x and R ⁷ forms a non-aromatic 4 to 7-membered monocyclic heterocyclic ring together with the atoms it is connected to, the heterocyclic ring is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic ring contains 1 to 4 selected from O, S, N heteroatoms.

The present invention relates to some embodiments of general formula (I), (II), (I-1), (II-1), (I-1-1) or (II-1-1), R ^x and R ⁷ forms azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine together with the atoms connected to it, and the azetidinyl, azacyclopentyl, piperidine, morpholine, piperazine The azine is optionally further substituted with 0, 1, 2, 3 or 4 R ^7a .

The present invention relates to some embodiments of general formula (I), ((I-1), (I-1-1), -X1-R ⁷ are each independently selected from

The present invention relates to some embodiments of general formula (II), (II-1) or (II-1-1), -X2-R ⁷ are each independently selected from

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), m is selected from 0, 1, 2, 3 or 4.

The present invention relates to some embodiments of general formula (I), (II), (I-1) or (II-1), m is selected from 1.

The present invention relates to a pharmaceutical composition, comprising the compound described in the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable Carrier.

The present invention relates to a compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of therapeutic and RET activity or expression levels The application in the medicine of related diseases, preferably the application in the preparation of medicines for IBS, tumor or autoimmune system diseases.

Synthetic method one:

The compound of the general formula (I-1-A) and the compound of the general formula (I-1-B) are coupled or substituted to obtain the corresponding compound of the general formula (I-1-C);

The compound of the general formula (I-1-C) and the compound of the general formula (I-1-D) are subjected to a coupling reaction to obtain the corresponding compound of the general formula (I-1-E);

The compound of the general formula (I-1-E) is hydrolyzed to obtain the compound of the general formula (I-1-F);

The compound of the general formula (I-1-F) and the compound of the general formula (I-1-G) are subjected to a condensation reaction to obtain the corresponding compound of the general formula (I-1);

R ^A , R ^B and R ^C are selected from Cl, Br, I, OTf, organoboron reagents, organotin reagents;

The definitions of the other substituents are the same as those in the embodiment of the compound of general formula (I-1).

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

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

"Halogen" means F, Cl, Br or I.

"Halogen substituted" refers to F, Cl, Br or I substitution, 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 substituted by a substituent of I, substituted by 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 linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; Alkyl group appearing in this article, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replace. Non-limiting examples include -X(CH ₂ )vX(CH ₂ )vX(CH ₂ )vH (v is an integer from 1 to 5, each of X is independently selected from a bond or a heteroatom, and the heteroatom includes but is not limited to N , O or S, and at least one X is selected from heteroatoms, and N or S in heteroatoms can be oxidized into various oxidation states). Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.

"Heteroalkylene" means a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitutions. Non-limiting examples include -X(CH ₂ )vX(CH ₂ )vX(CH ₂ )v-, v is an integer from 1 to 5, each of X is independently selected from a bond, N, O or S, and at least 1 X is selected from N, O or S.

"Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can 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 atoms selected from N, O or The heteroatoms of S, the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized into various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent

"Alkenyl" means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms, alkenyl examples include but are 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-1-but Alkenyl, 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, 4-heptenyl, 1-octenyl, 3-octene base, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-Hexadiene, etc.; alkenyl groups appearing in this text have the same definition as this one. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" means a substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 Carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, alkynyl examples include 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-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 Base, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be a valence, divalent, trivalent or quadrivalent.

"Alkoxy" means 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-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.

“碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring is optionally 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 Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,

A "carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

“杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered A bicyclic ring or a 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, and the ring of the heterocyclyl group is selected from Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl Base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azadi Cyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl alkyl,

A "heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro ring" or "spirocyclic group" refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Optional may contain 0 to 5 heteroatoms selected from N, O or S(=O) _n .

“螺环”或“螺环基”可以是一价、二价、三价或四价。

A "spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

“并环”或“并环基”可以是一价、二价、三价或四价。"Acyl ring" or "annyl ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more 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 from 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to be selected from N, S(=O) _n or O, n being 0, 1 or 2). The number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

"Alkyl" or "alkyl" may be monovalent, divalent, trivalent or tetravalent.

立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, may contain 0 or more double bonds, and any ring in the ring system It may contain 0 to 5 groups selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, wherein 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, adamantane. A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definitions of "carbospirocycle", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein are consistent with spirocycle.

"Carbocyclic", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" whose ring system consists only of carbon atoms. The definition of "carbocyclyl", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" used herein is consistent with that of paracyclyl.

"Carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged cycloyl" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring" appearing in this article are consistent with those of bridged ring.

"Heterocyclic group", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to the "heterocyclic group" or "heterocyclic group" of a monocyclic ring system, and the heterocyclic group, "monocyclic heterocyclic group" appearing herein group" or "heteromonocyclic group", the definition of which is consistent with that of heterocycle.

"Heterocyclyl", "heterocyclyl", "heterocyclic heterocyclyl" or "heterocyclyl" refers to "heterocycles" that contain heteroatoms. The definition of heterocyclic ring, "heterocyclic group", "heterocyclic heterocyclic group" or "heterocyclic group" used herein is consistent with that of parallel ring.

"Heterospiro", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" that contains heteroatoms. As used herein, heterospirocycle, "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" have the same definition as spirocycle.

"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "heterobridged ring group" refers to a "bridged ring" that contains heteroatoms. The definition of heterobridged ring, "heterobridged ring group", "bridged ring heterocyclyl group" or "heterobridged ring group" used herein is consistent with bridged ring.

“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is 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, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene,

"Aryl" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。"Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include

Where heteroaryl appears herein, its definition is consistent with this definition. Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.

"5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered condensed heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.

"5 and 6-membered heteroaryl ring" refers to a 5-6 membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.

"Substituted" or "substituted" means substituted by 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, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m - C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -ene -R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c Such groups, wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Sulfonyl, as an option, R ^b and R ^c can form a five or six membered cycloalkyl or heterocyclic group.

"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.

"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10. For example, "substituted by 0 to 4 substituents" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "substituted by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.

X-Y-membered rings (X is selected from integers less than Y and greater than 3, and Y is selected from any integer between 4 and 12) include X+1, X+2, X+3, X+4...Y-membered rings. Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.

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

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

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

"Prodrug" refers to a compound of the present invention that can be transformed into a biologically active compound through in vivo metabolism. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups of the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are both solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.

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

"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomer" refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.

"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group. Happening.

" _IC50 " is the concentration of drug or inhibitor required to inhibit a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.) by half.

Detailed ways

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

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) NMR instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , internal standard is tetramethylsilane (TMS);

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

The determination of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

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

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

Example 1

2-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2- (Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)acetamide (Compound 1)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2-(dimethylamino)ethoxy)- 5-(trifluoromethyl)phenyl)acetamide

The first step 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1C)

3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

4-Amino-3-iodo-1H-oxazololo[3,4-D]pyrimidine (1A) (3g, 11.49mmol) and potassium carbonate (3.18g, 22.98mmol) were dissolved in N,N-dimethylformaldehyde The amide (32mL) was dissolved, and under the protection of nitrogen atmosphere, 2-iodopropane (1B) (1.26mL, 12.64mmol) was slowly added dropwise in an ice bath. After the dropwise addition, it was raised to room temperature and stirred for 2 hours. Add 150mL of water to dilute the reaction, then use ethyl acetate to extract, the organic phase is washed with saturated brine, then the organic phase is dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column to obtain the target compound (1C) ( 1.614g, yield: 46%)

Ms m/z(ESI):304.1[M+H] ⁺

The second step is 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)methyl acetate (1E)

methyl 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetate

Compound 1C (1.5g, 4.95mmol) and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base) methyl acetate (1D) (2.19g, 7.43mmol) was dissolved in a mixed solvent of 12mL 1,4-dioxane and 1mL water, cesium carbonate (3.23g, 9.90mmol) was added, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (408 mg, 0.5 mmol). Under nitrogen protection, stir at 110°C for 3 hours. Cool to room temperature, then add 150 mL of water to dilute the reaction, then extract with ethyl acetate, wash the organic phase with saturated brine, then dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain the target Compound (1E) (1.42 g, yield: 90%)

Ms m/z(ESI):344.1[M+H] ⁺

The third step 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetic acid (1F)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetic acid(1F)

Compound 1E (1.742g, 5.08mmol) was dissolved in a mixed solvent of 12mL methanol and 12mL water, lithium hydroxide monohydrate (640mg, 15.52mmol) was added, and stirred at 50°C for 1.5 hours. Cool to room temperature, then add 1N dilute hydrochloric acid solution to adjust the pH to 7, collect the filter cake after filtration, and dry to obtain the target compound (1F) (1.64g, yield: 98%)

Ms m/z(ESI):330.2[M+H] ⁺

The fourth step 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3- (2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)acetamide (Compound 1)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2-(dimethylamino)ethoxy)- 5-(trifluoromethyl)phenyl)acetamide

Compound (1F) (140mg, 0.43mmol), 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (126mg, 0.51mmol) were dissolved in 12mL DMF, added N-methylimidazole (84mg, 1.02mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (177mg, 0.63mmol) were reacted at room temperature for 3 hours. Add 100mL of water for dilution, then extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain a white solid, which is the target compound 1 (63 mg, yield : 26%)

Ms m/z(ESI):560.3[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.39(s,1H),7.77(br.s,1H),7.58-7.48(m,4H),7.39–7.31(m,1H),6.92–6.86(m ,1H),5.45(br.s,2H),5.24–5.14(m,1H),4.22(t,2H),3.84(s,2H),2.95(t,2H),2.52(s,6H), 1.60(d,6H).

Example 2

2-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2- (Pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl)acetamide (Compound 2)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2-(pyrrolidin-1-yl )ethoxy)-5-(trifluoromethyl)phenyl)acetamide

The first step 1-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)pyrrolidine (2C)

1-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)pyrrolidine

1-fluoro-3-nitro-5-(trifluoromethyl)benzene (2A) (2g, 9.57mmol) and 2-(pyrrolidin-1-yl)ethan-1-ol (2B) (1.1g , 9.57mmol) was dissolved in N,N-dimethylformamide (20mL), then cesium carbonate (6.24g, 19.14mmol) was added, under the protection of nitrogen atmosphere, the reaction was stirred at 80°C for 6 hours. Add 150mL of water to dilute the reaction, then extract with ethyl acetate, wash the organic phase with saturated brine, then dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain the target compound (2C) ( 2.30g, yield: 79%)

Ms m/z(ESI):305.1[M+H] ⁺

The second step 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)aniline (2D)

3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)aniline

Compound 2C (2.30 g, 7.56 mmol) was dissolved in ethyl acetate (20 mL), then 10% palladium on carbon (0.3 g) was added, and the reaction was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, then the celite was washed with ethyl acetate (50 mL), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2D) (1.97 g, Yield: 95%)

Ms m/z(ESI):275.1[M+H] ⁺

The third step 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3- (2-(Pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl)acetamide (Compound 2)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-(2-(pyrrolidin-1-yl )ethoxy)-5-(trifluoromethyl)phenyl)acetamide

Compound (1F) (140mg, 0.43mmol), 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)aniline (2D) (140mg, 0.51mmol) were dissolved in In 12mL of DMF, N-methylimidazole (87mg, 1.07mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (179mg, 0.64mmol) were added, and reacted at room temperature for 3 hours. Add 100mL of water for dilution, then extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain a white solid, which is the target compound 2 (32 mg, yield : 13%)

Ms m/z(ESI):586.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.38(s,1H),8.03(br.s,1H),7.59–7.47(m,4H),7.43–7.36(m,1H),6.88–6.83(m ,1H),5.46(br.s,2H),5.23–5.14(m,1H),4.38–4.29(m,2H),3.85(s,2H),3.24–3.14(m,2H),3.12–2.93 (m,4H),2.06–1.95(m,4H),1.60(d,6H).

Example 3

2-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-((1 -Methylazetidin-3-yl)methoxy)-5-(trifluoromethyl)phenyl)acetamide (compound 3)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-((1-methylazetidin-3-yl )methoxy)-5-(trifluoromethyl)phenyl)acetamide

The first step 3-(((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylic acid tert-butyl ester (3B)

tert-butyl 3-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate

1-Fluoro-3-nitro-5-(trifluoromethyl)benzene (2A) (1 g, 4.78 mmol) and tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate ( 3A) (0.985g, 5.26mmol) was dissolved in N,N-dimethylformamide (10mL), then cesium carbonate (3.1g, 9.56mmol) was added, and stirred at 80°C for 6 hours under the protection of nitrogen atmosphere. Add 150mL of water to dilute the reaction, then extract with ethyl acetate, wash the organic phase with saturated brine, then dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain the target compound (3B) ( 1.5g, yield: 83%)

Ms m/z(ESI):321.1[M-55] ⁺

The second step 3-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine (3C)

3-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine

Compound 3B (1.5 g, 3.99 mmol) was dissolved in dichloromethane (15 mL), then trifluoroacetic acid (6 mL) was added, and the reaction was stirred at room temperature for 3 hours under a nitrogen atmosphere. Concentration under reduced pressure gave the target compound (3B) (1.1 g, yield: 99%) Ms m/z (ESI): 277.1 [M+H] ⁺

The third step 1-methyl-3-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine (3D)

1-methyl-3-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)azetidine

Compound 3C (1.1 g, 3.98 mmol) was dissolved in methanol (15 mL), then paraformaldehyde (3 mL) was added, and the reaction was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Sodium triacetoxyborohydride (0.844 g, 11.94 mmol) was then added, and the stirring reaction was continued at room temperature for 2 hours. Concentrate under reduced pressure, then add 50 mL of water to dilute the reaction, then slowly add 50 mL of saturated sodium bicarbonate solution to wash, then use ethyl acetate to extract, the organic phase is washed with saturated brine, then the organic phase is dried with anhydrous sodium sulfate, and after filtration, Concentrated under reduced pressure, purified by silica gel column to obtain the target compound (3D) (1 g, yield: 87%) Ms m/z (ESI): 291.2 [M+H] ⁺

The fourth step 3-((1-methylazetidin-3-yl)methoxy)-5-(trifluoromethyl)aniline (3E)

3-((1-methylazetidin-3-yl)methoxy)-5-(trifluoromethyl)aniline

Compound 3D (1 g, 3.44 mmol) was dissolved in ethyl acetate (15 mL), then 10% palladium on carbon (0.2 g) was added, and the reaction was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered through celite, then the celite was washed with ethyl acetate (50 mL), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (3E) (0.88 g, Yield: 98%)

Ms m/z(ESI):261.1[M+H] ⁺

The fifth step 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3- ((1-Methylazetidin-3-yl)methoxy)-5-(trifluoromethyl)phenyl)acetamide (Compound 3)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(3-((1-methylazetidin-3-yl )methoxy)-5-(trifluoromethyl)phenyl)acetamide

Compound (1F) (140mg, 0.43mmol), 3-((1-methylazetidin-3-yl)methoxy)-5-(trifluoromethyl)aniline (3E) (133mg, 0.51mmol) was dissolved in 12mL DMF, N-methylimidazole (87mg, 1.07mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (179mg, 0.64mmol) were added, and then React at room temperature for 3 hours. Add 100mL of water for dilution, then extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain a white solid, which is the target compound 3 (30 mg, yield : 12%)

Ms m/z(ESI):572.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.39(s,1H),7.81(br.s,1H),7.71–7.65(m,1H),7.58–7.48(m,3H),7.42–7.35(s ,1H),6.92–6.87(m,1H),5.45(br.s,2H),5.24–5.14(m,1H),4.21–3.99(m,4H),3.92–3.79(m,4H),3.31 –3.18(m,1H),2.78(s,3H),1.60(d,6H).

Example 4

3-(2-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N- (2-(3-Methylazetidin)-1-yl)ethyl)-5-(trifluoromethyl)benzamide (compound 4)

3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N-(2-(3-methylazetidin -1-yl)ethyl)-5-(trifluoromethyl)benzamide

The first step: 3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido )-N-(2-(3-methylazetidin)-1-yl)ethyl)-5-(trifluoromethyl)benzamide (compound 4)

3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N-(2-(3-methylazetidin -1-yl)ethyl)-5-(trifluoromethyl)benzamide

Compound (1F) (140mg, 0.43mmol), 3-amino-N-(2-(3-methylazetidin-1-yl)ethyl)-5-(trifluoromethyl)benzyl Amide (4A) (129 mg, 0.43 mmol) was dissolved in 8 mL of DMF, N-methylimidazole (88 mg, 1.08 mmol), N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate ( 181mg, 0.65mmol), and then reacted at room temperature for 3 hours. Add 100mL of water for dilution, then extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain a white solid, which is the target compound 4 (50 mg, yield : 19%)

Ms m/z(ESI):613.3[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.67(s,1H),8.58(s,1H),8.47–8.41(m,1H),8.37(s,1H),8.14(s,1H),7.98( s,1H),7.58–7.48(m,3H),5.65(s,2H),5.24–5.13(m,1H),4.27(s,2H),3.88(s,2H),3.74–3.57(m, 4H), 3.37–3.30(m,2H), 3.11–3.02(m,1H), 1.59(d,6H), 1.32(d,3H).

Example 5

3-(2-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N- (2-(Dimethylamino)ethyl)-5-(trifluoromethyl)benzamide (Compound 5)

3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N-(2-(dimethylamino)ethyl )-5-(trifluoromethyl)benzamide

The first step: 3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido )-N-(2-(dimethylamino)ethyl)-5-(trifluoromethyl)benzamide (compound 5)

3-(2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamido)-N-(2-(dimethylamino)ethyl )-5-(trifluoromethyl)benzamide

Compound (1F) (200mg, 0.61mmol), 3-amino-N-(2-(dimethylamino)ethyl)-5-(trifluoromethyl)benzamide (5A) (184mg, 0.67mmol ) was dissolved in 10mL DMF, N-methylimidazole (125mg, 1.53mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (257mg, 0.92mmol) were added, and then reacted at room temperature 3 hours. Add 100mL of water for dilution, then extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a silica gel column to obtain a white solid, which is the target compound 5 (89 mg, yield : 25%)

Ms m/z(ESI):587.3[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.38(s,1H),8.24(s,1H),8.11(s,1H),8.05(s,1H),7.75(s,1H),7.58–7.50( m,3H),7.24–7.16(m,1H),5.50(s,2H),5.24–5.15(m,1H),3.86(s,2H),3.57(dd,2H),2.62(t,2H) ,2.35(s,6H),1.60(d,6H).

biological test case

1. In vitro RET kinase assay

Kinase RET (Carna, Cat.No.08-159) was prepared into a 5× kinase solution, and the substrate TK Substtrate-biotin (Cisbio, Cat.No.62TK0PEB) was prepared with ATP (Sigma, Cat.No.A7699-1G) into a 2.5× substrate solution. Add 4 μL of different concentrations of compounds to a 384-well plate, add 2 μL of 5× kinase solution, add 4 μL of 2.5× substrate solution, incubate at 25°C for 30 min, add 10 μL of stop solution (5 μL Sa-XL665 and 5 μL TK antibody- Eu ³⁺ mixed (Cisbio, Cat. No. 62TKOPEB)) to terminate the reaction, using PHERAstar FSX instrument detection. _IC50 values were calculated using GraphPadPrism 6 software. The test results are shown in Table 1. Among them, the reference substance AD80 was purchased from Chengdu Huajieming Biotechnology Co., Ltd.

Table 1: Compounds for RET Kinase Activity

compound In vitro RET kinase IC₅₀(nM) Compound 1 0.15 Compound 2 0.22 Compound 3 0.25 Compound 4 0.64 Compound 5 0.21 AD80 1.08

Conclusion: the compound of the present invention has good inhibitory activity on RET kinase.

2. Cell Proliferation Inhibitory Activity

TT cell culture medium is F12K (containing 10% FBS, 1×Non-Essential Amino Acid, 1×Glutamax and 1×Penicillin/Streptomycin). Cells were cultured in a 37°C, 5% CO ₂ incubator. Cells were plated in 96-well plates. 6000 TT cells/well, 50 μL medium per well, cultured overnight at 37°C, 5% CO ₂ . On the second day, 50 μL of culture medium containing different concentrations of the test compound was added to each well, and three replicate wells were set up for each concentration. At the same time, a DMSO vehicle control group and a negative control group were set up, each with 3 replicate wells. Culture was continued for 7 days at 37°C, 5% CO ₂ . After 7 days, add 100 μL of detection reagent (Cell Viability Assay, Promega, G7573) to each well, place on a shaker and shake for 15 minutes in the dark, draw 100 μL of the solution into each well and place it in a 96-well plate with an opaque white bottom. A microplate reader (BMG LABTECH) was used to measure the fluorescence signal value. _IC50 values were calculated using GraphPad Prism software.

The Ba/F3-KIF5B-RET-G810R engineered cell line (provided by Zhongke Ruisheng) medium is RPMI-1640+10% FBS, and the cells are cultured in a 37°C, 5% CO ₂ incubator. Cells were plated in 96-well plates. 2000 cells/well, 95 μL per well. Then 5 μL of different concentrations of test compounds were added to each well, and two replicate wells were set up for each concentration, and the last column was the DMSO vehicle control group. Cultivate for 72 hours at 37°C and 5% CO ₂ . After 72 hours, 50 μL of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the fluorescence signal value was measured using SpectraMax Paradigm. IC ₅₀ values were calculated using GraphPad Prism7.0 software.

Table 2: Inhibitory activity of compounds on cell proliferation

Conclusion: the compound of the present invention has good inhibitory activity on the proliferation of TT cells and Ba/F3-KIF5B-RET-G810R engineered cell lines.

Claims (12)

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

Indicates that the ring is an aromatic ring; Z ₁ , Z ₂ , Z ₃ , Z ₆ or Z ₇ are each independently selected from CR ^z , NR ^z or N; Z ₄ or Z ₅ are each independently selected from C or N; A ₁ , A ₂ , A ₃ or A ₄ are each independently selected from CR ^a or N; Ring B is each independently selected from a benzene ring or a 6-membered heteroaryl ring, and the heteroaryl ring contains 1 to 3 heteroatoms selected from O, S, and N; R ^z are each independently selected from H, halogen, OH, =O, cyano, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _{1- 6} alkoxy, C _3-10 cycloalkyl, 4 to 10 membered heterocycloalkyl, CONH ₂ , CONHC _1-6 alkyl, COC _1-6 alkyl, CON(C _1-6 alkyl) ₂ , The alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, NH ₂ , C _1-6 alkyl, C Substituted by _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, halogen-substituted C _1-6 alkyl or C _1-6 alkoxy; R ¹ , R ² , R ⁵ or R ⁶ are each independently selected from H, C _1-6 alkyl, halogen substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, C _2-6 alkenes Base, C _2-6 alkynyl; R ³ , R ⁴ , R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene -C _3-12 carbocyclyl or -C _0-4 alkylene Alkyl-4 to 12-membered heterocyclic group, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, halogen, OH, = O, cyano, NH ₂ , C _1-6 alkyl, halogen substituted C _1-6 alkyl or C _1-6 alkoxy substituent; X1 is selected from a bond, -CH ₂ -, -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N( R ^x )-, -N(R ^x )C(=O)-; X2 is selected from -O-, -S-, -N(R ^x )-, -S(O) ₂ -, -C(=O)-, -C(=O)N(R ^x )-, -N (Rx)C( ⁼ O)-; R ^x are each independently selected from H or C _1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C _1-6 alkyl, Substituents of C _1-6 alkoxy or C _3-6 cycloalkyl; R ⁷ are each independently selected from C _1-6 alkyl, -C _0-4 alkylene-C _3-12 carbocyclyl, -C _0-4 alkylene-4 to 12 membered heterocyclyl, said R ⁷ is optionally further substituted by 0 to 4 R ^7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted by =O Or (=O) ₂ substitution; each R ^7a is independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _{1 -6} alkyl, -C _0-4 alkylene-N(C _1-6 alkyl) ₂ , -SO ₂ -C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -SO ₂ -C _3-7 carbocyclyl, C _3-12 carbocyclyl or 4 to 12 membered heterocyclyl, the R ^7a is optionally further By 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen Substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 ring Substituted by alkyl or C _1-6 alkoxyalkyl, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally Further replaced by =O or (=O) ₂ ; Alternatively, R ^x and R ⁷ together with the atoms they are attached to form a non-aromatic 4-12 membered heterocyclic ring optionally further substituted by 0 to 4 R ^7a , said heterocyclic ring containing 1 to 4 a heteroatom selected from O, S, N; m is selected from 0, 1, 2, 3 or 4. 2. The compound according to claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from general formula (I-1) or The compound represented by (II-1), wherein,

Z ₆ are each independently selected from CR ^z or N; R ¹ and R ² are each independently selected from H or C _1-4 alkyl. 3. The compound according to claim 2 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, R ^z are each independently selected from H, C _1-4 alkyl, COC _1-6 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, CONH ₂ , CONHC _1-4 alkyl, CON(C _1-4 alkyl) ₂ , the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, Substituents of NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy; R ^a or R ^b are each independently selected from H, halogen, OH, cyano, COOH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-7 carbocyclyl or -C _0-2 alkylene-4 to 7 A membered heterocyclyl, the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, Substituents of NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy; R ^x are each independently selected from H or C _1-4 alkyl, and said alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, C _1-4 alkyl, Substituents of C _1-4 alkoxy or C _3-6 cycloalkyl; R ⁷ are each independently selected from C _1-4 alkyl, -C _0-4 alkylene-C _3-7 monocyclic carbocyclyl, -C _0-4 alkylene-C _{4-11 alkane} carbocycle Base, -C _0-4 alkylene -C _5-11 spiro ring carbocyclyl, -C _0-4 alkylene -C _5-11 bridged ring carbocyclyl, -C _0-4 alkylene -4 to 7-membered monocyclic heterocyclyl, -C _0-4 alkylene-5 to 11-membered and ring heterocyclyl, -C _0-4 alkylene-5 to 11-membered spirocyclic heterocyclyl, -C _{0 -4} alkylene-5 to 11-member bridged ring heterocyclic group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , and the heterocyclic group contains 1 to 4 members selected from O, S, N A heteroatom, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ; R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, -C _0-4 alkylene-NH ₂ , -C _0-4 alkylene-NHC _1-4 alkyl, -C _{0 -4} alkylene-N(C _1-4 alkyl) ₂ , -SO ₂ -C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-7 carbocyclyl, 5 to 7 membered heterocyclyl, the R ^7a is optionally further selected from 0 to 4 selected from H, halogen, OH, =O , cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1- Substituents of ₄ alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ ; Alternatively, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic heterocyclic ring as follows: 4 to 7 membered monocyclic heterocyclic ring, 5 to 11 membered heterocyclic ring, 5 to 11 membered spirocyclic heterocyclic ring, 5 to 11 membered spirocyclic heterocyclic ring, 11-membered bridged ring heterocycle, said heterocycle is optionally further substituted by 0 to 4 R ^7a , said heterocycle contains 1 to 4 heteroatoms selected from O, S, N. 4. The compound according to claim 3 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Ring B is each independently selected from phenyl, pyridine, pyrazine, pyrimidine; R ¹ and R ² are each independently selected from H, methyl or ethyl; R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl and cyclopentyl are optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, cyclopropyl Substituents of radical, cyclobutyl, halogen-substituted C _1-4 alkyl or C _1-4 alkoxy; R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl, isobutyl, ethylene radical, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl base, -CH ₂ -cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, the methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy , ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Substituted by Br, I, OH, =O, cyano, NH ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl or C _1-4 alkoxy; R ^x are each independently selected from H, methyl, and ethyl, and the methyl and ethyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, cyano , C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents; R ⁷ are each independently selected from C _1-4 alkyl, C _3-7 monocyclic carbocyclyl, C _4-11 acyclic carbocyclyl, C _5-11 spirocyclic carbocyclyl, C _5-11 bridged ring Carbocyclyl, 4 to 7 membered monocyclic heterocyclic group, 5 to 11 membered heterocyclic heterocyclic group, 5 to 11 membered spirocyclic heterocyclic group, 5 to 11 membered bridged ring heterocyclic group, -CH ₂ -C _{3 -7} monocyclic carbocyclyl, -CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7-membered monocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered parallel heterocyclic group, -CH ₂ CH ₂ -5 to 11-membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5- to 11-membered bridged ring heterocyclyl, -CH ₂ CH ₂ -C _3-7 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 acyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 spirocyclic carbocyclyl, -CH ₂ CH ₂ -C _5-11 bridged ring carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ - 5 to 11 membered ring heterocyclic group, -CH ₂ CH ₂ -5 to 11 membered spirocyclic heterocyclic group, -CH ₂ CH ₂ -5 to 11 membered bridged ring heterocyclic group, the R ⁷ is optionally further 0 to 4 R ^7a are substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatom is selected from S, it is optionally further replaced by =O or (=O) ₂ replaced; R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _{1- 4} alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -SO ₂ -C _3-6 carbocyclyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, R ^7a is optionally further replaced by 0 to 4 members selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _{1 -4} alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _2-4 alkynyl, Substituents of C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further replaced by =O or (=O) ₂ ; Alternatively, R ^x and R ⁷ together with the atoms to which they are attached form a non-aromatic 4 to 7 membered monocyclic heterocyclic ring, said heterocyclic ring is optionally further substituted by 0 to 4 R ^7a , said heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N. 5. The compound according to claim 4 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Each R ⁷ is independently selected from C _1-4 alkyl, C _3-6 monocyclic carbocyclyl, -CH ₂ -C _3-6 monocyclic carbocyclyl, -CH ₂ CH ₂ -C _3-6 monocyclic Carbocyclyl, 3 to 6 membered monocyclic heterocyclic group, -CH ₂ -3 to 6 membered monocyclic heterocyclic group, -CH ₂ CH ₂ -3 to 6 membered monocyclic heterocyclic group, 3 to 4 membered carbocyclic group Base, 3 and 5-membered carbocyclyl, 3 and 6-membered carbocyclyl, 4 and 4-membered carbocyclyl, 4 and 5-membered carbocyclyl, 4 and 6-membered carbocyclyl, 5 and 5-membered carbocyclyl, 5 and 6-membered carbocyclyl, 6 and 6-membered carbocyclyl, 3-spiro 4-membered carbocyclyl, 3-spiro 5-membered carbocyclyl, 3-spiro 6-membered carbocyclyl, 4-spiro 4-membered carbocyclyl, 4-spiro 5-membered carbocyclyl, 4-membered 6-membered carbocyclyl, 5-membered 5-membered carbocyclyl, 5-membered 6-membered carbocyclyl, 6-membered 6-membered carbocyclyl, 3 and 4-membered heterocyclyl, 3 and 5-membered Heterocyclic group, 3 and 6-membered heterocyclic group, 4 and 4-membered heterocyclic group, 4 and 5-membered heterocyclic group, 4 and 6-membered heterocyclic group, 5 and 5-membered heterocyclic group, 5 and 6-membered heterocyclic group Base, 6 and 6-membered heterocyclyl, 3-spiro 4-membered heterocyclyl, 3-spiro 5-membered heterocyclyl, 3-spiro 6-membered heterocyclyl, 4-spiro 4-membered heterocyclyl, 4-spiro 5-membered heterocyclyl, 4-spiro 6-membered heterocyclyl, 5-spiro 5-membered heterocyclyl, 5-spiro 6-membered heterocyclyl, 6-spiro 6-membered heterocyclyl, C _5-10 member bridged ring carbocyclyl, -CH ₂ -C _{5- 10} -membered bridged ring carbocyclic group, 5-10-membered bridged ring heterobridged group, -CH ₂ -5- to 10-membered bridged ring heterobridged group, the R ⁷ is optionally further substituted by 0 to 4 R ^7a , The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ ; R ^7a are each independently selected from halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -CH ₂ NH ₂ , -CH ₂ NHC _1-4 alkyl, -CH ₂ N(C _1-4 alkyl) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHC _1-4 alkyl, -CH ₂ CH ₂ N(C _{1- 4} alkyl) ₂ , -SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-7 members Heterocycloalkyl, said R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 Alkyl) ₂ , C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, halogen substituted Substituents of C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl, the heterocycloalkyl contains 1 to 4 selected from O, S, N When the heteroatom is selected from S, it is optionally further substituted by =O or (=O) ₂ . 6. The compound according to claim 5 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert ^- butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine Azolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazine-3( 2H)-keto, oxetanyl, oxolyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ - Cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxolyl, -CH ₂ -oxanyl, - CH ₂ -azetidinyl, -CH ₂ -azetidinyl, -CH ₂ -piperidine, -CH ₂ -morpholine, -CH ₂ -piperazine, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ -oxetanyl, -CH ₂ CH ₂ -oxetanyl Pentyl, -CH ₂ CH ₂ -oxanyl, -CH ₂ CH ₂ -azetidinyl, -CH ₂ CH ₂ -azetidinyl, -CH ₂ CH ₂ -piperidine, -CH ₂ CH ₂ -morpholine, -CH ₂ CH ₂ -piperazine, -CH ₂ CH ₂ -imidazolidine, -CH ₂ CH ₂ -oxazolidine, -CH ₂ CH ₂ -pyrazole, -CH ₂ CH ₂ - Pyrrole, -CH ₂ CH ₂ -imidazole, -CH ₂ CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane, -CH ₂ -bicyclo[1.1.1]pentane base, -CH ₂ -bicyclo[2.1.1]hexyl, -CH ₂ -bicyclo[2.2.1]heptanyl, -CH ₂ -bicyclo[3.3.2]decyl, -CH ₂ -bicyclo[ 2.2.2] Octyl, -CH ₂ -bicyclo[3.2.1]octyl, -CH ₂ -bicyclo[3.3.3]undecyl, -CH ₂ -adamantyl,

Cyclopropylcyclopentyl, cyclobutylcyclopentyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutyl Spirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, Cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentyl Azacyclopentyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl Butyl, azetidinyl azetidinyl, azetidinyl piperidinyl, azetidinyl azetidinyl, azacyclopentyl azetidinyl, nitrogen Heterocyclopentylpiperidinyl, Azetiylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylpiperidinyl, Cyclobutylspiroazetidinyl Cyclobutylspiroazacyclopentyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazacyclopentyl, cyclopentylspiropiperidinyl, cyclohexane Basespiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidinylspiropiperidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiroazetidinyl, azacyclopentylspiropiperidinyl, azacyclohexylspiro Azetidinyl, Azacyclohexylspiroazolyl, Piperidylspiropiperidinyl, Oxetanyl, Oxolyl, Oxanyl, Cyclopropyloxetane Butyl, Cyclopropyloxolane, Cyclopropyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl, Cyclobutyloxetanyl Cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclopentyl oxetanyl, cyclohexyl oxetanyl, cyclohexyl oxetanyl base, cyclohexyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, azetidinyl and oxetanyl, piperidine Azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, azacyclopentyloxetanyl, piperidoxetanyl Base, piperidinyl and oxetanyl, piperidinyl oxetanyl, piperidinoxanyl, cyclobutylspirooxetanyl, cyclobutylspirooxetyl, Cyclobutylspiropiperidinyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclopentylspirooxetanyl, cyclohexylspirooxetanyl, cyclohexane Basespirooxolyl, cyclohexylspirooxetyl, azetidinylspirooxetyl, azetidinylspirooxolyl, azetidinylspirooxetyl Cyclohexyl, Azacyclopentylspirooxetanyl, Azacyclopentylspirooxetanyl, Azacyclopentylspirooxetyl, Azepanylspirooxetanyl Base, azacyclohexylspirooxolyl, azacyclohexylspirooxanexyl, piperidinespirooxetanyl, piperidinespirooxolyl, piperidinespirooxane Hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl,

The R ⁷ is optionally further substituted by 0 to 4 R ^7a ; R ^7a are each independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ NHCH ₂ CH ₃ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH _3. -CH ₂ CH ₂ NHCH ₂ CH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH _3. -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ -cyclopropyl, -SO ₂ -phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Azetidinyl, Azacyclopentyl, Piperidine, Morpholine Or piperazine, said R ^7a is optionally further replaced by 0 to 4 selected from H, halogen, OH, =O, cyano, COOH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl ) ₂ , C _1-4 alkyl, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by hydroxy, C _2-4 alkynyl, C _1-4 alkoxy, C ₁ substituted by halogen _-4 alkoxy, C _3-6 cycloalkyl or C _1-4 alkoxyalkyl substituents. 7. The compound according to claim 6 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Ring A is selected from

Ring B is selected from phenyl; m is selected from 1; R ^a or R ^b are each independently selected from H, F, Cl, Br, I, OH, cyano, COOH, NH ₂ , CF ₃ , methyl, ethyl, propyl, butyl, isobutyl, methyl Oxy, ethoxy or cyclopropyl; R ^z are each independently selected from H, methyl, ethyl, propyl, isopropyl; X1 is selected from a bond, -CH ₂ -, -O-, -C(=O)N(R ^x )-; X2 is selected from -O-, -C(=O)N(R ^x )-; Each R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert ^- butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridazine, pyridazine Oxazin-3(2H)-one, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutane -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclopentyl, -CH ₂ CH ₂ -cyclohexyl,

The R ⁷ is optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ; Alternatively, R ^x and R ⁷ form azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine together with the atoms they are connected to, and the azetidinyl, azetidinyl, azetidinyl, Piperidine, morpholine, piperazine are optionally further substituted by 0, 1, 2, 3 or 4 R ^7a ; R ^7a are each independently selected from F, OH, =O, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , methyl, ethyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxetanyl, Oxolyl, Oxetanyl, Azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a is optionally further selected from H, F, Cl, Br, I by 0, 1, 2, 3 or 4 , OH, =O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl substituents. 8. The compound according to claim 7 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the general formula (I-1-1 ), (I-1-2), (II-1-1) or the compound represented by (II-1-2), wherein,

Z ₆ are each independently selected from CH or N; -X1- ^R7 are each independently selected from

-X2- ^R7 are each independently selected from

9. The compound according to claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the following structures:

10. A pharmaceutical composition comprising the compound of any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutically acceptable carrier. 11. The compound according to any one of claims 1-9 or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation of treatment with RET Application in drugs for diseases related to activity or expression level. 12. The application according to claim 11, characterized in that the disease is selected from IBS, tumor or autoimmune system disease.