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

Abstract

The invention relates to a compound shown in a general formula (I) or (II) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of medicines for treating diseases related to RET activity or expression quantity.

Description

Heterocyclic derivative and application thereof in medicine

Technical Field

The invention relates to a compound shown in a general formula (I) or (II) or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to RET activity or expression quantity

Background

RET is a relatively rare oncogene located in the long arm of human chromosome 10 and encodes a receptor tyrosine kinase that spans the cell membrane. Receptor tyrosine kinases are the largest class of enzyme-linked receptors, which are both receptors and enzymes, can be combined with ligands, phosphorylate tyrosine residues of target proteins, then are combined with signal proteins in cells, expand information through a plurality of different signal transduction pathways, and activate a series of biochemical reactions in the cells; or combining different information to elicit a comprehensive response of the cell, such as cell proliferation, etc. Once dysregulated, receptor tyrosine kinases can cause tumorigenesis.

The activated RET protein can activate a plurality of downstream signal pathways, including RAS/RAF/ERK pathways, PI3K/Akt pathways, JNK pathways and the like, so as to cause 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, signaling pathway hyperactivity, which is also one of the major mechanisms of carcinogenesis. The abnormally activated RET protein participates in the proliferation and invasion of different tumor cells through various signal pathways, thereby influencing the occurrence and development of tumors. Therefore, inhibition of RET activity is of great medical value.

The invention develops a RET inhibitor with novel structure, good drug effect and higher safety, which is used for treating RET related diseases such as IBS, tumors or autoimmune system diseases.

Disclosure of Invention

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

The compound of the invention has good pharmacological property and bioavailability, oral property and good safety.

The invention provides a compound shown in a general formula (I) or (II) or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

Represents that the ring is aromatic;

in some embodiments, Z ₁ 、Z ₂ 、Z ₃ 、Z ₆ Or Z ₇ Each independently selected from CR ^z 、NR ^z Or N;

in some embodiments, Z ₁ 、Z ₃ Selected from N, Z ₆ Each independently selected from CR ^z Or N, Z ₇ Is selected from NR ^z ；

In some embodiments, Z ₁ 、Z ₃ Selected from N, Z ₆ Each independently selected from CH or N, Z ₇ Is selected from NR ^z ；

In some embodiments, Z ₆ Each independently selected from CR ^z Or N;

in some embodiments, Z ₆ Each independently selected from CH or N;

in some embodimentsIn the table, Z ₄ Or Z ₅ Each is independently selected from C or N;

in some embodiments, Z ₄ Or Z ₅ Each independently selected from C;

in some embodiments, a is ₁ 、A ₂ 、A ₃ Or A ₄ Each independently selected from CR ^a Or N;

in some embodiments, ring a is selected from

In some embodiments, rings B are each independently selected from a phenyl ring or a 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, 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, R ^z Each independently selected from H, halogen, OH, = O, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, CONH ₂ 、CONHC _1-6 Alkyl, COC _1-6 Alkyl, CON (C) _1-6 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, halogen-substituted C _1-6 Alkyl or C _1-6 Substituted by a substituent of alkoxy;

in some embodiments, R ^z Each independently selected from H and C _1-4 Alkyl, COC _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, CONH ₂ 、CONHC _1-4 Alkyl, CON (C) _1-4 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, halogen,OH, = O, cyano, NH ₂ 、C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, halogen-substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

in some embodiments, R ^z Each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl optionally being further substituted by 0 to 4 substituents selected from the group consisting of 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 Substituted by a substituent of alkoxy;

in some embodiments, R ^z Each independently selected from H, methyl, ethyl, propyl, isopropyl.

In some embodiments, R ^z Each independently selected from H, isopropyl;

in some embodiments, R ¹ 、R ² 、R ⁵ Or R ⁶ Each independently selected from H, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl;

in some embodiments, R ¹ 、R ² Each independently selected from H or C _1-4 An alkyl group;

in some embodiments, R ¹ 、R ² Each independently selected from H, methyl or ethyl;

in some embodiments, R ¹ 、R ² Each independently selected from H;

in some embodiments, R ⁵ Or R ⁶ Each independently selected from H;

in some embodiments, R ³ 、R ⁴ 、R ^a Or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical、C _2-6 Alkynyl, C _1-6 Alkoxy, -C _0-4 alkylene-C _3-12 Carbocyclic group or-C _0-4 Alkylene-4 to 12 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl or C _1-6 Substituted by a substituent of alkoxy;

in some embodiments, R ³ 、R ⁴ Each independently selected from H;

in some embodiments, R ^a Or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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 heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

in some embodiments, R ^a Or R ^b 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, said methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

in some embodiments, R ^a Or R ^b 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 Each independently selected from H, F, CF ₃ ；

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

In some embodiments, X1 is selected from the group consisting of a bond, -CH ₂ -、-O-、-C(＝O)N(R ^x )-；

In some embodiments, X1 is selected from the group consisting of a bond, -CH ₂ -、-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, R ^x Each independently selected from H or C _1-6 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy or C _3-6 Cycloalkyl substituted with a substituent;

in some embodiments, R ^x Each independently selected from H or C _1-4 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl substituted with a substituent;

in some embodiments, R ^x Each independently selected from H, methylEthyl, said methyl, ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl, substituted with a substituent;

in some embodiments, R ^x Each independently selected from H;

in some embodiments, R ⁷ 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 Optionally further substituted by 0 to 4R ^7a (iii) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

in some embodiments, R ⁷ Each independently selected from C _1-4 Alkyl, -C _0-4 alkylene-C _3-7 Monocyclic carbocyclic group, -C _0-4 alkylene-C _4-11 Carbocyclic group of a fused ring, -C _0-4 alkylene-C _5-11 Spiro carbocyclic group, -C _0-4 alkylene-C _5-11 Carbocyclic group of bridged ring, -C _0-4 Alkylene-4-to 7-membered monocyclic heterocyclyl, -C _0-4 Alkylene-5-to 11-membered heterocyclo, -C _0-4 Alkylene-5-to 11-membered spiroheterocyclyl, -C _0-4 Alkylene-5-to 11-membered bridged heterocyclo, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

in some embodiments, R ⁷ Each independently selected from C _1-4 Alkyl radical, C _3-7 Monocyclic carbocyclic group, C _4-11 And a cyclic carbocyclic group, C _5-11 Spirocyclic carbocyclic group, C _5-11 Bridged carbocyclyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 11-membered fused heterocyclic, 5-to 11-membered spiro heterocyclic, 5-to 11-membered bridged heterocyclic, -CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclyl, -CH ₂ CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 And cyclic carbocyclic group, -CH ₂ CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

in some embodiments, R ⁷ Each independently selected from C _1-4 Alkyl radical, 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 <xnotran> -3 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 </xnotran>Base, C _5-10 Cyclic ring radical of meta-bridged ring, -CH ₂ -C _5-10 Cyclic carbocyclic group of meta-bridged ring, heterocyclic bridging group of 5-10 membered bridged ring, -CH ₂ -a 5 to 10 membered cycloheteric bridging group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

in some embodiments, R ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazin-3 (2H) -one, oxetanyl, oxolanyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxocyclopentyl, -CH ₂ -oxacyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azacyclopentyl, -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 -oxocyclopentyl, -CH ₂ CH ₂ -oxacyclohexyl, -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 (pentane)、-CH ₂ -bicyclo [1.1.1]Pentyl alkyl, -CH ₂ -bicyclo [2.1.1]Hexyl, -CH ₂ -bicyclo [2.2.1]Heptenyl, -CH ₂ -bicyclo [3.3.2]Decyl, -CH ₂ -bicyclo [2.2.2]Octyl radical, -CH ₂ -bicyclo [3.2.1]Octyl, -CH ₂ -bicyclo [3.3.3]Undecyl, -CH ₂ An adamantyl group,

<xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran><xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , [1.1.1 </xnotran>]Pentyl alkyl, bicyclo [2.1.1 ] s]Hexane radical, bicyclo [2.2.1 ]]Heptenyl, bicyclo [3.3.2 ]]Decyl, bicyclo [2.2.2 ] 2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]An undecyl group an adamantyl group,

The R is ⁷ Optionally further substituted by 0 to4 of R ^7a Substitution;

in some embodiments, R ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 -cyclohexyl group,

Said R is ⁷ Optionally further substituted by 0, 1, 2, 3 or 4R ^7a Substitution;

in some embodiments, R ^7a Each 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 radical) ₂ 、-SO ₂ -C _1-6 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -SO ₂ -C _3-7 Carbocyclyl, C _3-12 Carbocyclyl or 4-to 12-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy-substituted C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or C _1-6 Substituted by alkoxyalkyl groupsAnd (ii) said heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, is optionally further substituted with = O or (= O) ₂ Substitution;

in some embodiments, R ^7a 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 radical) ₂ 、-SO ₂ -C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, -SO ₂ -C _3-6 Carbocyclyl, C _3-7 Carbocyclyl, 5-to 7-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ Substitution;

in some embodiments, R ^7a Each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, 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 Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 (ii) alkoxyalkyl having 1 to 4 heteroatoms selected from O, S, N, and optionally further having = O or (= O) when heteroatoms are selected from S ₂ Substitution;

in some embodiments, R ^7a Each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl having 1 to 4 heteroatoms selected from O, S, N, and optionally further substituted with = O or (= O) when heteroatoms are selected from S ₂ Substitution;

in some embodiments, R ^7a 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, oxolanyl, azetidinyl, piperidine, morpholine or piperazine, said R being a compound of formula (i) or (ii) wherein R is a substituent selected from the group consisting of phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolanyl, azetidinyl, piperidine, morpholine and piperazine ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Substituted with a substituent of alkoxyalkyl;

in some embodiments, R ^7a 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, oxolanylOxacyclohexyl, azetidinyl, azepinyl, piperidine, morpholine or piperazine, said R ^7a Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl;

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, said heterocyclic ring optionally further substituted with 0 to 4R ^7a (ii) substituted, said heterocycle containing 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 heterocyclic ring as follows: 4 to 7 membered monocyclic heterocycle, 5 to 11 membered fused cyclic heterocycle, 5 to 11 membered spirocyclic heterocycle, 5 to 11 membered bridged cyclic heterocycle, said heterocycle optionally further substituted with 0 to 4R ^7a Substituted, the heterocyclic ring containing 1 to 4 hetero atoms 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 optionally further substituted with 0 to 4R ^7a (ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R ^x And R ⁷ Together with the atom to which they are attached form an azetidinyl, an azacyclopentyl, a piperidine, a morpholine or a piperazine, said azetidinyl, azacyclopentyl, piperidine, morpholine, piperazine being optionally further substituted with 0, 1, 2, 3 or 4R ^7a Substitution;

in some embodiments, -X1-R ⁷ Each independently selected from

In some embodiments, -X2-R ⁷ Each 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 a first embodiment of the present invention, a compound represented by the aforementioned general formula (I) or (II) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

represents that the ring is aromatic;

Z ₁ 、Z ₂ 、Z ₃ 、Z ₆ or Z ₇ Each independently selected from CR ^z 、NR ^z Or N;

Z ₄ or Z ₅ Each independently selected from C or N;

A ₁ 、A ₂ 、A ₃ or A ₄ Each independently selected from CR ^a Or N;

each ring B is independently selected from a benzene ring or a 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N;

R ^z each independently selected from H, halogen, OH, = O, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, CONH ₂ 、CONHC _1-6 Alkyl, COC _1-6 Alkyl, CON (C) _1-6 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, halogen-substituted C _1-6 Alkyl or C _1-6 Substituted with a substituent of alkoxy;

R ¹ 、R ² 、R ⁵ or R ⁶ Each independently selected from H, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl;

R ³ 、R ⁴ 、R ^a or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -C _0-4 alkylene-C _3-12 Carbocyclic radical or-C _0-4 Alkylene-4 to 12 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl or C _1-6 Substituted with a substituent of alkoxy;

x1 is selected from the group consisting of 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(R ^x )C(＝O)-；

R ^x Each independently selected from H or C _1-6 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, halogen, OH, = O, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy or C _3-6 Cycloalkyl substituted with a substituent;

R ⁷ 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 Optionally further substituted by 0 to 4R ^7a (iii) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution; r is ^7a Each 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 radical) ₂ 、-SO ₂ -C _1-6 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -SO ₂ -C _3-7 Carbocyclic radical, C _3-12 Carbocyclyl or 4-to 12-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy-substituted C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or C _1-6 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ Substitution;

alternatively, R ^x And R ⁷ Together with the atoms to which they are attached form a non-aromatic 4-12 membered heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4R ^7a Substituted, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

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

As a second embodiment of the present invention, a compound represented by the following general formula (I-1) or (II-1) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

Z ₆ each independently selected from CR ^z Or N;

R ¹ 、R ² each independently selected from H or C _1-4 An alkyl group;

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

As a third embodiment of the present invention, a compound represented by the aforementioned general formula (I-1) or (II-1), or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ^z each independently selected from H and C _1-4 Alkyl, COC _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, CONH ₂ 、CONHC _1-4 Alkyl, CON (C) _1-4 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, halogen-substituted C _1-4 Alkyl or C _1-4 Substituted with a substituent of alkoxy;

R ^a or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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 heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

R ^x each independently selected from H or C _1-4 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy orC _3-6 Cycloalkyl, substituted with a substituent;

R ⁷ each independently selected from C _1-4 Alkyl, -C _0-4 alkylene-C _3-7 Monocyclic carbocyclic group, -C _0-4 alkylene-C _4-11 And cyclic carbocyclic group, -C _0-4 alkylene-C _5-11 Spiro carbocyclic group, -C _0-4 alkylene-C _5-11 Carbocyclic group of bridged ring, -C _0-4 Alkylene-4-to 7-membered monocyclic heterocyclyl, -C _0-4 Alkylene-5-to 11-membered heterocyclo, -C _0-4 Alkylene-5-to 11-membered spiroheterocyclyl, -C _0-4 Alkylene-5-to 11-membered bridged heterocyclo, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a 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 radical) ₂ 、-SO ₂ -C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, -SO ₂ -C _3-6 Carbocyclyl, C _3-7 Carbocyclyl, 5-to 7-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ Substitution;

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 heterocycle, 5-to 11-membered fused heterocyclic ring11 membered spirocyclic heterocycle, 5 to 11 membered bridged cyclic heterocycle, said heterocycle optionally further substituted with 0 to 4R ^7a Substituted, said heterocyclic ring containing 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 a fourth embodiment of the present invention, a compound represented by the aforementioned general formula (I-1) or (II-1), or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

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

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

R ^z each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl optionally being further substituted by 0 to 4 substituents selected from the group consisting of 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 Substituted by a substituent of alkoxy;

R ^a or R ^b 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, said methyl, ethyl, propyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

R ^x each independently selected from H, methyl, ethyl, said methyl, ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl, substituted with a substituent;

R ⁷ each independently selected from C _1-4 Alkyl radical, C _3-7 Monocyclic carbocyclic group, C _4-11 Cyclic fused ring group, C _5-11 Spiro carbocyclic group, C _5-11 Bridged carbocyclyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 11-membered fused heterocyclic, 5-to 11-membered spiro heterocyclic, 5-to 11-membered bridged heterocyclic, -CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, -CH ₂ CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, 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 Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 (ii) alkoxyalkyl having 1 to 4 heteroatoms selected from O, S, N, and optionally further having = O or (= O) when heteroatoms are selected from S ₂ Substitution;

alternatively, 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 optionally further substituted with 0 to 4R ^7a (ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

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

As a fifth embodiment of the present invention, a compound represented by the aforementioned general formula (I-1) or (II-1), or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ⁷ each independently selected from C _1-4 Alkyl radical, 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 heterocyclic group, 3-and 4-membered carbocyclic group, 3-and 5-membered carbocyclic group, 3-and 6-membered carbocyclic group, 4-and 4-membered carbocyclic group, 4-and 5-membered carbocyclic group, 4-and 6-membered carbocyclic group5 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 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 heterocyclyl, 4 and 4-membered heterocyclyl, 4 and 5-membered heterocyclyl, 4 and 6-membered heterocyclyl, 5 and 5-membered heterocyclyl, 5 and 6-membered heterocyclyl, 6 and 6-membered heterocyclyl, 3 spiro 4-membered heterocyclyl, 3 spiro 5-membered heterocyclyl, 4 spiro 4-membered heterocyclyl, 4 spiro 6-membered heterocyclyl, 5 spiro 5-membered heterocyclyl, 5 spiro 6-membered heterocyclyl, C _5-10 Ring carbon ring radical of meta-bridge, -CH ₂ -C _5-10 Cyclic carbocyclic radical of meta-bridged ring, heterocyclic bridging radical of 5-10 membered ring, -CH ₂ -a 5 to 10 membered cycloheteric bridging group, said R ⁷ Optionally further substituted by 0 to 4R ^7a Substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxy alkaneSaid heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted with = O or (= O) ₂ Substitution;

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

As a sixth embodiment of the present invention, a compound represented by the general formula (I-1) or (II-1) above or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ⁷ each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazin-3 (2H) -one, oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxocyclopentyl, -CH ₂ -oxacyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azacyclopentyl, -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 -oxocyclopentyl, -CH ₂ CH ₂ -oxacyclohexyl, -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 -azoles、-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]Heptenyl, -CH ₂ -bicyclo [3.3.2]Decyl, -CH ₂ -bicyclo [2.2.2]Octyl radical, -CH ₂ -bicyclo [3.2.1]Octyl radical, -CH ₂ -bicyclo [3.3.3]Undecyl, -CH ₂ An adamantyl group,

<xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran><xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran> Bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.1.1 ] s]Hexalkyl, bicyclo [2.2.1 ] s]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2 ] 2]Octyl, bicyclo [3.2.1 ]]Octyl, bicyclo [3.3.3]An undecyl group an adamantyl group,

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

R ^7a 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, oxolanyl, azetidinyl, piperidine, morpholine or piperazine, said R being a compound of formula (i) or (ii) wherein R is a substituent selected from the group consisting of phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolanyl, azetidinyl, piperidine, morpholine and piperazine ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Substituted with a substituent of alkoxyalkyl;

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

As a seventh embodiment of the present invention, a compound represented by the aforementioned general formula (I-1) or (II-1), or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

ring A is selected from

Ring B is selected from phenyl;

m is selected from 1;

R ^a or R ^b 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;

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

x1 is selected from the group consisting of a bond, -CH ₂ -、-O-、-C(＝O)N(R ^x )-；

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

R ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 -cyclohexyl group,

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

alternatively, R ^x And R ⁷ To which the original is connectedTogether form an azetidinyl, an aziridinyl, a piperidine, a morpholine or a piperazine, said azetidinyl, aziridinyl, piperidine, morpholine, piperazine optionally further substituted with 0, 1, 2, 3 or 4R ^7a Substitution;

R ^7a 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, oxolanyl, azetidinyl, piperidine, morpholine or piperazine, and R is an alkyl, aryl, heteroaryl, or heteroaryl group ^7a Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl;

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

As an eighth embodiment of the present invention, a compound represented by the following general formula (I-1-1), (I-1-2), (II-1-1) or (II-1-2) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

Z ₆ each independently selected from CH or N;

-X1-R ⁷ each independently selected from

-X2-R ⁷ Each independently selected from

The invention relates to a compound or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from one of the following structures:

in some embodiments of the general formula (I) or (II), Z ₁ 、Z ₂ 、Z ₃ 、Z ₆ Or Z ₇ Each independently selected from CR ^z 、NR ^z Or N.

In some embodiments of the general formula (I) or (II), Z ₁ 、Z ₃ Is selected from N, Z ₆ Each independently selected from CR ^z Or N, Z ₇ Is selected from NR ^z 。

In some embodiments of the general formula (I) or (II), Z ₁ 、Z ₃ Selected from N, Z ₆ Each independently selected from CH or N, Z ₇ Is selected from NR ^z 。

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein Z ₆ Each independently selected from CR ^z Or N.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein Z ₆ Each independently selected from CH or N.

In some embodiments of formula (I) or (II), Z ₄ Or Z ₅ Each independently selected from C or N.

In some embodiments of the general formula (I) or (II), Z ₄ Or Z ₅ Each independently selected from C.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein A ₁ 、A ₂ 、A ₃ Or A ₄ Each independently selected from CR ^a Or N.

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

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein each ring B is independently selected from a phenyl ring or a 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N.

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

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein ring B is selected from phenyl;

the present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ^z Each independently selected from H, halogen, OH, = O, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, CONH ₂ 、CONHC _1-6 Alkyl, COC _1-6 Alkyl, CON (C) _1-6 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, halogen-substituted C _1-6 Alkyl or C _1-6 Alkoxy groups.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein R ^z Each independently selected from H, C _1-4 Alkyl, COC _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, CONH ₂ 、CONHC _1-4 Alkyl, CON (C) _1-4 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, halogen-substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ^z Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl optionally further substituted by 0 to 4 substituents 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 groups.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ^z Each independently selected from H, methyl, ethyl, propyl, isopropyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein R ^z Each independently selected from H, isopropyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein R ¹ 、R ² 、R ⁵ Or R ⁶ Each independently selected from H, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy-substituted C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ¹ 、R ² Each independently selected from H or C _1-4 An alkyl group.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ¹ 、R ² Each independently selected from H, methyl or ethyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein R ¹ 、R ² Each independently selected from H.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ⁵ Or R ⁶ Each independently selected from H.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ³ 、R ⁴ 、R ^a Or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -C _0-4 alkylene-C _3-12 Carbocyclic radical or-C _0-4 Alkylene-4 to 12 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl or C _1-6 Substituted by a substituent of alkoxy.

In some embodiments of formula (I) or (II), R ³ 、R ⁴ Each independently selected from H.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ^a Or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, -C _0-2 alkylene-C _3-7 Carbocyclic radical or-C _0-2 Alkylene-4 to 7 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy.

The present invention relates to certain embodiments of formula (I), (II), (I-1), or (II-1) wherein R ^a Or R ^b 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, said methyl, ethyl, propyl, butyl, isobutyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy.

The present invention relates to certain embodiments of formula (I), (II), (I-1) or (II-1) wherein R ^a Or R ^b 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.

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

The present invention relates to certain embodiments of the general formulae (I), (I-1-1) wherein X1 is selected from the group consisting of a bond, -CH ₂ -、-O-、-C(＝O)NH-。

The present invention relates to certain embodiments of formula (II), (II-1) or (II-1-1) wherein X2 is selected from the group consisting of-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 the general formula (II), (II-1) or (II-1-1), X2 is selected from-O-, -C (= O) N (R) ^x )-。

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

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^x Each independently selected from H or C _1-6 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy or C _3-6 Cycloalkyl substituents.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^x Each independently selected from H or C _1-4 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl substituents.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ^x Each independently selected from H, methyl, ethyl, said methyl, ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl substituents.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^x Each independently selected from H.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ⁷ Each 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, said R ⁷ Optionally further substituted by 0 to 4R ^7a (iii) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ⁷ Each independently selected from C _1-4 Alkyl, -C _0-4 alkylene-C _3-7 Monocyclic carbocyclic group, -C _0-4 alkylene-C _4-11 Carbocyclic group of a fused ring, -C _0-4 alkylene-C _5-11 Spiro carbocyclic group, -C _0-4 alkylene-C _5-11 Carbocyclic group, -C of the bridged ring _0-4 Alkylene-4-to 7-membered monocyclic heterocyclyl, -C _0-4 Alkylene-5-to 11-membered heterocyclo, -C _0-4 Alkylene-5-to 11-membered spiroheterocyclyl, -C _0-4 Alkylene-5-to 11-membered bridged heterocyclo, said R ⁷ Optionally further substituted by 0 to 4R ^7a Substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, optionally further substituted by = O or (= O) ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ⁷ Each independently selected from C _1-4 Alkyl radical, C _3-7 Monocyclic carbocyclic group, C _4-11 And a cyclic carbocyclic group, C _5-11 Spirocyclic carbocyclic group, C _5-11 Bridged carbocyclyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 11-membered fused heterocyclic, 5-to 11-membered spiro heterocyclic, 5-to 11-membered bridged heterocyclic, -CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, -CH ₂ CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ⁷ Each independently selected from C _1-4 Alkyl radical, 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 heterocyclic group, 3-and 4-membered carbocyclic group, 3-and 5-membered carbocyclic group, 3-and 6-membered carbocyclic group, 4-and 4-membered carbocyclic group, 4-and 5-membered carbocyclic group, 4-and 6-membered carbocyclic group, 5-and 5-membered carbocyclic group, 5-and 6-membered carbocyclic group, 6-and 6-membered carbocyclic group, 3-spiro 4-membered carbocyclic group, 3-spiro 5-membered carbocyclic group, 3-spiro 6-membered carbocyclic group, 4-spiro 4-membered carbocyclic group, 4-spiro 5-membered carbocyclic group, 4-spiro 6-membered carbocyclic group, 5-spiro 5-membered carbocyclic group, 5-spiro 6-membered carbocyclic group, 6-spiro 6-membered carbocyclic group, 3-and 4-membered heterocyclic group, 3-and 5-membered heterocyclic group, 3-and 6-membered heterocyclic group, 4-and 4-membered heterocyclic group, 4-and 5-membered heterocyclic group, 5-and 6-membered heterocyclic group, 6-and 6-membered heterocyclic group, 3-spiro 6-membered heterocyclic group, 3-and 5-membered heterocyclic group4-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 Cyclic ring radical of meta-bridged ring, -CH ₂ -C _5-10 Cyclic carbocyclic group of meta-bridged ring, heterocyclic bridging group of 5-10 membered bridged ring, -CH ₂ -5 to 10 membered cyclobridgework group, said R ⁷ Optionally further substituted by 0 to 4R ^7a Substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, optionally further substituted by = O or (= O) ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazin-3 (2H) -one, oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxocyclopentyl, -CH ₂ -oxacyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azacyclopentyl, -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 -oxocyclopentyl, -CH ₂ CH ₂ -oxacyclohexyl, -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 alkyl, -CH ₂ -bicyclo [2.1.1]Hexyl, -CH ₂ -bicyclo [2.2.1]Heptylalkyl, -CH ₂ -bicyclo [3.3.2]Decyl, -CH ₂ -bicyclo [2.2.2]Octyl radical, -CH ₂ -bicyclo [3.2.1]Octyl, -CH ₂ -bicyclo [3.3.3]Undecyl, -CH ₂ An adamantyl group,

<xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran>A spiroazetidinyl group, an azetidinyl spiroazetidinyl group, a piperidinyl spiropiperidinyl group, an oxetanyl group, an oxolanyl group, an oxocyclohexyl group, a cyclopropyloxocyclobutyl group, a cyclopropyloxocyclopentyl group, a cyclopropyloxocyclohexyl group, a cyclobutyloxocyclobutyl group, a cyclobutyloxocyclopentyl group, a cyclobutyloxocyclohexyl group, a cyclopentoxocyclobutyl group, a cyclopentoxocyclopentyl group, a cyclopentoxooxetanyl group, a cyclohexyloxooxetanyl group, a cyclohexyloxocyclopentyl group, a cyclohexyloxooxetanyl group, an azetidinoxooxetanyl group, an azetidinylborooxocyclopentyl group, an azetidinylboroxyoxetanyl group, a piperidinooxycyclobutyl group, an azetidinoyloxocyclobutyl group, an azetidinoyloxocyclopentyl group, an piperidinoyloxocyclopentyl group, a piperidinoyloxocyclopentyl group, <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , [ 1.1.1. </xnotran>]Pentyl alkyl, bicyclo [2.1.1 ] s]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]Undecyl, adamantyl, alkyl, aryl, heteroaryl, and heteroaryl,

Said R is ⁷ Optionally further substituted by 0 to 4R ^7a And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 -cyclohexyl, n,

The R is ⁷ Optionally further substituted by 0, 1, 2, 3 or 4R ^7a And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^7a Each 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 radical) ₂ 、-SO ₂ -C _1-6 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -SO ₂ -C _3-7 Carbocyclyl, C _3-12 Carbocyclyl or 4-to 12-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or C _1-6 (ii) alkoxyalkyl having 1 to 4 heteroatoms selected from O, S, N, and optionally further substituted with = O or (= O) when heteroatoms are selected from S ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ^7a 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 radical) ₂ 、-SO ₂ -C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, -SO ₂ -C _3-6 Carbocyclyl, C _3-7 Carbocyclyl, 5-to 7-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ^7a Each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, 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 Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 (ii) alkoxyalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N, and optionally further substituted with = O or (= O) when the heteroatom is selected from S ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^7a Each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ And (4) substitution.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^7a 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, oxolanyl, azetidinyl, piperidine, morpholine or piperazine, said R being a compound of formula (i) or (ii) wherein R is a substituent selected from the group consisting of phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolanyl, azetidinyl, piperidine, morpholine and piperazine ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Substituted by a substituent of alkoxyalkyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ^7a 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, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^x And R ⁷ Together with the atoms to which they are attached form a non-aromatic 4-12 membered heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4R ^7a And (b) substituted, wherein said heterocycle contains 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^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 heterocycle, 5 to 11 membered fused cyclic heterocycle, 5 to 11 membered spirocyclic heterocycle, 5 to 11 membered bridged cyclic heterocycle, said heterocycle optionally further substituted with 0 to 4R ^7a Substituted, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) ^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 optionally further substituted with 0 to 4R ^7a And (b) substituted, wherein said heterocycle contains 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to certain embodiments of formula (I), (II), (I-1), (II-1), (I-1-1), or (II-1-1) wherein R ^x And R ⁷ Together with the atom to which they are attached form an azetidinyl, an azacyclopentyl, a piperidine, a morpholine or a piperazine, said azetidinyl, azacyclopentyl, piperidine, morpholine, piperazine being optionally further substituted with 0, 1, 2, 3 or 4R ^7a And (4) substitution.

The present invention relates to certain embodiments of the general formula (I), ((I-1), (I-1-1) — X1-R ⁷ Each independently selected from

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

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

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

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to an application of the compound or the stereoisomer, the deutero-compound, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof in preparing a medicament for treating diseases related to RET activity or expression, preferably preparing IBS, tumor or autoimmune system diseases.

The first synthesis method comprises the following steps:

carrying out coupling or substitution reaction on the general formula compound (I-1-A) and the general formula compound (I-1-B) to obtain a corresponding general formula compound (I-1-C);

carrying out coupling reaction on the general formula compound (I-1-C) and the general formula compound (I-1-D) to obtain a corresponding general formula compound (I-1-E);

the compound (I-1-E) is subjected to hydrolysis reaction to obtain a compound (I-1-F);

carrying out condensation reaction on a general formula compound (I-1-F) and a general formula compound (I-1-G) to obtain a corresponding general formula compound (I-1);

R ^A ，R ^B and R ^C Selected from the group consisting of Cl, br, I, OTf, organoboron reagents, organotin reagents;

the other substituents are as defined above for the embodiment of the compound of the general formula (I-1).

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

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include ¹² C、 ¹³ C and ¹⁴ c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur including ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen include ¹⁴ N and ¹⁵ isotopes of N, F include ¹⁷ F and ¹⁹ isotopes of F, chlorine including ³⁵ Cl and ³⁷ cl, isotopes of bromine including ⁷⁹ Br and ⁸¹ Br。

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

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

"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups, as used herein, are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

"heteroalkyl" means that 1 or more (including but not limited to 2, 3,4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O, or S). Non-limiting examples include-X (CH) ₂ )v-X(CH ₂ )v-X(CH ₂ ) v-H (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom including but not limited to N, O or S, and at least 1X is selected from a heteroatom in which N or S may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.

"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH) ₂ ) _v - (v is an integer of 1 to 10), examples of the alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

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

"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl as found herein, is as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

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

"alkenyl" means substituted or unsubstituted straight and branched chain unsaturated hydrocarbon groups having at least 1, and typically 1, 2 or 3 carbon double bonds, the backbone includes, but is not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl 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-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-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1, 4-hexadiene, 1,4, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

"alkynyl" refers to substituted or unsubstituted, straight and branched chain, monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1, 2 or 3 carbon-carbon triple bonds, and backbones including from 2 to 10 carbon atoms, including but not limited to from 2 to 6 carbon atoms in the backbone and from 2 to 4 carbon atoms in the backbone, and examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"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-hexoxy, cyclopropoxy, and cyclobutoxy.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, and mixtures thereof,

"carbocyclyl" or "carbocycle" may be monovalent, divalent, or trivalentValence or tetravalent.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and contain 1 or more (including but not limited to 2, 3,4, or 5) heteroatoms selected from N, O, or S, optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. A heterocyclic group may be attached to a heteroatom or carbon atom, a heterocyclic group may be attached to an aromatic ring or non-aromatic ring, a heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuryl, dihydropyranyl, dithiapentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroisoimidazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrryl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrinyl, piperazinyl, azabicyclo [ 3.1.2.1.1.1.1.]Octyl, azabicyclo [5.2.0 ] groups]Nonyl, oxatricyclo [5.3.1.1]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclic" refers to a polycyclic group that shares a single atom (referred to as a spiro atom) between substituted or unsubstituted single rings, the number of ring atoms in the spiro ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, where one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 substituents selected from N, O, or S (= O) _n A heteroatom of (a).

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

"fused ring" or "fused 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 of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (= O) _n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly connected, which may contain 0 or more double bonds, andany ring in the ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom containing groups (including but not limited to N, S (= O) N or O, where N is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubane and adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent or tetravalent.

"carbospiro", "spirocarbocyclic" or "carbospiro" refers to "spiro" rings whose ring system consists of only carbon atoms. The definition of "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic group" as appearing herein is consistent with the definition of spirocyclic.

"carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. "carbocyclic", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl", or "carbobridyclyl" as used herein, is defined in accordance with the definition of bridged ring.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, where heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" is present, the definition of which is consistent with that of a heterocycle.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The term "fused ring" as used herein refers to a "fused ring," fused ring group, "fused heterocyclic group," or "fused ring group," which is defined as being fused.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.

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

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

"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O) N, N 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 groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include

Heteroaryl, as used herein, is defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.

The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include a pyrrolopyrrole ring, a pyrazolopyrrole ring, a pyrazolopyrazole ring, a pyrrolofuran ring, a pyrazolofuran ring, a pyrrolothiophene ring, and a pyrazolothiophene ring.

"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3,4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, = 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 -alkenyl-R ^a 、OR ^d Or- (CH) ₂ ) _m -alkynyl-R ^a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR ^b R ^c Etc. wherein R is ^b And R ^c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b And R ^c Shape changeableForm five or six membered cycloalkyl or heterocyclyl.

"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 with 0 to X substituents" means substituted with 0, 1, 2, 3 \8230Xsubstituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3,4, or 5 substituents. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.

The ring of X-Y element (X is selected from integer less than Y and greater than 3, and Y is selected from any integer between 4 and 12) includes X +1, X +2, X +3, X +4 \8230andY element ring. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heteroatomic, heterocyclic spiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

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

"pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, tautomers, deuterons, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

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

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

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent 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 livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"tautomer" refers to isomers of functional groups resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-alcohol isomers, among others.

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

“IC ₅₀ "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).

Detailed Description

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

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS);

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

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X 4.6mm, 3.5. Mu.M);

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

the column chromatography is carried out by using 200-300 mesh silica gel of Litsea crassirhizomes as 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

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-oxazolo [3,4-D ] pyrimidine (1A) (3 g, 11.49mmol) and potassium carbonate (3.18g, 22.98mmol) were dissolved in N, N-dimethylformamide (32 mL), and 2-iodopropane (1B) (1.26mL, 12.64mmol) was slowly added dropwise under a nitrogen atmosphere in an ice bath, and after completion of the addition, the mixture was warmed to room temperature and stirred for 2 hours. The reaction was diluted with 150mL of water, followed by extraction with ethyl acetate, and the organic phase was washed with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a silica gel column to obtain the objective compound (1C) (1.614 g, yield: 46%)

Ms m/z(ESI):304.1[M+H] ⁺

Second step methyl 2- (4- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluorophenyl) 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 methyl 2- (2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) acetate (1D) (2.19g, 7.43mmol) were dissolved in a mixed solvent of 12mL of 1, 4-dioxane and 1mL of water, and cesium carbonate (3.23g, 9.90mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (408mg, 0.5mmol) were added. Stirring was carried out at 110 ℃ for 3 hours under nitrogen. After cooling to room temperature, the reaction was diluted with 150mL of water and extracted with ethyl acetate, the organic phase was washed with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a silica gel column to obtain the objective 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 of methanol and 12mL of water, and lithium hydroxide monohydrate (640mg, 15.52mmol) was added thereto, followed by stirring at 50 ℃ for 1.5 hours. Cooled to room temperature, then 1N diluted hydrochloric acid solution was added to adjust pH to 7, and after filtration and collection of a filter cake, the objective compound (1F) (1.64 g, yield: 98%) was obtained after drying

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 of DMF, and N-methylimidazole (84mg, 1.02mmol), N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (177mg, 0.63mmol) was added, followed by reaction at room temperature for 3 hours. Diluting with 100mL of water, extracting with ethyl acetate three times, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column to obtain white solid as the objective 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

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) were dissolved in N, N-dimethylformamide (20 mL), and cesium carbonate (6.24g, 19.14mmol) was added and the reaction stirred at 80 ℃ for 6 hours under nitrogen. The reaction was diluted with 150mL of water, followed by extraction with ethyl acetate, and the organic phase was washed with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a silica gel column to obtain the objective compound (2C) (2.30 g, yield: 79%)

Ms m/z(ESI):305.1[M+H] ⁺

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

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

Compound 2C (2.30g, 7.56mmol) was dissolved in ethyl acetate (20 mL), and then 10% palladium on carbon (0.3 g) was added, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through celite, followed by washing with ethyl acetate (50 mL), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the objective 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 12mL of DMF, and N-methylimidazole (87mg, 1.07mmol), N, N, N ', N' -tetramethylformamidine hexafluorophosphate (179mg, 0.64mmol) were added, followed by reaction at room temperature for 3 hours. Diluting with 100mL of water, extracting with ethyl acetate three times, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column to obtain white solid as the objective 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

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

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

1-fluoro-3-nitro-5- (trifluoromethyl) benzene (2A) (1g, 4.78mmol) and tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (3A) (0.985g, 5.26mmol) were dissolved in N, N-dimethylformamide (10 mL) and cesium carbonate (3.1g, 9.56mmol) was added and the reaction stirred at 80 ℃ for 6 hours under nitrogen. The reaction was diluted with 150mL of water, followed by extraction with ethyl acetate, and the organic phase was washed with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a silica gel column to obtain the objective compound (3B) (1.5 g, yield: 83%)

Ms m/z(ESI):321.1[M-55] ⁺

Second step 3- ((3-Nitro-5- (trifluoromethyl) phenoxy) methyl) azetidine (3C)

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

Compound 3B (1.5g, 3.99mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (6 mL) was added thereto, and the reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours. Concentration under reduced pressure to obtain the objective 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 (1.1g, 3.98mmol) was dissolved in methanol (15 mL), and then paraformaldehyde (3 mL) was added, and the reaction was stirred at room temperature under nitrogen for 1.5 hours. Sodium triacetoxyborohydride (0.844g, 11.94mmol) was then added and the reaction was stirred at room temperature for an additional 2 hours. Concentrated under reduced pressure, then diluted with 50mL of water, followed by slow addition of 50mL of saturated sodium bicarbonate solution for washing, followed by extraction with ethyl acetate, washing of the organic phase with saturated brine, followed by drying of the organic phase with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by silica gel column to give the title compound (3D) (1 g, yield: 87%) Ms m/z (ESI): 2)91.2[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 (1g, 3.44mmol) was dissolved in ethyl acetate (15 mL), and then 10% palladium on carbon (0.2 g) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through celite, followed by washing with ethyl acetate (50 mL), and the organic phases were combined, followed by drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure to obtain the objective 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) were dissolved in 12mL of DMF, and N-methylimidazole (87mg, 1.07mmol), N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (179mg, 0.64mmol) were added, followed by reaction at room temperature for 3 hours. Diluting with 100mL of water, extracting with ethyl acetate three times, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column to obtain a white solid as the objective 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) acetylamino) -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

In the first step, 3- (2- (4- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluorophenyl) acetylamino) -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) benzamide (4A) (129mg, 0.43mmol) were dissolved in 8mL of DMF, and N-methylimidazole (88mg, 1.08mmol), N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (181mg, 0.65mmol) were added, followed by reaction at room temperature for 3 hours. Diluting with 100mL of water, extracting with ethyl acetate three times, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column to obtain white solid as 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) acetylamino) -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

In the first step, 3- (2- (4- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluorophenyl) acetylamino) -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) were dissolved in 10mL of DMF, and N-methylimidazole (125mg, 1.53mmol), N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (257mg, 0.92mmol) were added, followed by reaction at room temperature for 3 hours. Diluting with 100mL of water, extracting with ethyl acetate three times, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column to obtain a white solid as the objective 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 example

1. In vitro RET kinase assay

Kinase RET (Carna, cat.No. 08-159) was prepared as a 5X kinase solution, and substrate TK Substrate-biotin (Cisbio, cat.No. 62TK0PEB) was prepared as a 2.5X substrate solution with ATP (Sigma, cat.No. A7699-1G). mu.L of compounds of different concentrations were added to 384 well plates, 2. Mu.L of 5 Xkinase solution was added, 4. Mu.L of 2.5 Xsubstrate solution was added, incubation was performed at 25 ℃ for 30min, and 10. Mu.L of stop solution (5. Mu.L of Sa-XL665 and 5. Mu.L of TK antibody-Eu) was added ³⁺ The reaction was stopped by mixing (Cisbio, cat. No. 62TK0PEB)) and examined using a PHERAStar FSX instrument. IC calculation Using GraphPad Prism 6 software ₅₀ The value is obtained. The test results are shown in Table 1. The reference AD80 was purchased from Kyowa Jieming Biotechnology Ltd.

Table 1: compounds active on RET kinase

Compound (I)	In vitro RET kinase IC 50 (nM)
		Compound 1	0.15
Compound 2	0.22
		Compound 3	0.25
Compound 4	0.64
		Compound 5	0.21
AD80	1.08

And (4) conclusion: the compound of the invention has good inhibitory activity on RET kinase.

2. Cell proliferation inhibitory Activity

TT cell culture medium was F12K (containing 10% FBS,1 XNon-Essential Amino Acid,1 XGlutamax and 1 XPenicillin/Streptomyces). Cell culture at 37 ℃ and 5% CO ₂ In an incubator. Cells were plated in 96-well plates. 6000 TT cells/well, 50 μ L of medium per well, at 37 ℃, 5% ₂ Incubated under conditions overnight. The following day 50. Mu.L of medium containing different concentrations of test compound was added to each well, 3 more wells per concentration. And a DMSO solvent control group and a negative control group are arranged at the same time, and the DMSO solvent control group and the negative control group are respectively provided with 3 multiple holes. At 37 ℃ C, 5% CO ₂ The culture was continued for 7 days under the conditions. After 7 days, 100. Mu.L of detection reagent (Cell Viability Assay, promega, G7573) was added to each well, placed on a shaker for 15 minutes in the dark, 100. Mu.L of the solution was pipetted into a 96-well opaque white-bottom plate, and the fluorescence signal value was measured on a PHERAstar FSX multifunctional microplate reader (BMG LABTECH). Application of GraphPad Prism software, calculating IC ₅₀ The value is obtained.

The culture medium of Ba/F3-KIF5B-RET-G810R engineered cell strain (provided by Zhongkepu san-Shen) is RPMI-1640+10% of FBS, the cell culture is carried out at 37 ℃ and 5% of CO ₂ In an incubator. Cells were plated in 96-well plates. Cells were 2000 cells/well, 95. Mu.L per well. Then 5 μ L of test compound was added to each well at different concentrations, 2 more wells per concentration, and the final column was DMSO vehicle control. At 37 ℃ 5% CO ₂ Culturing for 72h under the condition. After 72h, 50. Mu.L of detection reagent (Cell Viability Assay, promega, G7573) was added to each well, mixed for 2 minutes, incubated for 10 minutes at room temperature, and the fluorescence signal was measured using SpectraMax Paradigm. IC was calculated using GraphPad prism7.0 software ₅₀ The value is obtained.

Table 2: cell proliferation inhibitory Activity of Compounds

And (4) conclusion: the compound has good inhibitory activity on the proliferation of TT cells and Ba/F3-KIF5B-RET-G810R engineering cell strains.

Claims (12)

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

Represents that the ring is aromatic;

Z ₁ 、Z ₂ 、Z ₃ 、Z ₆ or Z ₇ Each independently selected from CR ^z 、NR ^z Or N;

Z ₄ or Z ₅ Each independently of each otherIndependently selected from C or N;

A ₁ 、A ₂ 、A ₃ or A ₄ Each independently selected from CR ^a Or N;

each ring B is independently selected from a phenyl ring or a 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N;

R ^z each independently selected from H, halogen, OH, = O, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, CONH ₂ 、CONHC _1-6 Alkyl, COC _1-6 Alkyl, CON (C) _1-6 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, halogen-substituted C _1-6 Alkyl or C _1-6 Substituted with a substituent of alkoxy;

R ¹ 、R ² 、R ⁵ or R ⁶ Each independently selected from H, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl;

R ³ 、R ⁴ 、R ^a or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -C _0-4 alkylene-C _3-12 Carbocyclic radical or-C _0-4 Alkylene-4 to 12 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl or C _1-6 Substituted by a substituent of alkoxy;

x1 is selected from the group consisting of 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(R ^x )C(＝O)-；

R ^x Each independently selected from H or C _1-6 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy or C _3-6 Cycloalkyl, substituted with a substituent;

R ⁷ each 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, said R ⁷ Optionally further substituted by 0 to 4R ^7a (iii) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution; r ^7a Each 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 radical) ₂ 、-SO ₂ -C _1-6 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, -SO ₂ -C _3-7 Carbocyclyl, C _3-12 Carbocyclyl or 4-to 12-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or C _1-6 (ii) alkoxyalkyl having 1 to 4 heteroatoms selected from O, S, N, and optionally further substituted with = O or (= O) when heteroatoms are selected from S ₂ Substitution;

alternatively, the，R ^x And R ⁷ Together with the atoms to which they are attached form a non-aromatic 4-12 membered heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4R ^7a Substituted, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

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

2. The compound of claim 1, wherein the compound is selected from the group consisting of compounds represented by general formula (I-1) and compounds represented by general formula (II-1), or stereoisomers, deuterons, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, and co-crystals thereof,

Z ₆ each independently selected from CR ^z Or N;

R ¹ 、R ² each independently selected from H or C _1-4 An alkyl group.

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

R ^z each independently selected from H and C _1-4 Alkyl, COC _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, CONH ₂ 、CONHC _1-4 Alkyl, CON (C) _1-4 Alkyl radical) ₂ Said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 4-to 7-membered heterocycloalkyl, halogen-substituted C _1-4 Alkyl or C _1-4 Substituted with a substituent of alkoxy;

R ^a or R ^b Each independently selected from H, halogen, OH, cyano, COOH, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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 heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

R ^x each independently selected from H or C _1-4 Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl, substituted with a substituent;

R ⁷ each independently selected from C _1-4 Alkyl, -C _0-4 alkylene-C _3-7 Monocyclic carbocyclyl, -C _0-4 alkylene-C _4-11 Carbocyclic group of a fused ring, -C _0-4 alkylene-C _5-11 Spiro carbocyclic group, -C _0-4 alkylene-C _5-11 Carbocyclic group, -C of the bridged ring _0-4 Alkylene-4-to 7-membered monocyclic heterocyclyl, -C _0-4 Alkylene-5-to 11-membered heterocyclo, -C _0-4 Alkylene-5-to 11-membered spiroheterocyclyl, -C _0-4 Alkylene-5-to 11-membered bridged heterocyclo, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a 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 radical) ₂ 、-SO ₂ -C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, -SO ₂ -C _3-6 Carbocyclic group、C _3-7 Carbocyclyl, 5-to 7-membered heterocyclyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ Substitution;

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 heterocycle, 5 to 11 membered fused heterocyclic ring, 5 to 11 membered spiro heterocyclic ring, 5 to 11 membered bridged heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4R ^7a And (b) substituted, wherein said heterocycle contains 1 to 4 heteroatoms selected from O, S, N.

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

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

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

R ^z each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl optionally being further substituted by 0 to 4 substituents selected from the group consisting of 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 Substituted by a substituent of alkoxy;

R ^a or R ^b 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, said methyl, ethyl, propyl, butyl, isobutyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

R ^x each independently selected from H, methyl, ethyl, said methyl, ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy or C _3-6 Cycloalkyl substituted with a substituent;

R ⁷ each independently selected from C _1-4 Alkyl radical, C _3-7 Monocyclic carbocyclic group, C _4-11 Cyclic fused ring group, C _5-11 Spirocyclic carbocyclic group, C _5-11 Bridged carbocyclyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 11-membered fused heterocyclic, 5-to 11-membered spiroheterocyclic, 5-to 11-membered bridged heterocyclic, -CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclyl, -CH ₂ CH ₂ -C _3-7 Monocyclic carbocyclyl, -CH ₂ CH ₂ -C _4-11 And a carbocyclic group, -CH ₂ CH ₂ -C _5-11 Spiro carbocyclic group, -CH ₂ CH ₂ -C _5-11 Endocyclic carbocyclyl, -CH ₂ CH ₂ -4 to 7 membered monocyclic heterocycleCyclyl, -CH ₂ CH ₂ -5 to 11 membered heterocyclo, -CH ₂ CH ₂ -5 to 11 membered spiroheterocyclyl, -CH ₂ CH ₂ -5 to 11 membered bridged heterocyclic group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a each independently selected from halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, 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 Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 (ii) alkoxyalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N, and optionally further substituted with = O or (= O) when the heteroatom is selected from S ₂ Substitution;

alternatively, 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 optionally further substituted with 0 to 4R ^7a And (b) substituted, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N.

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

R ⁷ each independently selected from C _1-4 Alkyl radical, 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 <xnotran> -3 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 ,3 4 ,3 5 ,3 6 ,4 4 ,4 5 ,4 6 ,5 5 ,5 6 , 6 6 , C </xnotran> _5-10 Cyclic ring radical of meta-bridged ring, -CH ₂ -C _5-10 Cyclic carbocyclic radical of meta-bridged ring, heterocyclic bridging radical of 5-10 membered ring, -CH ₂ -a 5 to 10 membered cycloheteric bridging group, said R ⁷ Optionally further substituted by 0 to 4R ^7a And (b) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, and when said heteroatoms are selected from S, optionally further substituted by = O or (= O) ₂ Substitution;

R ^7a each independently selected from halogen, OH, = O, cyano, COOH and NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、-CH ₂ NH ₂ 、-CH ₂ NHC _1-4 Alkyl, -CH ₂ N(C _1-4 Alkyl radical) ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ NHC _1-4 Alkyl, -CH ₂ CH ₂ N(C _1-4 Alkyl radical) ₂ 、-SO ₂ C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, said R ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Alkoxyalkyl containing 1 to 4 heteroatoms selected from O, S, N, optionally further substituted by = O or (= O) when the heteroatom is selected from S ₂ And (4) substitution.

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

R ⁷ each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine, pyridazin-3 (2H) -one, oxetanyl, oxolanyl, oxetanyl, azetidinyl, piperidine, morpholine, piperazine, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -oxetanyl, -CH ₂ -oxocyclopentyl, -CH ₂ -oxacyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azacyclopentyl, -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 -Oxetazetidinesradical-CH ₂ CH ₂ -oxocyclopentyl, -CH ₂ CH ₂ -oxacyclohexyl, -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 alkyl, -CH ₂ -bicyclo [2.1.1]Hexyl, -CH ₂ -bicyclo [2.2.1]Heptylalkyl, -CH ₂ -bicyclo [3.3.2]Decyl, -CH ₂ -bicyclo [2.2.2]Octyl, -CH ₂ -bicyclo [3.2.1]Octyl radical, -CH ₂ -bicyclo [3.3.3]Undecyl, -CH ₂ An adamantyl group,

Cyclopropylcyclopenta-cyclopentyl, cyclobutylcyclopenta-pentyl, cyclopenta-cyclopentyl, cyclopenta-cyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylpspirocyclopentyl, cyclopentylpirocyclohexyl cyclohexylspirocyclohexyl, cyclopropyloazetidinyl, cyclopropyloaiperidyl, cyclobutyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl cyclopentoazetidibuthyl, cyclopentoazetidinyl, cyclopentadiiperidyl, cyclohexyloazetidiyl, cyclohexyloazetidinyl, azetidineazetidiyl, azetidineazetidinyl, azetidinobiperidyl, azetidinobutylazyl, azetidioazetidinyl, azetidinopiperidyl, azetidinyl, and azetidinyl<xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran> Cyclohexyl spirooxetanyl, azetidinyl spirooxetanyl, and mixtures thereof azetidinyl spirooxetanyl, and the like azacyclopentyl spirooxetanyl, azacyclohexyl spirooxetanyl, piperidino spirooxetanyl, bicyclohexyl[1.1.1]Pentyl alkyl, bicyclo [2.1.1]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]Undecyl, adamantyl, alkyl, aryl, heteroaryl, and heteroaryl,

Said R is ⁷ Optionally further substituted by 0 to 4R ^7a Substitution;

R ^7a 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, oxolanyl, azetidinyl, piperidine, morpholine or piperazine, said R being a compound of formula (i) or (ii) wherein R is a substituent selected from the group consisting of phenyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolanyl, azetidinyl, piperidine, morpholine and piperazine ^7a Optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, = O, cyano, COOH, NH ₂ 、NHC _1-4 Alkyl, N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, hydroxy-substituted C _1-4 Alkyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy radical, C _3-6 Cycloalkyl or C _1-4 Substituted by a substituent of alkoxyalkyl.

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

ring A is selected from

Ring B is selected from phenyl;

m is selected from 1;

R ^a or R ^b 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;

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

x1 is selected from the group consisting of a bond, -CH ₂ -、-O-、-C(＝O)N(R ^x )-；

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

R ⁷ Each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 -cyclohexyl group,

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

alternatively, R ^x And R ⁷ Together with the atom to which they are attached form an azetidinyl, an azacyclopentyl, a piperidine, a morpholine or a piperazine, said azetidinyl, azacyclopentyl, piperidine, morpholine, piperazine being optionally further substituted with 0, 1, 2, 3 or 4R ^7a Substitution;

R ^7a 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, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, piperidine, morpholine or piperazine, said R ^7a Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, cl, br, I, OH, = O, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl.

8. The compound according to claim 7, wherein the compound is selected from the group consisting of compounds represented by general formula (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,

Z ₆ each independently selected from CH or N;

-X1-R ⁷ each independently selected from

-X2-R ⁷ Each independently selected from

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

10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1-9, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with RET activity or expression.

12. The use of claim 11, wherein the disease is selected from IBS, a tumor or an autoimmune disease.