7-azaindole derivatives and uses thereof

Abstract

The present application relates to a kind of 7-azaindole derivatives and its use. Particularly, the present application relates to the compound shown in general formula (I), its preparation method, its pharmaceutical composition, and the use of the compound shown in general formula (I) or its pharmaceutical composition, the compound can be used as the drug for preventing and / or treating ActR II mediated related diseases, wherein each substituent in general formula (I) is the same as defined in the specification.

Description

Technical Field

[0001] This invention relates to a 7-azaindole, its stereoisomers or pharmaceutically acceptable salts thereof, and their use in the pharmaceutical field. Background Technology

[0002] Activin type II receptor (ActRII, also known as ACVR2) is a member of the transforming growth factor β (TGF-β) receptor family. It is the type II receptor for other TGF-β family members, including Activin A, Activin B, BMP7, BMP9, BMP10, GDF1, GDF8 (myostatin), GDF11, and Nodal. ActRII is present in adipocytes and muscle cells. In adipocytes, activins store lipids via ActRII, a key driver of obesity; blocking this signaling pathway promotes fat metabolism. In muscle cells, the ActRII receptor signaling pathway inhibits muscle growth and leads to muscle atrophy. Blocking activin signaling in skeletal muscle can inhibit this atrophy and promote muscle mass increase, helping obese patients improve body composition and metabolism while losing weight. Activation of ActRII receptor signaling leads to muscle atrophy and fat accumulation in adipose tissue. Therefore, targeting this pathway is expected to increase muscle mass in patients while driving fat loss, thus playing a dual role and solving the pain point of GLP-1. Summary of the Invention

[0003] This invention provides a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, which have good physicochemical properties, such as high solubility, physical and / or chemical stability, ActRII inhibitory activity, improved pharmacokinetic characteristics, high bioavailability, good safety, low toxicity and side effects, and advantages such as oral administration, rapid absorption and high clearance.

[0004] This invention relates to compounds represented by general formulas (I), (II), (III), (II-1), (III-1), (IA), (I-A1), (I-A2), and (I-A3), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0005]

[0006] ,

[0007] In some implementations, X is CH or N;

[0008] In some embodiments, R1 is a 4-12-membered heterocyclic alkyl, a 5-14-membered heteroaryl, -(O)-(4-12-membered heterocyclic alkyl), -(NR)-(4-12-membered heterocyclic alkyl), or -(NR)-(4-12-membered heterocyclic alkyl). a -(4-12-membered heterocyclic alkyl), -(CO)-(4-12-membered heterocyclic alkyl), -(CONR a )-(4-12-membered heterocyclic alkyl), =(4-12-membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-12-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace;

[0009] In some embodiments, R1 is a 4-6 membered heterocyclic alkyl, a 6-11 membered spirocyclic alkyl, a 6-11 membered annealed heterocyclic alkyl, a 6-11 membered bridged heterocyclic alkyl, a 5-6 membered heteroaryl-5-6 membered heterocyclic alkyl, -(O)-(4-6 membered heterocyclic alkyl), -(NR a -(4-6 membered heterocyclic alkyl), -(CO)-(4-6 membered heterocyclic alkyl), -(CONR a )-(4-6 membered heterocyclic alkyl), =(4-6 membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-8-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace;

[0010] In some implementations, R2 is -CONR b R c , 3-12-membered heterocyclic alkyl, 5-14-membered heteroaryl, -(O)-(3-12-membered heterocyclic alkyl), -(O)-(5-14-membered heteroaryl), -(NR a -(3-12 membered heterocyclic alkyl), -(NR a -(5-14-membered heteroaryl), -(CO)-(3-12-membered heterocycloalkyl), -(CO)-(5-14-membered heteroaryl), -(CONR a -(3-12 membered heterocyclic alkyl), -(CONR a )-(5-14-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace;

[0011] In some implementations, R2 is -CONR b R c, 4-6-membered heterocyclic alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-4-6-membered heterocyclic alkyl, benzo5-6-membered heteroaryl, 5-6-membered heteroaryl-phenyl, 5-6-membered heteroaryl-5-6-membered heteroaryl, -(O)-(4-6-membered heterocyclic alkyl), -(O)-(5-6-membered heteroaryl), -(NR a -(4-6 membered heterocyclic alkyl groups), -(NR a -(5-6-membered heteroaryl), -(CO)-(4-6-membered heterocycloalkyl), -(CO)-(5-6-membered heteroaryl), -(CONR a -(4-6 membered heterocyclic alkyl groups), -(CONR a )-(5-6-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace;

[0012] In some embodiments, R3, R4, and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0013] In some embodiments, R3, R4, and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0014] In some embodiments, R3, R4, and R5 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, or ethyl.

[0015] In some implementations, R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0016] In some implementations, R A and R1, R A and R x The carbon atoms attached thereto form 4-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits;

[0017] In some implementations, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-8 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits;

[0018] In some implementations, R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0019] In some implementations, RA The radicals are hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, and ethynyl.

[0020] In some implementations, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0021] In some implementations, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0022] In some implementations, R a R b and R c Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups;

[0023] In some implementations, R a R b and R c Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3Haloalkyl groups, preferably hydrogen, deuterium, methyl, ethyl, or propyl;

[0024] In some implementations, R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy group, -(CO)-C 1-6 Alkyl group, -(NHCO)-C 1-6 Alkyl, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the alkyl halide group;

[0025] In some implementations, R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy group, -(CO)-C 1-3 Alkyl group, -(NHCO)-C 1-3 Alkyl, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The group substituted by the alkyl halide group;

[0026] In some implementations, R x C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the alkyl halide group;

[0027] In some implementations, R x C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The group substituted by the alkyl halide group;

[0028] In some implementations, R x Methyl or ethyl;

[0029] In some implementations, R A Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; in some embodiments, R A Hydrogen, deuterium, halogens, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; in some embodiments, R A The radicals are hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, and ethynyl.

[0030] In some implementations, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0031] In some implementations, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0032] In some embodiments, R1 is optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, or the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0033] In some implementations, R A and R x The carbon atoms connected to it link to form the following groups: , , or R A R1 and the carbon atom to which it is attached form optional groups selected from 1-3 groups chosen from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2: ;

[0034] In some implementations, any two adjacent R A The carbon atoms connected thereto form groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, such as cyclobutyl and cyclopentyl.

[0035] In some embodiments, R1 is a group that includes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0036] In some embodiments, R2 is -CONHCH3 or optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, -CH2OH, -CH2CH2OH, and tetrahydropyranyl groups: , , , , , , , , , , , , ;

[0037] In some implementations, X1 is selected from O or NR. 1a ;

[0038] In some implementations, X1 is selected from O;

[0039] In some implementations, X1 is selected from NR 1a ;

[0040] In some implementations, R 1a Selected from -C(R) 11 (R) 12 (R) 13 );

[0041] In some implementations, L is selected from key, -OC(R) x1 )2C(Rx2 )2-*,* indicates the site where it is bonded to a nitrogen atom;

[0042] In some implementations, L is selected from key;

[0043] In some implementations, L is selected from -OC(R) x1 )2C(R x2 )2-*,* indicates the site where it is bonded to a nitrogen atom;

[0044] In some implementations, R2 is selected from... , ;

[0045] In some implementations, R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 Each is independently selected from either hydrogen or deuterium;

[0046] In some implementations, R 11 R 12 R 13 Selected from deuterium;

[0047] In some implementations, R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Selected from deuterium;

[0048] In some implementations, R 11 R 12 R 13 R21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Selected from deuterium;

[0049] In some implementations, R x1 Selected from deuterium;

[0050] In some implementations, R x2 Selected from deuterium;

[0051] In some implementations, R x1 R x2 Selected from deuterium;

[0052] In some implementations, R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x1 Selected from deuterium;

[0053] In some implementations, R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x2 Selected from deuterium;

[0054] In some implementations, R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x1 R x2 Selected from deuterium;

[0055] In some implementations, R 31 R 32 R 33 R 34 Selected from deuterium;

[0056] In some implementations, R 41 R 42 R43 Selected from deuterium;

[0057] In some implementations, R 51 R 52 Selected from deuterium;

[0058] In some implementations, R 61 R 62 R 63 R 64 R 65 Selected from deuterium;

[0059] The condition is that R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 At least one group is selected from deuterium;

[0060] In some implementations, n is 0, 1, 2, 3, 4; in some implementations, n is 0, 1, 2, 3; in some implementations, n is 0, 1, 2.

[0061] The premise is: when R1 is When R3, R4, and R5 are all hydrogen and n is 0, R2 is not hydrogen. , , , , , , , , , , , , , , , , , , , , , .

[0062] The specific first technical solution involves a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0063]

[0064] in:

[0065] R1 is a 4-12 membered heterocyclic alkyl, a 5-14 membered heteroaryl, -(O)-(4-12 membered heterocyclic alkyl), or -(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(NR)-(R ... a -(4-12-membered heterocyclic alkyl), -(CO)-(4-12-membered heterocyclic alkyl), -(CONR a )-(4-12-membered heterocyclic alkyl), =(4-12-membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-12-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace;

[0066] R2 is -CONR b R c , 3-12-membered heterocyclic alkyl, 5-14-membered heteroaryl, -(O)-(3-12-membered heterocyclic alkyl), -(O)-(5-14-membered heteroaryl), -(NR a -(3-12 membered heterocyclic alkyl), -(NR a -(5-14-membered heteroaryl), -(CO)-(3-12-membered heterocycloalkyl), -(CO)-(5-14-membered heteroaryl), -(CONR a -(3-12 membered heterocyclic alkyl), -(CONR a )-(5-14-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace;

[0067] R3, R4, and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups;

[0068] R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0069] Or, R A and R1, R A and R x The carbon atoms attached thereto form 4-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits;

[0070] Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-8 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits;

[0071] R a R b and R c Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl groups;

[0072] R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy group, -(CO)-C 1-6 Alkyl group, -(NHCO)-C 1-6 Alkyl, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the alkyl halide group;

[0073] n is 0, 1, 2, 3, or 4;

[0074] The premise is: when R1 is When R3, R4, and R5 are all hydrogen and n is 0, R2 is not hydrogen. , , , , , , , , , , , , , , , , , , , , , .

[0075] Specifically, in the second technical solution, the compound of general formula (I), its stereoisomer, or its pharmaceutically acceptable salt satisfies one or more of the following conditions:

[0076] (1) R1 is a 4-6 membered heterocyclic alkyl, a 6-11 membered spirocyclic alkyl, a 6-11 membered anionic heterocyclic alkyl, a 6-11 membered bridged heterocyclic alkyl, a 5-6 membered heteroaryl alkyl, -(O)-(4-6 membered heterocyclic alkyl), -(NR a -(4-6 membered heterocyclic alkyl), -(CO)-(4-6 membered heterocyclic alkyl), -(CONR a )-(4-6 membered heterocyclic alkyl), =(4-6 membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-8-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace;

[0077] (2) R2 is -CONR b R c , 4-6-membered heterocyclic alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-4-6-membered heterocyclic alkyl, benzo5-6-membered heteroaryl, 5-6-membered heteroaryl-phenyl, 5-6-membered heteroaryl-5-6-membered heteroaryl, -(O)-(4-6-membered heterocyclic alkyl), -(O)-(5-6-membered heteroaryl), -(NR a -(4-6 membered heterocyclic alkyl groups), -(NR a -(5-6-membered heteroaryl), -(CO)-(4-6-membered heterocycloalkyl), -(CO)-(5-6-membered heteroaryl), -(CONR a -(4-6 membered heterocyclic alkyl groups), -(CONR a )-(5-6-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace;

[0078] (3) R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group; in some embodiments, R3, R4 and R5 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, ethyl;

[0079] (4) R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; in some embodiments, R A The radicals are hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, and ethynyl.

[0080] Or, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0081] Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0082] (5) R a R b and R c Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl; in some embodiments, R a R b and Rc Each is independently hydrogen, deuterium, methyl, ethyl, or propyl;

[0083] (6) R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy group, -(CO)-C 1-3 Alkyl group, -(NHCO)-C 1-3 Alkyl, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The group substituted by the alkyl halide group;

[0084] (7) n is 0, 1, or 2.

[0085] Specifically, in the third technical solution, the general formula (I) is further shown as general formula (II), general formula (III), general formula (II-1), and general formula (III-1):

[0086]

[0087] in:

[0088] X is CH or N;

[0089] R x C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the haloalkyl subunit; in some embodiments, R x C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The group substituted by the haloalkyl subunit; in some embodiments, R x Methyl or ethyl;

[0090] R A Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; in some embodiments, R A Hydrogen, deuterium, halogens, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; in some embodiments, R A The radicals are hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, and ethynyl.

[0091] Or, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0092] Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits;

[0093] n is 0, 1, or 2;

[0094] R1 and R2 are as described in the first to second technical solutions.

[0095] Specifically, in the fourth technical solution, the compounds of general formula (I), general formula (II), general formula (III), general formula (II-1), and general formula (III-1), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0096] R1 is optionally replaced by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, or any of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or R A and R x The carbon atoms connected to it link to form the following groups: , , or R A R1 and the carbon atom to which it is attached form optional groups selected from 1-3 groups chosen from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2: or any two adjacent R A The carbon atoms connected thereto form groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, such as cyclobutyl and cyclopentyl; in some embodiments, R1 is a group that is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0097] And / or, R2 is -CONHCH3 or optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, -CH2OH, -CH2CH2OH, tetrahydropyranyl, or the following groups: , , , , , , , , , , , , ;

[0098] The remaining definitions are the same as those in the specific first, second, or third implementation scheme.

[0099] Specifically, in the fifth technical solution, the general formula (I) is further shown as general formula (IA), general formula (I-A1), general formula (I-A2), and general formula (I-A3):

[0100]

[0101]

[0102] X1 is selected from O or NR 1a ;

[0103] R 1a Selected from -C(R) 11 (R) 12 (R) 13 );

[0104] L is selected from the bond, -OC(R) x1 )2C(R x2 )2-*,* indicates the site where it is bonded to a nitrogen atom;

[0105] R2 is selected from , ;

[0106] Among them, R11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 Each is independently selected from either hydrogen or deuterium;

[0107] The condition is that R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 At least one group is selected from deuterium;

[0108] The remaining definitions are the same as those in the specific first, second, third, and fourth implementation schemes.

[0109] Specifically, in the sixth technical solution, the compounds of general formulas (IA), (I-A1), (I-A2), and (I-A3), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0110] R 11 R 12 R 13 Selected from deuterium; or

[0111] R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Selected from deuterium; or

[0112] R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 Selected from deuterium; or

[0113] R x1 Selected from deuterium; or

[0114] R x2 Selected from deuterium; or

[0115] R x1 R x2 Selected from deuterium; or

[0116] R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x1 Selected from deuterium; or

[0117] R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x2 Selected from deuterium; or

[0118] R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R x1 R x2 Selected from deuterium; or

[0119] R 31 R 32 R 33 R 34 Selected from deuterium; or

[0120] R 41 R 42 R 43 Selected from deuterium; or

[0121] R 51 R 52 Selected from deuterium; or

[0122] R 61 R 62 R 63 R 64 R 65 Selected from deuterium;

[0123] The remaining definitions are the same as those in the specific fifth implementation plan.

[0124] Specifically, in the seventh embodiment, the general formulas (I), (II), (III), (II-1), (III-1), (IA), (I-A1), (I-A2), and (I-A3) are selected from one of the compounds in Tables 1 and 2 below:

[0125] Table 1:

[0126]

[0127] Table 2:

[0128]

[0129] Secondly, the present invention also provides a pharmaceutical composition comprising any of the compounds described in any of the foregoing technical solutions, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0130] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0131] Furthermore, the present invention also provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in any of the foregoing embodiments in the preparation of a medicament, preferably the medicament being a medicament for the prevention and / or treatment of ActRII-mediated related diseases; in some embodiments, the disease is obesity, diabetes, or musculoskeletal disorders, preferably type II diabetes.

[0132] The present invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably obesity, diabetes, or musculoskeletal disease.

[0133] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammals described in the present invention include humans.

[0134] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound, conjugate, or pharmaceutically acceptable salt thereof disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0135] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of any of the compounds shown above, their stereoisomers, or their pharmaceutically acceptable salts.

[0136] The present invention further relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of any of the compounds shown above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, in any of the above amounts of 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0137] The present invention further relates to a method for treating a disease in mammals, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or multiple doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day; in some embodiments, the daily dose includes, but is not limited to, 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0138] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims of this invention, wherein the amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is the same as that in the preceding pharmaceutical composition.

[0139] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0140] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0141] Synthetic route

[0142] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0143] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services, including those listed above.

[0144] the term

[0145] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0146] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. When the alkyl group is substituted with a substituent, the substituent is no longer subject to further substitution.

[0147] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0148] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0149] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically comprising 2 to 18 carbon atoms, further comprising 2 to 8 carbon atoms, further comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable linker. When the alkynyl group is substituted by a substituent, the substituent is not further substituted.

[0150] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups), more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C2 ... 3-8 cycloalkyl groups), more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C146 ... 3-6 Cycloalkyl groups, most preferably cycloalkyl groups having 3 to 5 carbon atoms (i.e., C14-C5 ...3-5 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0151] The term "spirocycloalkyl" refers to a polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of its rings has a fully conjugated π-electron system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Spirocycloalkyl. The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C14). 6-14 Spirocycloalkyl), more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C 7-10 Spirocycloalkyl. Based on the number of spiroatoms shared between rings, spirocycloalkyl is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocycloalkyl.

[0152] The term "fused-cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Fused cyclic alkyl groups. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cyclic alkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Fused cycloalkyl groups), more preferably fused cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Fused cyclic alkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups based on the number of constituent rings. Bicyclic or tricyclic fused cyclic alkyl groups are preferred, and ternary / quadrivalent, ternary / quinary, ternary / sixary, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / sixary, quinary / trivalent, quinary / quadrivalent, quinary / quinary, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, or quinary / sixary bicyclic fused cyclic alkyl groups are more preferred.

[0153] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Bridged cycloalkyl groups. They contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Bridged cycloalkyl groups), more preferably bridged cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Bridged cycloalkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups based on the number of rings, with bicyclic or tricyclic bridged cycloalkyl groups being preferred.

[0154] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, for example including C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, C 5-6 The cycloalkyl group is preferably a 5-6 membered heterocycloalkyl group, such as cyclopentyl 5-membered heterocycloalkyl, cyclopentyl 6-membered heterocycloalkyl, cyclopentyl 5-membered heteroaryl, cyclopentyl 6-membered heteroaryl, cyclohexyl 5-membered heterocycloalkyl, cyclohexyl 6-membered heterocycloalkyl, cyclohexyl 5-membered heteroaryl, or cyclohexyl 6-membered heteroaryl. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point. When the cycloalkyl group is substituted by a substituent, the substituent is not further substituted.

[0155] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic alkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic alkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heterocyclic alkyl group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. The heterocyclic alkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocyclic alkyl groups), containing 1 to 4 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; even more preferably, it has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; and most preferably, it has 5 to 6 ring atoms (i.e., 5-6 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocyclic alkyl groups include: azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, or azirropentyl. Non-limiting examples of the polycyclic heterocyclic alkyl groups include: spiroheterocyclic alkyl, fused heterocyclic alkyl, and bridged heterocyclic alkyl.

[0156] The term "spiroheteroalkyl" refers to a polycyclic heterocyclic alkyl group that shares a single atom (called a spiro atom) between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheteroalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe spiroheteroalkyl group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The spiroheteroalkyl group is preferably a spiroheteroalkyl group having 6 to 14 ring atoms (i.e., a 6-14 membered spiroheteroalkyl group), more preferably a spiroheteroalkyl group having 7 to 10 ring atoms (i.e., a 7-10 membered spiroheteroalkyl group). The spiroheterocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups based on the number of shared spiroatoms between the rings. Monospirocyclic alkyl groups or bispirocyclic alkyl groups are preferred, and more preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl groups. Non-limiting examples include: , , wait.

[0157] The term "fused heterocyclic alkyl" or "parylcyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. This group has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The fused heterocyclic alkyl group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The fused heterocyclic alkyl group is preferably a fused heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 membered fused heterocyclic alkyl groups), more preferably a fused heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 membered fused heterocyclic alkyl groups). Based on the number of constituent rings, they are classified as bicyclic, tricyclic, tetracyclic, or polycyclic heterocyclic alkyl groups, preferably bicyclic or tricyclic fused heterocyclic alkyl groups, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic alkyl groups. Non-limiting examples include: , , wait.

[0158] The term "bridged heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group that shares two non-directly connected atoms with any two rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The bridged heterocyclic alkyl group consists of heteroatoms (where m and n are integers from 0 to 2), but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic alkyl group is preferably a bridged heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 membered bridged heterocyclic alkyl), more preferably a bridged heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 membered bridged heterocyclic alkyl). Depending on the number of constituent rings, it is classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl, with bicyclic or tricyclic bridged heterocyclic alkyl being preferred. Non-limiting examples include: , wait.

[0159] The heterocyclic alkyl group includes polycyclic heterocyclic alkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group, such as 5-6 membered heterocyclic alkyl phenyl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, and 5-6 membered heterocyclic alkyl 5-6 membered C 5-6 Cycloalkyl groups, preferably 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, etc. The heterocycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the heterocycloalkyl group is substituted by a substituent, the substituent is no longer further substituted.

[0160] The term "aryl" refers to a monocyclic group with a conjugated π-electron system (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl), having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12 Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C). 6-10Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthrene, etc.

[0161] The aryl group includes polycyclic systems that can be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 heterocycloalkyl, benzo5-6 heteroaryl, preferably benzoC 4-6 The aryl group comprises cycloalkyl, benzo4-6-membered heterocycloalkyl, and benzo5-6-membered heteroaryl groups, with further preferred groups being benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazacyclobutyl, benzooxacyclobutyl, benzooxacyclopentyl, benzoazacyclopentyl, benzooxacyclohexyl, benzozacyclohexyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridonel, benzopyrazinyl, and benzopyridazinyl. The aryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is not further substituted.

[0162] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C group. 6-10 Aryl or C 6-10The aryl 5-10-membered heteroaryl group is preferred, with 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl or phenyl 5-6-membered heteroaryl as further preferred. Non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene-phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene-pyridyl, pyridothiophene, pyridopyrrole, benzo-γ-pyranone, pyrido-γ-pyranone, etc.

[0163] The heteroaryl group includes a polycyclic system fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl rings with C positrons. 3-8 Cycloalkyl, 5-6-membered heteroaryl, 3-8-membered heterocycloalkyl, 5-6-membered heteroarylphenyl, preferably 5-6-membered heteroaryl-C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocycloalkyl, 5-6-membered heteroarylphenyl. The heteroaryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted. Non-limiting examples include: , wait.

[0164] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C2). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups), more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups), preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.

[0165] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein the alkyl and cycloalkyl groups are defined as described above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C14). 1-8Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12). 1-3 Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0166] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0167] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2 2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0168] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2 -Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0169] The term "alkyl subunit" refers to a divalent free alkyl structure formed by the loss of two hydrogen atoms, wherein the alkyl group is as defined above. Non-limiting examples include: methyl subunits ( ), β-subunit ( ), 1-methylethylidene ( ).

[0170] The term "halogenated alkyl subunit" refers to an alkyl subunit substituted with one or more halogens, wherein the alkyl subunit is as defined above. Non-limiting examples include: fluoromethyl subunits (...). ), difluoromethyl subunit ( ).

[0171] The term "thiol" refers to -SH.

[0172] The term "hydroxyl group" refers to -OH.

[0173] The term "nitro" refers to -NO2.

[0174] The term "amino" refers to -NH2.

[0175] The term "cyano" refers to -CN.

[0176] The term "carboxyl group" refers to -C(O)OH.

[0177] The term "aldehyde group" refers to -CHO.

[0178] The term "oxo" or "oxo group" refers to =O.

[0179] The term "carbonyl" refers to C=O.

[0180] The term "aminoacyl" refers to -C(O)NH2.

[0181] The term "sulfonyl" refers to -S(O)2.

[0182] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0183] The term “deuterated alkoxy” refers to an alkoxy group that is substituted with one or more deuterium groups, wherein the alkoxy group is as defined above.

[0184] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0185] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0186] The term "alkylamine" refers to alkyl-NH-, where the alkyl group is as defined above.

[0187] The term "alkenyl" refers to divalent straight-chain and branched alkenyl groups.

[0188] The term "ethynyl" refers to divalent straight-chain and branched ethynyl groups.

[0189] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0190] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0191] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0192] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0193] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8"Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0194] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0195] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes both cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0196] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Furthermore, when a structural unit is substituted, even if the structural unit is marked with a hydrogen atom, it does not mean that the hydrogen atom cannot be substituted, but rather that any position in the structural unit including the hydrogen atom can be substituted. For example, structural unit... Substitution means that any position, including the hydrogen atom on the nitrogen atom, can be substituted. Combinations of substituents and / or variables are only permitted if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing each carbon atom in a group as optionally being replaced by a heteroatom, the condition is that it does not exceed the normal valence of all atoms in the group under the current condition, and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -CO-(C 3-8 cycloalkyl), -CO- (3-8 membered heterocycloalkyl), -CO- (C 5-12 aryl), -CO- (5-12 membered heteroaryl), hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C1-6 Alkyl)2、-HC(=O)NH(C 1-6 Alkyl groups), -NHC(=O)NH2, -CH=N(C 1-6 Alkyl group), -CH=NO(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0197] If a substituent is described as "optionally...substituted", then the substituent may be unsubstituted or may be substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogen atoms on that atom or group may be substituted by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is a subunit (e.g., ... When the substituent is hydrogen, it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also indicate that the corresponding group is "unsubstituted" or "unreplaced". Unless otherwise specified, as used herein, the connection point of the substituent can come from any suitable position of the substituent.

[0198] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0199] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the option of each R substituent in each case is independent of each other.

[0200] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of linking in the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes the cases of AMWB and AWMB, with AMWB being preferred.

[0201] The compounds of this invention can exist in specific geometric or stereoisomeric forms. Stereoisomers are isomers that exist in molecules with the same order of interconnection of atoms or groups of atoms, but different spatial arrangements. All such compounds of this invention include cis-trans isomers, optical isomers, and racemic mixtures and other mixtures thereof, such as cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers; all such mixtures are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. The purification and separation of such substances can be achieved using standard techniques known in the art.

[0202] The compounds of this invention also include their tautomer forms. Tautomers refer to compounds that can interconvert through a reversible chemical reaction known as tautomerization, typically caused by the associated migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation of one functional group into another. Examples include the following paired compounds: aldehyde / ketone–enol, imine–enamine.

[0203] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0204] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F,36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0205] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0206] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0207] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0208] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0209] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0210] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0211] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0212] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0213] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0214] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0215] As used herein, “individual” includes humans or non-human animals. Exemplary human individuals include individuals with a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0216] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0217] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, with the basic raw material used in each step as a reference (1 equivalent).

[0218] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Detailed Implementation

[0219] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0220] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0221] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0222] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100 × 4.6mm, 3.5 μM);

[0223] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm-0.20 mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4 mm-0.5 mm in diameter.

[0224] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0225] DCM: Dichloromethane;

[0226] DMF: N,N-dimethylformamide;

[0227] DIEA: N,N-diisopropylethylamine;

[0228] MeOH: Methanol;

[0229] TFA: Trifluoroacetic acid;

[0230] DMSO: Dimethyl sulfoxide;

[0231] DIC: N,N'-Diisopropylcarbodiimide;

[0232] HOBT: 1-Hydroxybenzotriazole;

[0233] HOAT: N-hydroxy-7-azabenzotriazole.

[0234] Example

[0235] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0236] Intermediate 1:

[0237]

[0238] Step 1: Dissolve 1A (20 g, 101.5 mmol) in tetrahydrofuran (200 mL), and add N-iodosuccinimide (25.1 g, 111.65 mmol) in portions at room temperature, reacting for 1 h at room temperature. Add sodium thiosulfate aqueous solution (100 mL), stir for 10 min, then add water (500 mL), filter, wash the solid with water, and air dry to obtain 1B (32 g, 97.62%). LC-MS (ESI): m / z = 322.9; 324.9 [M+H] + .

[0239] Step 2: Dissolve 1B (32 g, 99.09 mmol) in tetrahydrofuran (300 mL), add 60% sodium hydride (5.55 g, 138.72 mmol) in portions at 0 °C, stir for 30 min, then add p-toluenesulfonyl chloride (22.67 g, 118.91 mmol) in portions, and react at room temperature for 1 h. Pour the reaction solution into water (1000 mL), filter, wash the solid with water, and air dry to obtain 1C (45 g, 95.18%). LC-MS (ESI): m / z = 476.9; 478.9 [M+H] + .

[0240] Step 3: 1C (10 g, 20.96 mmol), 1H-pyrazole-3-boronate pinacol ester (6.1 g, 31.44 mmol), potassium carbonate (8.68 g, 62.88 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (730 mg, 1 mmol) were added sequentially to a mixture of 1,4-dioxane (120 mL) and water (30 mL). After N2 replacement, the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1D (3.6 g, 41.16%). LC-MS (ESI): m / z = 417; 419 [M+H] + .

[0241] Step 4: 1D (2 g, 4.79 mmol), pinacol diborate (2.43 g, 9.56 mmol), potassium acetate (1.41 g, 14.4 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (350 mg, 0.48 mmol) were added sequentially to 1,4-dioxane (30 mL). After N2 replacement, the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 1 (1.5 g, 67.4%). LC-MS (ESI): m / z = 465.2 [M+H] + .

[0242] Example 1:

[0243]

[0244] Step 1: 1A (200 mg, 0.743 mmol) (prepared according to the method described in WO2019238067), intermediate 1 (345 mg, 0.743 mmol), potassium carbonate (205 mg, 1.49 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (108 mg, 0.15 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). After N2 replacement, the mixture was heated to 90 °C and reacted for 16 h. After the reaction was complete, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1B (110 mg, 28.11%). LC-MS (ESI): m / z = 527.2 [M+H] + .

[0245] Step 2: 1B (110 mg, 208.86 μmol) and potassium carbonate (144 mg, 1.04 mmol) were added to methanol (10 mL), and the mixture was heated to 80 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 1 (10 mg, 12.85%). LC-MS (ESI): m / z = 373.2 [M+H] + .

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 13.02-12.65 (m, 1H), 11.76 (s, 1H), 8.61-8.50 (m, 2H), 7.87 (d, 1H), 7.72-7.50 (m, 3H), 7.13 (d, 1H), 6.68 (s, 1H), 2.89 (t, 4H), 2.52-2.50 (m, 4H), 2.34 (s, 3H), 2.25 (s, 3H).

[0247] Example 2:

[0248]

[0249] Step 1: Using 2A (200 mg, 0.732 mmol) (prepared according to the method described in WO2019233883) and intermediate 1 (340 mg, 0.732 mmol) as starting materials, 2B (200 mg, 51.48%) was obtained according to the synthesis method in Step 1 of Example 1. LC-MS (ESI): m / z = 531.2 [M+H] + .

[0250] Step 2: Using 2B (200 mg, 377.36 μmol) as the starting material, compound 2 (30 mg, 21.14%) was synthesized according to the method described in Step 2 of Example 1. LC-MS (ESI): m / z = 377.2 [M+H] + .

[0251] 1H NMR (400 MHz, DMSO-d6) δ 13.04-12.67 (m, 1H), 12.04-11.78 (m, 1H), 8.64-8.55 (m, 2H), 7.90 (s, 1H), 7.80-7.43 (m, 3H), 7.16-7.11 (m, 1H), 6.71 (s, 1H), 3.11-3.04 (m, 4H), 2.54-2.50 (m, 4H), 2.25 (s, 3H).

[0252] Example 3:

[0253]

[0254] Step 1: Dissolve 3A (1.02 g, 5.29 mmol) in ethanol (15 mL), then add dichloromethyldiethylamine hydrochloride (2.04 g, 10.58 mmol) and triethylamine (3.68 mL, 26.46 mmol) sequentially. Heat to 100 °C and stir for 10 h. After the reaction is complete, cool to room temperature, add water, and extract twice with ethyl acetate. Dry the combined organic phases with anhydrous Na₂SO₄, concentrate under reduced pressure, and purify the crude product by reversed-phase column chromatography to obtain 3B (0.62 g, 43.1%). LC-MS (ESI): m / z = 273.1 [M+H] + .

[0255] Step 2: Using 3B (0.18 g, 0.66 mmol) (prepared according to the method described in patent WO2019233883) and intermediate 1 (0.26 mg, 0.55 mmol) as starting materials, 3C (0.20 g, 57.1%) was obtained according to the synthesis method in step 1 of Example 1. LC-MS (ESI): m / z = 531.3 [M+H] + .

[0256] Step 3: Using 3C (0.20 g, 0.38 mmol) as the starting material, compound 3 (16 mg, 11.2%) was synthesized according to the method described in step 2 of Example 1. LC-MS (ESI): m / z = 377.1 [M+H] + .

[0257] 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 11.82 (s, 1H), 8.51 (s,1H), 8.36 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.69 (s, 1H), 7.44 (t, J = 9.2Hz, 1H), 6.92-6.84 (m, 2H), 6.64 (d, J = 2.1 Hz, 1H), 3.25-3.21 (m, 4H), 2.48-2.44 (m, 4H), 2.24 (s, 3H).

[0258] Example 4:

[0259]

[0260] Step 1: Compound 4A (5.00 g, 29.5 mmol) was dissolved in dichloromethane (90 mL), and trifluoroacetic acid (30 mL) was added. The mixture was stirred at room temperature. After the starting material disappeared as monitored by LCMS, it was directly concentrated under reduced pressure. The residue obtained was the trifluoroacetate salt of compound 4B (5.50 g), which was used directly in the next reaction without purification.

[0261] Step 2: The crude trifluoroacetate of compound 4B (5.50 g) obtained in the previous step was dissolved sequentially in dry DMSO (250 mL) with p-bromoiodobenzene (13.9 g, 49.2 mmol), cuprous iodide (12.5 g, 65.6 mmol), and potassium carbonate (13.6 g, 98.4 mmol). The solution was heated to 100°C under nitrogen protection. 0 The reaction was carried out overnight at step C. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4C (1.09 g, two-step yield 16.5%). LC-MS (ESI): m / z = 224.0 [M+H] + .

[0262] Step 3: Using compound 4C (106 mg, 0.475 mmol) and intermediate 1 (200 mg, 0.431 mmol) as starting materials, compound 4D (60 mg, 28.9%) was obtained under the same synthesis conditions as in Step 1 of Example 1. LC-MS (ESI): m / z = 482.2 [M+H] + .

[0263] Step 4: Using compound 4D (60 mg, 0.125 mmol) as the starting material, compound 4 (3 mg, 7.4%) was obtained under the same synthesis conditions as in Step 2 of Example 1. LC-MS (ESI): m / z = 328.2 [M+H] + .

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 13.07-12.64 (m, 1H), 11.99 -11.63 (m, 1H), 8.67-8.35 (m, 2H), 7.96- 7.72 (m, 2H), 7.71-7.48 (m, 2H), 6.77-6.52 (m, 3H), 5.14-5.02 (m, 2H), 4.54-4.41 (m, 4H).

[0265] Example 5:

[0266]

[0267] Step 1: 5A (5 g, 28.90 mmol) was dissolved in 2-butanone (80 mL), and 1,2-bromochloroethane (20 g, 144.51 mmol) and potassium carbonate (15.9 g, 115.6 mmol) were added. The mixture was heated to 90 °C and reacted for 16 h under a nitrogen atmosphere. After the reaction was completed by TLC, the mixture was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5B (6.8 g, 100.00%).

[0268] 1 H NMR (400 MHz, CDCl3) δ 7.41-7.34 (m, 2H), 6.83-6.75 (m, 2H), 4.19 (t, J = 5.9 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H).

[0269] Step 2: Dissolve 5B (500 mg, 2.12 mmol) in acetonitrile (10 mL), add 5C (346 mg, 2.55 mmol), potassium iodide (35 mg, 0.21 mmol), and potassium carbonate (878 mg, 6.37 mmol), and heat under reflux for 16 h under a nitrogen atmosphere. After the reaction is complete as monitored by TLC, cool to room temperature, filter through a diatomaceous earth liner, wash the filter cake with ethyl acetate, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography to obtain 5D (543 mg, 85.90%). LC-MS (ESI): m / z = 298.0 / 300.0 [M+H] + .

[0270] Step 3: 5D (400 mg, 1.34 mmol) was dissolved in dry dioxane (12 mL), and pinacol diboronate (510 mg, 2.01 mmol), Pd(dpp)Cl2 dichloromethane complex (109 mg, 0.13 mmol), and potassium acetate (329 mg, 3.35 mmol) were added. The mixture was heated to 90 °C under a nitrogen atmosphere and reacted for 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and 1D (391 mg, 0.94 mmol), Pd(dpp)Cl2 dichloromethane complex (109 mg, 0.13 mmol), potassium carbonate (370 mg, 2.68 mmol), and water (3 mL) were added to the system. The mixture was then heated to 90 °C under a nitrogen atmosphere and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5E (315 mg, 60.30%).

[0271] Step 4: Using 5E (315 mg, 0.57 mmol) as the starting material, compound 5 (81 mg, 34.87%) was synthesized according to the method described in step 2 of Example 1. LC-MS (ESI): m / z = 402.2 [M+H] + .

[0272] 1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.57-8.42 (m, 2H), 7.74-7.55(m, 2H), 7.52-7.43 (m, 2H), 7.01-6.89 (m, 2H), 6.62-6.49 (m, 1H), 4.48-4.38(m, 1H), 4.21-4.05 (m, 3H), 3.75-3.61 (m, 2H), 3.17-2.96 (m, 3H), 2.76-2.63(m, 1H), 1.94 (s, 1H), 1.80 (s, 1H).

[0273] Example 6:

[0274]

[0275] Compound 6 was obtained from compounds 5B and 6A using the synthetic method described in steps two through four of Example 5. LC-MS (ESI): m / z = 402.2 [M+H] + .

[0276] 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.61-8.47 (m, 2H), 7.72-7.67(m, 1H), 7.63 (s, 1H), 7.57-7.50 (m, 2H), 7.02-6.94 (m, 2H), 6.61-6.58 (m,1H), 4.44 (s, 1H), 4.25-4.10 (m, 3H), 3.74-3.66 (m, 2H), 3.18-3.01 (m, 3H),2.76-2.68 (m, 1H), 2.01-1.93 (m, 1H), 1.85-1.78 (m, 1H).

[0277] Example 7:

[0278]

[0279] Step 1: Using 7A (300 mg, 0.72 mmol) (prepared according to the method described in patent WO2021127561) and intermediate 1 (270 mg, 0.65 mmol) as starting materials, 7B (250 mg, 60.58%) was synthesized according to the method described in Step 1 of Example 1. LC-MS (ESI): m / z = 639.2 [M+H] + .

[0280] Step 2: Compound 7B (0.25 g, 0.39 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (5 mL, 4 mol / L) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, compound 7C (0.22 g, 99.99% yield) was obtained. LC-MS (ESI): m / z = 539.3 [M+H] + .

[0281] Step 3: Compound 7C (0.20 g, 0.37 mmol) was dissolved in methanol (10 mL), and an aqueous formaldehyde solution (0.67 g, 36% wt, 8 mmol) and 2 drops of acetic acid were added. After reacting at room temperature for 2 hours, sodium cyanoborohydride (63 mg, 1.0 mmol) was added, and the reaction was continued at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to give compound 7D (0.11 g, yield 53.60%). LC-MS (ESI): m / z = 553.2 [M+H] + .

[0282] Step 4: Using 7D (110 mg, 0.2 mmol) as the starting material, compound 7 (3 mg, 3.78%) was synthesized according to the method described in step 2 of Example 1. LC-MS (ESI): m / z = 399.3 [M+H] + .

[0283] 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.45-8.44 (m, 1H), 7.87 (s,1H), 7.79-7.78 (m, 1H), 7.63-7.61 (m, 2H), 7.52 (s, 1H), 7.09-7.07 (m, 2H),6.74-6.73 (m, 1H), 4.41-4.40 (m, 2H), 3.56-3.54 (m, 2H), 3.29-3.23 (m, 4H),2.94 (s, 3H), 2.27-2.24 (s, 4H).

[0284] Example 8:

[0285]

[0286] Step 1: Using compound 8A (0.6 g, 1.77 mmol) and intermediate 1 (0.82 g, 1.77 mmol) as starting materials, compound 8B (0.6 g, 56% yield) was obtained by following the procedure in Step 1 of Example 1. LC-MS (ESI): m / z = 598.2 [M+H] + .

[0287] Step 2: Compound 8B (0.6 g, 1.01 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (10 mL, 4 mol / L) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 8C (0.4 g, 79% yield). LC-MS (ESI): m / z = 498.2 [M+H] + .

[0288] Step 3: Compound 8C (0.4 g, 0.8 mmol) was dissolved in methanol (20 mL), and an aqueous formaldehyde solution (0.67 g, 36% wt, 8 mmol) and 2 drops of acetic acid were added. After reacting at room temperature for 2 hours, sodium cyanoborohydride (61 mg, 0.96 mmol) was added, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 8D (0.23 g, yield 56%). LC-MS (ESI): m / z = 512.2 [M+H] + .

[0289] Step 4: Using compound 8D (0.23 g, 0.45 mmol) as the starting material, compound 8 (0.1 g, 63% yield) was obtained by following the procedure in Step 2 of Example 1. LC-MS (ESI): m / z = 358.2 [M+H] + .

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 13.03-12.68 (m, 1H), 12.00-11.75 (m, 1H), 8.67-8.53 (m, 2H), 7.89 (s, 1H), 7.76-7.55 (m, 3H), 7.38-7.36 (m, 2H), 6.68(s, 1H), 2.91-2.89 (m, 2H), 2.55-2.51 (m, 1H), 2.22 (s, 3H), 2.04-1.98 (m,2H), 1.80-1.66 (m, 4H).

[0291] Example 9:

[0292]

[0293] Step 1: Dissolve 9A (1.45 g, 6 mmol) in THF (50 mL), add NaH (360 mg, 60% wt, 7.5 mmol), react for 0.5 h, then add deuterated iodomethane (1.04 g, 7.2 mmol), react for 1 h. Quench with water, extract twice with ethyl acetate, dry the combined organic phases with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography to obtain 9B (1.2 g, 77% yield). LC-MS (ESI): m / z = 258.0; 260.0 [M+H] + .

[0294] Step 2: 9B (258 mg, 1 mmol) was dissolved in THF (30 mL), and n-butyllithium (0.88 mL, 2.5 M in n-hexane, 2.2 mmol) was added dropwise at -78 °C. After reacting for 0.5 h, pinacol isopropoxide borate (408 mg, 2 mmol) was added dropwise. After the reaction was complete, the mixture was slowly brought to room temperature. After the reaction was complete, the mixture was quenched with water, extracted twice with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography to give 9C (256 mg, 84% yield). LC-MS (ESI): m / z = 306.2 [M+H] + .

[0295] Step 3: 9C (256 mg, 0.84 mmol) and 1D (350 mg, 0.84 mmol) were dissolved in dioxane (40 mL) and water (8 mL). Pd(dppf)Cl2 (123 mg, 0.168 mmol) and potassium carbonate (348 mg, 2.52 mmol) were added sequentially, followed by heating to 100 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 9D (187 mg, yield 43%). LC-MS (ESI): m / z = 516.2 [M+H] + .

[0296] Step 4: Dissolve 9D (187 mg, 0.363 mmol) in methanol (10 mL), add potassium carbonate (201 mg, 1.45 mmol), and react at 80 °C for 3 hours. After the reaction is complete, cool to room temperature, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography to obtain compound 9 (28 mg, yield 21%). LC-MS (ESI): m / z = 362.2 [M+H] + .

[0297] 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.73 (s, 1H), 8.64-8.52(m, 1H), 8.50 (s, 1H), 7.86 (d, 1H), 7.77-7.65 (m, 1H), 7.60 (d, 2H), 7.07(d, 2H), 6.67 (d, 1H), 3.27-3.12 (m, 4H), 2.61-2.51 (m, 4H).

[0298] Biological test evaluation

[0299] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0300] 1. In vitro activity assay

[0301] H_ACVR2B Reporter cells were added to 96-well cell culture plates at a density of 100 μL / well, and the plates were incubated overnight. After incubation, the plates were removed, and the supernatant was discarded. Then, serially diluted working solutions of the compound were added, 50 μL to each well, mixed well, and the plates were incubated for 1 h. After 1 h, the plates containing the incubated mixture were removed, and 50 μL of Activin A protein solution was added to each well. The plates were then incubated for another 6 h. Samples were then collected to detect Luciferase, and the data were exported in Excel format. PrismGraphPad was used to calculate the logarithm of the sample concentrations, and a four-parameter fitting was performed to obtain the IC50 curve. 50 value.

[0302] The compounds of the present invention, such as the compounds in the examples, have an IC50 of less than 10 μm against ACVR2B (also known as ActRIIB). 50 Values, IC50 values ​​of some preferred compounds less than 1 μm 50 IC50 values ​​for some preferred compounds 50<500 nM, IC50 of some preferred compounds 50 <100 nM. Experimental results for some specific compounds are shown in Table 1, where A represents IC50. 50 <500 nM; B indicates 500 nM ≤ IC 50 <5 μm, C represents 5 μm ≤ IC 50 .

[0303] Table 1. Inhibitory activity of compounds against ACVR2B

[0304] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> Compound 1 A Compound 2 A Compound 3 A Compound 4 A Compound 5 A Compound 6 A Compound 7 A Compound 8 A Compound 9 A

[0305] Conclusion: The compounds of this invention exhibit excellent inhibitory activity against ActRIIB.

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: R1 is a 4-12 membered heterocyclic alkyl, a 5-14 membered heteroaryl, -(O)-(4-12 membered heterocyclic alkyl), or -(NR)- ...R1)-(NR)-(NR) a -(4-12-membered heterocyclic alkyl), -(CO)-(4-12-membered heterocyclic alkyl), -(CONR a )-(4-12-membered heterocyclic alkyl), =(4-12-membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-12-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace; R2 is -CONR b R c , 3-12-membered heterocyclic alkyl, 5-14-membered heteroaryl, -(O)-(3-12-membered heterocyclic alkyl), -(O)-(5-14-membered heteroaryl), -(NR a -(3-12 membered heterocyclic alkyl), -(NR a -(5-14-membered heteroaryl), -(CO)-(3-12-membered heterocycloalkyl), -(CO)-(5-14-membered heteroaryl), -(CONR a -(3-12 membered heterocyclic alkyl), -(CONR a )-(5-14-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace; R3, R4, and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Or, R A and R1, R A and R x The carbon atoms attached thereto form 4-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits; Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-8 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Group substitution of haloalkyl subunits; R a R b and R c Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups; R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy group, -(CO)-C 1-6 Alkyl group, -(NHCO)-C 1-6 Alkyl, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the alkyl halide group; n is 0, 1, 2, 3, or 4; The premise is: when R1 is When R3, R4, and R5 are all hydrogen and n is 0, R2 is not hydrogen. , , , , , , , , , , , , , , , , , , , , , .

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It satisfies one or more of the following conditions: (1) R1 is a 4-6 membered heterocyclic alkyl, a 6-11 membered spirocyclic alkyl, a 6-11 membered anionic heterocyclic alkyl, a 6-11 membered bridged heterocyclic alkyl, a 5-6 membered heteroaryl alkyl, -(O)-(4-6 membered heterocyclic alkyl), -(NR a -(4-6 membered heterocyclic alkyl), -(CO)-(4-6 membered heterocyclic alkyl), -(CONR a )-(4-6 membered heterocyclic alkyl), =(4-6 membered heterocyclic alkyl), -(O)-(C 1-3 (alkylene)-(4-8-membered heterocyclic alkyl), wherein the heterocyclic alkyl, heteroaryl, and alkylene are optionally further surrounded by 1-4 R... x replace; (2) R2 is -CONR b R c , 4-6-membered heterocyclic alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-4-6-membered heterocyclic alkyl, benzo5-6-membered heteroaryl, 5-6-membered heteroaryl-phenyl, 5-6-membered heteroaryl-5-6-membered heteroaryl, -(O)-(4-6-membered heterocyclic alkyl), -(O)-(5-6-membered heteroaryl), -(NR a -(4-6 membered heterocyclic alkyl groups), -(NR a -(5-6-membered heteroaryl), -(CO)-(4-6-membered heterocycloalkyl), -(CO)-(5-6-membered heteroaryl), -(CONR a -(4-6 membered heterocyclic alkyl groups), -(CONR a )-(5-6-membered heteroaryl), wherein the heterocyclic alkyl group or heteroaryl group is optionally further surrounded by 1-4 R groups. y replace; (3) R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 The haloalkoxy group is preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, or ethyl. (4) R A It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, preferably hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, or ethynyl; Or, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits; Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits; (5) R a R b and R c Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl groups, preferably hydrogen, deuterium, methyl, ethyl, or propyl; (6) R x and R y Each is independently a deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy group, -(CO)-C 1-3 Alkyl group, -(NHCO)-C 1-3 Alkyl, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The group substituted by the alkyl halide group; (7) n is 0, 1, or 2.

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formula (II), general formula (III), general formula (II-1), and general formula (III-1): in: X is CH or N; R x C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl subunits, C 1-6 The group substituted by the haloalkyl subunit is preferred, C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 The alkyl halide group is replaced by a group, preferably methyl or ethyl; R A Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, preferably hydrogen, deuterium, halogen, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, more preferably hydrogen, deuterium, methyl, ethyl, propyl, vinyl, allyl, or ethynyl; Or, R A and R1, R A and R x The carbon atoms attached thereto form 5-8 membered heterocyclic alkyl groups, optionally further bonded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits; Or, any two adjacent R A The carbon atoms linked to it form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Group substitution of haloalkyl subunits; n is 0, 1, or 2; R1 and R2 are as described in claim 1.

4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R1 is optionally replaced by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, or any of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or R A and R x The carbon atoms connected to it link to form the following groups: , , or R A R1 and the carbon atom to which it is attached form optional groups selected from 1-3 groups chosen from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2: or any two adjacent R A The carbon atoms connected thereto form groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, such as cyclobutyl or cyclopentyl, preferably R1 is a group consisting of: , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； And / or, R2 is -CONHCH3 or optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, -CH2OH, -CH2CH2OH, tetrahydropyranyl, or the following groups: , , , , , , , , , , , , .

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formula (IA), general formula (I-A1), general formula (I-A2), and general formula (I-A3): X1 is selected from O or NR 1a ; R 1a Selected from -C(R) 11 (R) 12 (R) 13 ); L is selected from the bond, -OC(R) x1 )2C(R x2 )2-*,* indicates the site where it is bonded to a nitrogen atom; R2 is selected from , ; Among them, R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 Each is independently selected from either hydrogen or deuterium; The condition is that R 11 R 12 R 13 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 41 R 42 R 43 R 51 R 52 R 61 R 62 R 63 R 64 R 65 R x1 R x2 At least one of the groups is selected from deuterium.

6. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures: 。 7. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition according to claim 7, comprising 1-1500 mg of the compound of any one of claims 1-6, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-6, or the pharmaceutical composition according to claim 7 or 8, in the preparation of a medicament, preferably a medicament for the prevention and / or treatment of ActRII-mediated diseases.

10. The use according to claim 9, wherein the disease is obesity, diabetes, or musculoskeletal disease.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-6, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7 or 8, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably obesity, diabetes, or musculoskeletal disorders.

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