Substituted azole compound as APJ receptor agonist

Abstract

The present invention provides a compound as an APJ receptor agonist. The compound is a compound represented by formula (I), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof. The present invention further provides a pharmaceutical composition comprising the compound, and a use thereof in the treatment or prevention of diseases associated with APJ.

Description

A class of substituted azole compounds as APJ receptor agonists Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an APJ receptor agonist. Background Art

[0002] The angiotensin protein J receptor (APJ) is a rhodopsin-like G protein-coupled receptor. By binding to the Gαi subunit, it regulates the downstream PI3K-pAKT-eNOS-NO pathway related to blood pressure, the AMPK pathway related to glucose uptake, lipid metabolism, and oxidation, the β-arrestin pathway related to protein degradation after phosphorylation, and ion channels associated with heart failure. Apelin is the natural ligand of APJ, expressed by the APLN gene. The complete peptide is apelin-77, which is degraded in the body into shorter peptides of varying lengths, such as apelin-13 and apelin-36, thereby activating the physiological functions of APJ.

[0003] Apelin / APJ is widely distributed throughout the human body, including in the fat, brain, lungs, and heart. Apelin, also known as an adipokine, has been reported to be expressed at higher levels in the adipose tissue of obese individuals with insulin resistance. While insulin promotes apelin expression in adipose tissue, apelin can also feedback-inhibit insulin secretion. By increasing apelin expression, insulin resistance and metabolic disorders can be suppressed. Therefore, APJ agonists may be useful in treating diabetes, obesity, and other related conditions.

[0004] Furthermore, apelin / APJ plays an important role in the cardiovascular system. Studies have shown that acute apelin infusion in rats with chronic heart failure restores ejection fraction, increases cardiac output, and reduces left ventricular end-diastolic pressure in heart failure (Circulation 110:187-193, 2004). Exogenous apelin potently enhances myocardial contractility without inducing left ventricular hypertrophy and associated reductions in ventricular preload and afterload (Heart 96:1011-1016, 2010). APJ agonists have the potential to treat heart failure.

[0005] In addition, there is evidence that apelin / APJ signaling plays an important role in maintaining pulmonary vascular homeostasis (Kim, J. Mol. Cells 2014; 37(3): 196-201), and its agonists can be used to treat pulmonary hypertension. The apelin / APJ pathway is also associated with the treatment of diseases such as sepsis, renal failure, scleroderma, and idiopathic pulmonary fibrosis (Critical Care 2018, 22: 10).

[0006] In summary, apelin / APJ is closely related to the occurrence and treatment of various diseases. APJ receptor activity can regulate the competitive level of downstream G protein signaling (activation) and β-arrestin recruitment. Studies have shown that APJ receptor signaling through β-arrestin can lead to cardiac hypertrophy (Nature 2012, 488, 394-398). Currently, there are many studies on APJ receptor agonists, but most existing small molecule agonists (AMG986, BMS986224, etc.) also have strong activity on β-arrestin recruitment, lack obvious bias, and may have potential side effects. Therefore, the development of safe and effective small molecule APJ agonists with G protein bias would be of great value. Summary of the Invention

[0007] In the present invention, we discovered a series of small molecule agonists that have strong agonist activity on APJ receptors and significant G protein preference.

[0008] In one aspect, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof:

[0009] in,

[0010] R 1 -(L1) n -R 11 ;

[0011] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0012] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0013] R 1a Independently selected from halogen, cyano, hydroxy, amino, C1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0014] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0015] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0016] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0017] R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6Alkyl)2;

[0018] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0019] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0020] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0021] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0022] R 3 Independently selected from C 6-10 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic group, wherein said aryl, heteroaryl or heterocyclic group is substituted by 1, 2, 3, 4 or 5 R 3a replace;

[0023] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O; R 3aa and R 3abSelected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl substitution;

[0024] The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0025] Or when R 3 When it is a bicyclic group, the two R 3a Together with the ring atoms to which they are connected, they form a 3-8 membered cycloalkyl group or a 4-8 membered heterocyclic group; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0026] m is selected from 0, 1, 2, or 3;

[0027] n is selected from 0, 1, 2, or 3.

[0028] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0029] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0030] In another aspect, the present invention provides use of a compound of the present invention in the preparation of a medicament for treating and / or preventing diseases associated with APJ receptor activity.

[0031] In another aspect, the present invention provides a method for treating and / or preventing a disease associated with APJ receptor activity in a subject, comprising administering to the subject a compound or composition of the present invention.

[0032] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in the treatment and / or prevention of diseases associated with APJ receptor activity.

[0033] In some embodiments, the disease associated with APJ receptor activity is obesity, diabetes, sarcopenia or wasting due to various causes, pulmonary hypertension, heart failure, hypertension, chronic kidney disease, idiopathic pulmonary fibrosis, systemic sclerosis (such as scleroderma).

[0034] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0035] definition

[0036] Chemical definition

[0037] Definitions of specific functional groups and chemical terms are described in more detail below.

[0038] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0039] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6"Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0040] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0041] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0042] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl and C 3-5 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Cycloalkyl also includes spirocyclic cycloalkyl, i.e., a carbon-containing cyclic structure formed by at least two rings sharing one carbon atom. Spirocyclic cycloalkyl includes but is not limited to spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.4]octyl, spiro[2.6]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.7]decyl, spiro[3.6]decyl, spiro[4.5]decyl, spiro[3.7]undecyl, spiro[4.6]undecyl, spiro[5.5]undecyl, spiro[4.7]dodecyl or spiro[5.6]dodecyl. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0044] "3-10 membered heterocyclyl" refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 4-9 membered heterocyclyl is preferably a 4-9 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl is preferably a 3-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-7 membered heterocyclyl is preferably a 4-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl.Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include spiro heterocyclyl groups, which are spiro rings containing a heteroatom selected from oxygen, nitrogen, or sulfur. Spiro heterocyclyl groups include 5-14 membered spiro heterocyclyl groups, which are carbon-containing cyclic structures formed by at least two rings sharing a single carbon atom. Spiro C5-C14 heterocyclyl rings include, but are not limited to, azaspiro[2.2]pentyl, azaspiro[2.3]hexyl, azaspiro[2.4]heptyl, azaspiro[3.3]heptyl, azaspiro[2.5]octyl, azaspiro[3.4]octyl, azaspiro[2.6]nonyl, azaspiro[3.5]nonyl, azaspiro[4.4]nonyl, azaspiro[2.7]decyl, azaspiro[3.6]decyl, azaspiro[4.5]decyl, azaspiro[3.7]undecyl 1-Heptyl, ... , diazaspiro[2.7]decyl, diazaspiro[3.6]decyl, diazaspiro[4.5]decyl, diazaspiro[3.7]undecyl, diazaspiro[4.6]undecyl, diazaspiro[5.5]undecyl, diazaspiro[4.7]dodecyl, diazaspiro[5.6]dodecyl, azaoxaspiro[2.2]pentyl, azaoxaspiro[2.3]hexyl, azaoxaspiro[2.4]heptyl, azaoxaspiro[3.3]heptyl, azaoxaspiro[ [2.5]octyl, azaoxspiro[3.4]octyl, azaoxspiro[2.6]nonyl, azaoxspiro[3.5]nonyl, azaoxspiro[4.4]nonyl, azaoxspiro[2.7]decyl, azaoxspiro[3.6]decyl, azaoxspiro[4.5]decyl, azaoxspiro[3.7]undecyl, azaoxspiro[4.6]undecyl, azaoxspiro[5.5]undecyl, azaoxspiro[4.7]dodecyl or azaoxspiro[5.6]dodecyl. The heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0045] “C 6-10"Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0046] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred and are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mol%. The term "deuterated" refers to a group or compound in which one or more hydrogen atoms H are replaced by D.

[0048] Isotopic variants of the present invention include deuterated compounds. "Deuterated compound" refers to a compound in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, for example, "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," etc. For example, "deuterated alkyl" refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium atom; a single carbon atom may be bonded to multiple deuterium atoms; and multiple carbon atoms in an alkyl group may also be bonded to deuterium. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium; monodeuterated methyl and dideuterated methyl are also included. For example, deuterated piperazinyl means that one or more hydrogen atoms on the piperazinyl group are replaced by deuterium, including all 8 hydrogen atoms replaced by deuterium. In some embodiments, the compounds of the present invention include deuterated compounds.

[0049] As used herein, the term "optionally substituted" or "optionally substituted" or "optionally substituted with" refers to optional substitution with one or more of the stated groups, where one or more refers to 1-5, 1-4, 1-3, 1-2 or 1 substitutions, depending on valence theory.

[0050] Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., as defined herein, are optionally substituted groups.

[0051] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bbCO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bbP(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0052] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0053] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0054] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0055] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0056] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(Rff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0057] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0058] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ffThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0059] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -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(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0060] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0061] Other definitions

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0063] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0064] "Disease," "disorder," and "condition" are used interchangeably herein.

[0065] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0066] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0067] As used herein, the term "compound of the present invention" refers to the compound of the following formula (I) (including sub-formulas, such as formula (II), (III), (IV), (V-1), (V-2) or (VI)), or its isotopic variants, tautomers, stereoisomers or pharmaceutically acceptable salts, and mixtures thereof.

[0068] In one embodiment, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof:

[0069] in,

[0070] R 1 -(L1) n -R 11 ;

[0071] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0072] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0073] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0074] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0075] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0076] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0077] R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0078] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0079] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0080] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0081] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0082] R 3 Independently selected from C 6-10 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic group, wherein said aryl, heteroaryl or heterocyclic group is substituted by 1, 2, 3, 4 or 5 R 3a replace;

[0083] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O; R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl substitution;

[0084] The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0085] Or when R 3 When it is a bicyclic group, the two R 3a Together with the ring atoms to which they are connected, they form a 3-8 membered cycloalkyl group or a 4-8 membered heterocyclic group; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0086] m is selected from 0, 1, 2, or 3;

[0087] n is selected from 0, 1, 2, or 3.

[0088] In another embodiment, the present invention relates to a compound of formula (II), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0089] in,

[0090] R 1 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 1 Optionally R 1a replace;

[0091] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 alkyl;

[0092] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A and -5-7 membered heterocyclyl-A, wherein said C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group may be optionally replaced by R 2f replace;

[0093] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0094] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0095] R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0096] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0097] A is C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, the aryl, heteroaryl, cycloalkyl or heterocyclic group may be optionally replaced by R A replace;

[0098] RA Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0099] R 3 Independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, saturated or partially unsaturated 4-8 membered heterocyclic group, wherein the aryl, heteroaryl or heterocyclic group is substituted by 1, 2, 3 or 4 R 3a replace;

[0100] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-8 membered heterocyclic group, C 1-6 4-8 membered heterocyclic group substituted by alkyl or halogen, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O; R 3aa and R 3ab Selected from H and C 1-6 Alkyl; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0101] Provided that when both Y and Z are N, the substituent R 3a At least one of them is C 3-6 Cycloalkyl or 4-6 membered heterocyclic group.

[0102] In another embodiment, the present invention relates to a compound of formula (II), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0103] in,

[0104] R 1 -(L1) n -R 11 ;

[0105] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0106] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0107] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0108] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0109] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0110] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0111] R 2d and R 2e independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0112] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0113] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0114] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0115] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab)-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0116] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O; R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0117] The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0118] m is selected from 0, 1, 2, or 3;

[0119] n is selected from 0, 1, 2, or 3;

[0120] p is selected from 0, 1, 2, 3, 4 or 5.

[0121] In another embodiment, the present invention relates to a compound of formula (III), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0122] in,

[0123] R 1 -(L1) n -R 11 ;

[0124] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0125] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0126] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0127] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0128] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0129] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0130] R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0131] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0132] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0133] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0134] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0135] Ring B and Ring C together form a bicyclic heteroaryl group or a bicyclic heterocyclic group;

[0136] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O; R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0137] And the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0138] Or 2 R 3a Together with the ring atoms to which they are attached, they form a 3-8 membered cycloalkyl or a 4-8 membered heterocyclyl;

[0139] m is selected from 0, 1, 2, or 3;

[0140] n is selected from 0, 1, 2, or 3;

[0141] p is selected from 0, 1, 2, 3, 4 or 5.

[0142] In another embodiment, the present invention relates to a compound of formula (IV), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0143] R 1 -(L1) n -R 11 ;

[0144] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0145] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0146] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0147] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0148] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0149] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0150] R 2d and R 2e independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0151] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0152] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0153] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0154] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0155] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O, where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0156] The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0157] m is selected from 0, 1, 2, or 3;

[0158] n is selected from 0, 1, 2, or 3;

[0159] p is selected from 0, 1, 2 or 3.

[0160] In another embodiment, the present invention relates to a compound of formula (V-1), (V-2), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0161] R 1 -(L1) n -R 11 ;

[0162] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0163] R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0164] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0165] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0166] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0167] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0168] R 2d and R 2e independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0169] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0170] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0171] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0172] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0173] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O, where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0174] m is selected from 0, 1, 2, or 3;

[0175] n is selected from 0, 1, 2, or 3;

[0176] p is selected from 0, 1, 2 or 3;

[0177] t is selected from 1, 2, 3 or 4.

[0178] In another embodiment, the present invention relates to a compound of formula (VI), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following general structure:

[0179] R 1 -(L1) n -R 11 ;

[0180] L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens;

[0181] R 11 Selected from C 6-10Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace;

[0182] R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2- 6-alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated;

[0183] R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated;

[0184] R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2;

[0185] R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0186] R 2d and R 2e independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2;

[0187] R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O;

[0188] A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1-6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace;

[0189] Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace;

[0190] R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated;

[0191] R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1- 6-membered alkyl or halogen-substituted 4-8-membered heterocyclic group, 4-8-membered heterocycloalkenyl, phenyl, 5-6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R3aa and = O; where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated;

[0192] The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0193] m is selected from 0, 1, 2, or 3;

[0194] n is selected from 0, 1, 2, or 3;

[0195] p is selected from 0, 1, 2, 3 or 4;

[0196] X and Y are each independently selected from N or CH, and at least one of X and Y is N.

[0197] R 1 Definition of

[0198] In some embodiments, n is 0. In some embodiments, R 1 is phenyl, 5-6 membered monocyclic heteroaryl, 7-12 membered bicyclic heteroaryl, 5-6 membered monocyclic heterocyclic group, 7-12 membered bicyclic heterocyclic group or C 3-8 Cycloalkyl, wherein the R 1 Optionally R 1a Replacement, R 1a Independently selected from halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2, R 1aEach group defined in can be optionally deuterated, up to fully deuterated. In some embodiments, R 1 is a 5-6 membered monocyclic heteroaryl group, which is R 1a Replacement, R 1a Independently selected from halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2, R 1a Each group defined in can be optionally deuterated, up to fully deuterated. In some embodiments, R 1 is phenyl; pyridyl (e.g., pyridin-3-yl, pyridin-2-yl, pyridin-4-yl or pyridin-5-yl), thienyl, furanyl, pyridazinyl, pyrazinyl, pyrimidinyl; tetrahydrofuranyl, 1,4-dioxane; or spiro[2.2]pentyl, spiro[3.3]heptyl, spiro[3.4]octyl or spiro[2.2.1]heptyl, wherein R 1 Optionally R 1a Replacement, R 1a independently selected from halogen, methyl, ethyl, propyl, deuterated methyl (methyl-d3), hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 1,1,1-trifluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, C 1-6 In some embodiments, R 1 is pyridin-3-yl, which is R 1a Replacement, R 1a independently selected from halogen, methyl, ethyl, propyl, deuterated methyl (methyl-d3), hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 1,1,1-trifluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, C 1-6 haloalkyl, methoxy, ethoxy, isopropoxy, propoxy, ethynyl, dimethylamino or methylamino.

[0199] In some embodiments, R 1 for

[0200] R 3 Definition of

[0201] In some embodiments, R 3 for where R 3a1 and R 3a5 Each is independent of -OC 1-6 Alkyl or halogen, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or R 3a1 and R 3a5 One of them is C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, R 3a1 and R 3a5 The other one is -OC 1-6 Alkyl, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, and R 3a2 、R 3a4 and R 3a3 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 In some embodiments, R 3 for where R 3a1 and R 3a5 Each is independent of -OC 1-6 Alkyl (e.g., methoxy, ethoxy, or isopropoxy) or halogen, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 Alkyl or halogen substituted C 3-6 cycloalkyl (e.g., methyl-substituted cyclopropyl, methyl-substituted cyclobutyl, methyl-substituted cyclopentyl, methyl-substituted cyclohexyl, halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl or halogen-substituted cyclohexyl), 4-8 membered heterocyclyl (e.g., pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, morpholinyl or piperidinyl), C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl (e.g., dihydropyranyl), phenyl, or 5-6 membered heteroaryl (e.g., pyrazolyl, pyridyl, or pyrrolyl); or R 3a1 and R 3a5 One of them is C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 Alkyl or halogen substituted C 3-6 cycloalkyl (e.g., methyl-substituted cyclopropyl, methyl-substituted cyclobutyl, methyl-substituted cyclopentyl, methyl-substituted cyclohexyl, halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl or halogen-substituted cyclohexyl), 4-8 membered heterocyclyl (e.g., pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, morpholinyl or piperidinyl), C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl (e.g., dihydropyranyl), phenyl or 5-6 membered heteroaryl (e.g., pyrazolyl, pyridyl or pyrrolyl), R 3a1 and R 3a5 The other one is -OC 1-6 Alkyl, halogen, C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 Alkyl or halogen substituted C 3-6cycloalkyl (e.g., methyl-substituted cyclopropyl, methyl-substituted cyclobutyl, methyl-substituted cyclopentyl, methyl-substituted cyclohexyl, halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl or halogen-substituted cyclohexyl), 4-8 membered heterocyclyl (e.g., pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, morpholinyl or piperidinyl), C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl (e.g., dihydropyranyl), phenyl or 5-6 membered heteroaryl (e.g., pyrazolyl, pyridyl or pyrrolyl), and R 3a2 、R 3a4 and R 3a3 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 In some embodiments, R 3 for where R 3a1 and R 3a5 is methoxy, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 Alkyl or halogen substituted C 3-6 cycloalkyl (e.g., methyl-substituted cyclopropyl, methyl-substituted cyclobutyl, methyl-substituted cyclopentyl, methyl-substituted cyclohexyl, halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl or halogen-substituted cyclohexyl), 4-8 membered heterocyclyl (e.g., pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, morpholinyl or piperidinyl), C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl (e.g., dihydropyranyl), phenyl, or 5-6 membered heteroaryl (e.g., pyrazolyl, pyridinyl, or pyrrolyl). In some embodiments, R 3 for where R 3a1 and R 3a5 is halogen (e.g. fluorine), R 3a2 and R3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 Alkyl or halogen substituted C 3-6 cycloalkyl (e.g., methyl-substituted cyclopropyl, methyl-substituted cyclobutyl, methyl-substituted cyclopentyl, methyl-substituted cyclohexyl, halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl or halogen-substituted cyclohexyl), 4-8 membered heterocyclyl (e.g., pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, morpholinyl or piperidinyl), C 1-6 alkyl or halogen-substituted 4- to 8-membered heterocyclyl, 4- to 8-membered heterocycloalkenyl (e.g., dihydropyranyl), phenyl, or 5- to 6-membered heteroaryl (e.g., pyrazolyl, pyridyl, or pyrrolyl).

[0202] In some embodiments, R 3 for

[0203] R 2 Definition of

[0204] In some embodiments, R 2 For-(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A or -(CR 2b R 2c )-(NR 2d )-A, wherein A is pyrimidinyl (e.g., pyrimidin-2-yl), pyridazinyl (e.g., pyridazin-3-yl), pyridinyl (e.g., pyridin-3-yl), pyrazolyl, thiazolyl, or phenyl, and the A is optionally replaced by R A Substituted, where R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 2b and R 2c independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6haloalkyl; and R 2d and R 2e independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 In some embodiments, R 2 for where R 2d For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl; and R A Halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl or C 3-6 Cycloalkyl.

[0205] In some embodiments, R 2 for

[0206] In another embodiment, the present invention provides a compound, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0207] Those skilled in the art will appreciate that the present invention also includes isotopically labeled compounds (isotopic variants) that are identical to those described in Formula (I), (II), (III), (IV), (V-1), (V-2) or (VI), but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example, 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P.35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0208] Pharmaceutical compositions and kits

[0209] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0210] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0211] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0212] Drug administration

[0213] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0214] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0215] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0216] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0217] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0218] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0219] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0220] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0221] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0222] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0223] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0224] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0225] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0226] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0227] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0228] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0229] Example

[0230] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0231] Notes on commonly used abbreviations:

[0232] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; MeCN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; THF = tetrahydrofuran; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; D IEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propylphosphoric acid cyclic anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride; DMA = N,N-dimethylacetamide; hAPJ = human apelin receptor; β-arrestin = β-arrestin; cAMP = cyclic adenosine monophosphate.

[0233] Example 1 Preparation of key intermediates

[0234] Synthesis of intermediate int 1

[0235] Step 1: Under nitrogen, the raw materials int 1-1 (6.7 g, 52.12 mmol) and int 1-2 (8.4 g, 52.12 mmol) were added to a reaction flask. 1,4-dioxane (80 mL) was then added, followed by tricyclohexylphosphane (2.9 g, 10.42 mmol), Pd2(dba)3 (4.8 g, 5.21 mmol), K3PO4 (33.2 g, 156.36 mmol), and H2O (14 mL). The reaction system was heated to 100°C for 12 h. LC-MS confirmed the reaction was complete, and the reaction was stopped. The solvent was concentrated to dryness, extracted with EA, and then purified by silica gel column chromatography (PE / EA = 5:1) to obtain the target product int 1-3 (6.5 g, yield: 84.2%). LC-MS: ESI-MS (m / z): [M+H] + =149.

[0236] Step 2: Under nitrogen, int 1-4 (6.4 g, 57.02 mmol) was dissolved in DCM (128 mL). SOCl2 (6.8 g, 57.02 mmol) was added in an ice bath and allowed to react for 1 h. The mixture was then cooled to room temperature and a DCM solution of int 1-3 (6.5 g, 43.86 mmol) was added dropwise. The reaction was allowed to react for 12 h after the addition was complete. LC-MS confirmed the reaction was complete. The solvent was evaporated, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the product was extracted with EA. The product was then purified by silica gel column chromatography (PE / EA = 3:1 elution) to obtain the target product int 1-5 (5.8 g, yield: 44.9%). LC-MS: ESI-MS (m / z): [M+H] + =295.

[0237] Step 3: Under nitrogen protection, int 1-5 (5.8 g, 19.67 mmol) was dissolved in DCM (116 mL), and m-CPBA (10.2 g, 59.01 mmol) was added. The reaction was allowed to react at room temperature for 12 h. LC-MS confirmed the reaction was complete. The reaction was quenched by adding saturated aqueous sodium thiosulfate (100 mL). The pH was then adjusted to 8 with saturated aqueous sodium bicarbonate. The product was extracted with EA and purified by silica gel column chromatography (PE / EA = 5:1 elution) to obtain the target product int 1-6 (6.0 g, yield: 93.3%). LC-MS: ESI-MS (m / z): [M+H] + =327.

[0238] Step 4: Under nitrogen, int 1-6 (6.0 g, 18.36 mmol) was dissolved in MeOH (120 mL) and K2CO3 (5.1 g, 36.72 mmol) was added. The reaction was stirred at room temperature for 12 h. The reaction was concentrated to dryness, and H2O (120 mL), KOAc (3.6 g, 36.72 mmol), and hydroxylaminesulfonic acid (4.2 g, 36.72 mmol) were added. Stirring was continued at room temperature under nitrogen for 1 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, the product was extracted with EA, and concentrated to obtain the crude product. The product was then separated and purified by Prep-Achiral-SFC to obtain the desired product, int 1-7 (1.2 g, yield: 28.8%). The product elution time was RT2 = 5.98 min. LC-MS: ESI-MS (m / z): [M+H] + =228.

[0239] Split conditions:

[0240] Chromatographic column: DAICEL DCpak P4VP 3*25cm, 5μm;

[0241] Mobile phase: Phase A:CO 2, Mobile Phase B: MeOH (20mM NH3.M);

[0242] Flow rate: 60 mL / min; Gradient: isocratic 38% B;

[0243] Column Temperature (℃): 35;

[0244] Pressure (bar): 100; Detection wavelength: 254 nm; Retention time: RT1 (min): 3.78; RT2 (min): 5.98; Injection volume: 3.5 mL;

[0245] Step 5: Under nitrogen, int 1-7 (300 mg, 1.32 mmol) was dissolved in MeOH (6 mL), and Rh(COD)BF4 (10.5 mg, 0.027 mol), Josiphos SL-J216-2 (19.5 mg, 0.03 mol), and Zn(OTf)2 (96 mg, 0.27 mol) were added. The reaction system was stirred under a hydrogen atmosphere (10 atm) at room temperature for 12 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, the product was extracted with EA, and concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 5%-60% MeCN, elution over 20 min) to obtain the target intermediate int 1 (200 mg, yield: 66%). LC-MS: ESI-MS (m / z): [M+H] + =230.

[0246] Synthesis of intermediate int 2

[0247] Step 1: Under nitrogen, int 2-1 (1.0 g, 4.63 mmol) and int 2-2 (1.5 g, 4.63 mmol, 1.0 eq.) were dissolved in DMF (10 mL). CuI (0.01 g, 0.046 mmol) and Pd(PPh3)4 (0.05 g, 0.046 mmol) were added at room temperature. The reaction system was then heated to 80°C for 1 h. LC-MS analysis confirmed the reaction was complete. The solvent was evaporated, the mixture was extracted with EA, and the crude product was concentrated to afford the crude product. This was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 min) to afford the target intermediate, int 2-3 (700 mg, yield: 86.3%). LC-MS: ESI-MS (m / z): [M+H] + =176.

[0248] Step 2: Dissolve the intermediate int 2-3 (350 mg, 2.00 mmol) in EtOH (2 mL) and add hydrazine hydrate (250.0 mg, 4.00 mmol, 80% wt). Heat the reaction system to 85°C for 1 h. LC-MS analysis confirmed the reaction was complete. Evaporate the solvent to obtain the target product int 2 (300 mg). LC-MS: ESI-MS (m / z): [M+H] + =176.

[0249] Synthesis of intermediate int 3

[0250] Step 1: Dissolve compound int 3-1 (2.0 g, 8.62 mmol) and cyclopropylboronic acid (3.7 g, 43.10 mmol) in Toluene (20 mL) under nitrogen protection.

[0251] To a solution of 2 mL of H₂O, K₂CO₃ (10.7 g, 77.58 mmol) and Pd(AMPHOS)₂Cl₂ (0.31 g, 0.43 mmol) were added at room temperature. The reaction system was heated to 90°C for 1 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, the mixture was extracted with EA, and the crude product was concentrated to afford the crude product. This was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 50%-80% MeCN, elution over 20 min) to afford the target intermediate int 3-2 (1 g, yield: 60%). LC-MS: ESI-MS (m / z): [M+H] + =194.

[0252] Step 2: Under nitrogen, compound int 3-2 (520 mg, 2.69 mmol) was dissolved in DCM (15.6 mL) and compound int 3-3 (750 mg, 3.23 mmol) was added. The reaction system was allowed to react at room temperature for 2 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, and the mixture was extracted with EA. The crude product was concentrated to yield the target compound int 3 (500 mg, yield: 79.0%). LCMS: ESI-MS (m / z): [M+H] + =236.

[0253] Synthesis of intermediate int 4

[0254] Step 1: Dissolve compound int 4-1 (500 mg, 3.81 mmol) in 10 mL of THF. Under nitrogen, add NBS (679 mg, 3.81 mmol) at 0°C. Stir at room temperature for 20 minutes after addition. LC-MS confirms complete consumption of the starting material. Evaporate the solvent, extract three times with EA, combine the organic phases, and concentrate. The resulting crude product is purified by silica gel column chromatography (PE / EA = 10:1) to obtain the target compound int 4-2 (540 mg, yield: 63.4%). LCMS: ESI-MS (m / z): [M+H] + =224 / 226.

[0255] Step 2: Under nitrogen, compound int 4-2 (510 mg, 2.28 mmol) was dissolved in diethyl carbonate (2.6 mL), and CH3ONa (185.2 mg, 3.42 mmol) was added. The reaction system was heated to 126°C for 30 min. LC-MS confirmed complete consumption of the starting material. The mixture was cooled to room temperature and extracted with methyl tert-butyl ether and water. The organic phase was concentrated to obtain the crude product, which was purified by silica gel column chromatography (elution with PE / EA = 1:1) to obtain the target compound int 4-3 (300 mg, yield: 63.9%). LCMS: ESI-MS (m / z): [M+H] + =205 / 207.

[0256] Step 3: Under nitrogen, in a pressurized autoclave, compound int 4-3 (300 mg, 1.46 mmol) was dissolved in 6 mL of MeOH. TEA (296.1 mg, 2.92 mmol) and Pd(dppf)Cl2 (64.2 mg, 0.088 mmol) were added. The reaction system was deoxygenated with nitrogen for 5 min, then pressurized to 100°C under a CO atmosphere for 2 days. The reaction was terminated. LC-MS confirmed the complete reaction of the starting material. The insoluble solid was filtered off, and the solvent was evaporated. The crude product was purified by silica gel column chromatography (PE / EA = 5:1 elution) to obtain the target compound int 4-4 (210 mg, yield: 77.9%). LCMS: ESI-MS (m / z): [M+H] + =185.

[0257] Step 4: Under nitrogen, compound int 4-4 (210 mg, 1.14 mmol) was dissolved in 1 mL of EtOH, and hydrazine hydrate (142.7 mg, 2.28 mmol, 80% wt) was added. The reaction system was heated to 85°C for 2 h. LC-MS analysis confirmed complete consumption of the starting material. The reaction system was cooled, concentrated to dryness, and washed with EA to yield the desired product, int 4 (98.0 mg). LCMS: ESI-MS (m / z): [M+H] + =185.

[0258] Synthesis of intermediate int 5

[0259] Step 1: Under nitrogen, DMA (12 mL) was added to compound int 3-1 (600.0 mg, 2.59 mmol). Int 5-1 (42.2 mg, 0.26 mmol), bromocyclobutane (418.8 mg, 3.10 mmol), zinc powder (338.1 mg, 5.17 mmol), trifluoroacetic acid (59.0 mg, 0.52 mmol), NiCl2 (33.5 mg, 0.26 mmol), and NaI (193.8 mg, 1.29 mmol) were then added. The mixture was heated to 80°C for 16 h. LC-MS analysis confirmed complete consumption of the starting material. The reaction system was cooled to room temperature and quenched by the addition of H2O (30 mL). The reaction was extracted three times with EA, and the combined organic phases were concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 1%-30% MeCN, 2 min elution; 30%-60% MeCN, 5 min elution; 60%-95% MeCN, 25 min elution) to obtain the target intermediate int 5-2 (300 mg, yield: 55.9%). LCMS: ESI-MS (m / z): [M+H] + =207.

[0260] Step 2: Under nitrogen, compound int 5-2 (300 mg, 1.45 mmol) and compound int 3-3 (403.4 mg, 1.74 mmol) were dissolved in DCM (6 mL). The reaction system was allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated and the product was concentrated to obtain the crude product, which was purified by silica gel column chromatography (elution with PE / EA = 10:1) to obtain the target compound int 5 (500 mg, yield: 55.4%). LCMS: ESI-MS (m / z): [M+H] + =250.

[0261] Synthesis of intermediate int 6

[0262] Step 1: Under nitrogen, toluene (5 mL) and water (0.5 mL) were added to int 3-1 (500.0 mg, 2.15 mmol) and int 6-1 (905.2 mg, 4.31 mmol). KCO (2.7 g, 19.4 mmol) and Pd(Amphos)Cl (76.3 mg, 0.11 mmol) were then added. The mixture was heated to 90°C for 45 min. LC-MS confirmed complete consumption of the starting material. The reaction system was cooled to room temperature and quenched with H2O (30 mL). The reaction was extracted three times with EA, and the combined organic phases were concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 20%-80% MeCN, elution over 20 min) to afford the target intermediate, int 6-2 (360 mg, yield: 71%). LCMS:ESI-MS(m / z):[M+H] + =236.

[0263] Step 2: Under nitrogen, compound int 6-2 (360 mg, 1.53 mmol) and compound int 3-3 (426.5 mg, 1.84 mmol) were dissolved in DCM (7.2 mL). The reaction system was allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated and the product was concentrated to obtain the crude product, which was purified by silica gel column chromatography (elution with PE / EA = 10:1) to obtain the target compound int 5 (300 mg, yield: 70.7%). LCMS: ESI-MS (m / z): [M+H] + =278.

[0264] Synthesis of intermediate int 7

[0265] Step 1: Under nitrogen, compound int 7-1 (387 mg, 1.67 mmol) and cyclopropylboronic acid (716.2 mg, 8.34 mmol) were dissolved in toluene (38.7 mL) and H₂O (3.87 mL). K₂CO₃ (1.59 g, 15.01 mmol) and Pd(AMPHOS)₂Cl₂ (59.1 mg, 0.08 mmol) were added at room temperature. The reaction system was heated to 90°C for 1 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, the product was extracted with EA, and concentrated to afford the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (0.1% FA), 20%-80% MeCN, elution over 20 min) to afford the target intermediate int 7-2 (292 mg, yield: 90.6%). LC-MS: ESI-MS (m / z): [M+H] + =194.

[0266] Step 2: Under nitrogen, compound int 7-2 (292 mg, 1.51 mmol) was dissolved in DCM (8.7 mL) and compound int 3-3 (421.1 mg, 1.81 mmol) was added. The reaction system was allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated and the mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (elution with PE / EA = 10:1) to yield the target compound int 7 (167 mg, yield: 46.9%). LCMS: ESI-MS (m / z): [M+H] + =236.

[0267] Synthesis of intermediate int 8

[0268] Under nitrogen, ethanol (5 mL) and hydrazine hydrate (142.1 mg, 2.85 mmol) were added to int 8-1 (250 mg, 1.42 mmol). The reaction system was heated to 100°C overnight. LC-MS confirmed the reaction was complete. The reaction system was cooled to room temperature and then stirred at 0°C for 1 hour. A solid precipitated from the reaction system. The solid was filtered, washed with ethanol, and dried to obtain the target product, int 8 (80 mg, yield: 32%). LCMS: ESI-MS (m / z): [M+H] + =177.

[0269] Synthesis of intermediate int 9

[0270] Step 1: Under nitrogen, compound int 9-1 (600 mg, 2.97 mmol) and cyclopropylboronic acid (369.1 mg, 4.45 mmol) were dissolved in toluene (6.4 mL) and H₂O (1.8 mL). K₃PO₄ (1.89 g, 8.91 mmol) and Pd(dppf)Cl₂ (0.22 g, 0.29 mmol) were added at room temperature. The reaction system was heated to 90°C for 1 h. LC-MS confirmed the reaction was complete. The solvent was evaporated, the product was extracted with EA, and concentrated to afford the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 35%-85% MeCN, elution over 20 min) to afford the target intermediate int 9-2 (200 mg, yield: 41.2%). LC-MS: ESI-MS (m / z): [M+H] + =164.

[0271] Step 2: Under nitrogen, compound int 9-2 (200 mg, 1.22 mmol) was dissolved in DCM (8.7 mL) and compound int 3-3 (341.5 mg, 1.47 mmol) was added. The reaction system was allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated and the product was concentrated to obtain a crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 45%-90% MeCN, elution time: 20 min) to obtain the target compound int 9 (220 mg, yield: 87.4%). LCMS: ESI-MS (m / z): [M+H] + =206.

[0272] Synthesis of intermediate int 10

[0273] Step 1: Under nitrogen, compound int 10-1 (160 mg, 0.74 mmol) and (bpy)CuSCF3 (380.1 mg, 0.88 mmol) were dissolved in 1,4-dioxane (3.2 mL). The reaction system was heated to 110°C for 1 hour. LC-MS confirmed the reaction was complete, and the reaction was quenched with water. The solvent was evaporated, and the product was extracted with EA and concentrated to obtain a crude product. This was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 10%-60% MeCN, elution over 20 minutes) to obtain the target intermediate int 10-2 (50 mg, yield: 28.4%). LC-MS: ESI-MS (m / z): [M+H] + =238.

[0274] Step 2: Under nitrogen, ethanol (0.5 mL) and hydrazine hydrate (52.7 mg, 1.05 mmol) were added to int 10-2 (50 mg, 0.21 mmol). The reaction system was heated to 90°C for 1 h. LC-MS confirmed the reaction was complete. The reaction system was cooled to room temperature and the mixture was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 10%-60% MeCN, elution time 20 min). The target intermediate int 10 (20 mg, yield: 40%) was obtained. LC-MS: ESI-MS (m / z): [M+H] + =238.

[0275] Synthesis of intermediate int 11

[0276] Under nitrogen, compounds int 11-1 (250 mg, 1.52 mmol) and int 11-2 (201.7 mg, 1.52 mmol) were dissolved in DMSO (2.5 mL). DIEA (983.7 mg, 7.61 mmol) was added, and the reaction system was heated to 100°C for 2 hours. LC-MS confirmed the reaction was complete. The solvent was evaporated and the mixture was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 10%-60% MeCN, elution over 10 minutes) to obtain the target intermediate int 11 (231 mg, yield: 58.3%). LC-MS: ESI-MS (m / z): [M+H] + =261.

[0277] Synthesis of intermediate int 12

[0278] Step 1: Under nitrogen, compound int 12-1 (2.2 g, 8.76 mmol) and cyclopropylboronic acid (1.1 g, 13.15 mmol) were dissolved in toluene (22 mL) and H2O (8.8 mL). K3PO4 (5.5 g, 26.30 mmol), Pd(OAc)2 (396 mg, 1.75 mmol), and tricyclohexylphosphine (0.49 g, 1.75 mmol) were added at room temperature. The reaction system was heated to 100°C for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated, the mixture was extracted with EA, and the crude product was concentrated to obtain the target compound int 12-2 (1.1 g, yield: 72.4%). LC-MS: ESI-MS (m / z): [M+H] + =174.

[0279] Step 2: Under nitrogen, compound int 12-2 (400 mg, 2.30 mmol) was dissolved in DCM (8 mL) and compound int 3-3 (640 mg, 2.77 mmol) was added. The reaction system was allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was evaporated, and the mixture was extracted with DCM and concentrated to obtain the crude product. This was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 min) to yield the target compound int 12 (470 mg, yield: 94.5%). LC-MS: ESI-MS (m / z): [M+H] + =216.

[0280] Synthesis of intermediate int 13

[0281] Step 1: Under nitrogen, int 13-1 (1.0 g, 4.31 mmol) was dissolved in toluene (10 mL). Int 13-2 (1.7 g, 8.62 mmol), potassium carbonate (1.2 g, 8.62 mmol), Pd(amphos) (0.3 g, 0.43 mmol), and water (1 mL) were added. The reaction system was heated to 100°C and incubated for 16 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by C-18 column chromatography (elution with 0-60% MeCN / H2O) to obtain int 13-3 as a pale yellow solid (0.3 g, yield: 31.8%). LC-MS: ESI-MS (m / z): [M+H] + =220.

[0282] Step 2: Under nitrogen, compound int 13-3 (0.3 g, 1.36 mmol) and compound int 3-3 (0.6 g, 2.72 mmol) were dissolved in DCM (5 mL) and reacted at room temperature for 3 h. TLC monitored the reaction completion and stopped the reaction. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The combined organic phases were washed once with saturated sodium chloride and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (0-10% EA / PE) to obtain compound int 13 as a white solid (0.3 g, yield: 89.3%). LC-MS: ESI-MS (m / z): [M+H] + =262.

[0283] Synthesis of intermediate int 14

[0284] Under nitrogen, compound int 14-1 (1.0 g, 5.12 mmol) and hydrazine hydrate (384.6 mg, 7.68 mmol) were dissolved in ethanol (5 mL). After addition, the reaction was stirred at 80°C for 16 h. LC-MS monitored the reaction completion and stopped the reaction. The mixture was concentrated under reduced pressure and the crude product was slurried with water to obtain compound int 14 as a white solid (600.0 mg, 3.31 mmol, yield: 64.6%). LC-MS: ESI-MS (m / z): [M+H] + =182.

[0285] Synthesis of intermediate int 15

[0286] Under nitrogen, compound int 15-1 (500.0 mg, 2.82 mmol) was dissolved in hydrazine hydrate (3 mL), and the reaction system was heated to 50°C with stirring for 4 h. Upon completion of the reaction, the reaction was stopped by LC-MS. The reaction solution was cooled to room temperature and concentrated to afford compound int 15 as a brown solid (440.0 mg, yield: 88.0%). LC-MS: ESI-MS (m / z): [M+H] + =178.

[0287] Synthesis of intermediate int 16

[0288] Step 1: Under nitrogen, int 16-1 (7.0 g, 54.45 mmol) and int 16-2 (9.7 g, 65.34 mmol) were dissolved in 1,4-dioxane (127 mL) and H₂O (12.7 mL). Potassium phosphate (34.7 g, 163.35 mmol) and dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (1.9 g, 2.72 mmol) were added. The reaction system was heated to 90°C and allowed to react overnight. LC-MS analysis confirmed the reaction was complete and the reaction was stopped. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluted with PE) to obtain the target compound, int 16-3 (7.0 g, yield: 95.8%). LC-MS: ESI-MS (m / z): [M+H] + =135.

[0289] Step 2: Under nitrogen, AD-mix-β (CAS: 148618-32-0, i.e., a mixture of hydroquinidine 1,4-naphthylidene ethers) (61.0 g, 78.25 mmol) and methanesulfonamide (5.0 g, 52.17 mmol) were dissolved in t-BuOH (72 mL) and H₂O (48 mL). The mixture was stirred at room temperature for 15 min. Compound int 16-3 (7.0 g, 52.17 mmol) was then added portionwise at 0°C. The reaction was then allowed to react overnight at room temperature. LC-MS monitored the reaction completion and the reaction was stopped. The reaction mixture was filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography (CHCl / MeOH = 100:1) to afford the target compound int 16-4 (8.5 g, 96.9% yield). LC-MS: ESI-MS (m / z): [M+H] + =169.

[0290] Step 3: Under nitrogen, int 16-4 (8.5 g, 50.54 mmol) and trimethyl orthoacetate (20.6 g, 171.82 mmol) were dissolved in DCM (127 mL) and trimethylsilyl chloride (18.7 g, 171.82 mmol) was added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was then concentrated and redissolved in methanol (119 mL). Potassium carbonate (8.7 g, 63.17 mmol) was added and the reaction continued for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1:1) to obtain the target compound int 16-5 (3.5 g, yield: 46.1%). LC-MS: ESI-MS (m / z): [M+H] + =151.

[0291] Step 4: Under nitrogen, int 16-5 (3.5 g, 23.31 mmol) and int 16-6 (4.3 g, 25.64 mmol) were dissolved in DCM (70 mL) and ytterbium trifluoromethanesulfonate (1.5 g, 2.33 mmol) was added. The mixture was stirred at 35°C overnight. LC-MS monitored the reaction for completion and the reaction was stopped. The reaction solution was filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 3:1) to obtain the target compound int 16-7 (7 g, yield: 94.6%). LC-MS: ESI-MS (m / z): [M+H] + =318.

[0292] Step 5: Under nitrogen, int 16-7 (2.5 g, 7.88 mmol) was dissolved in THF (40 mL) and KHMDS (9.45 mL, 9.45 mmol) was added dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 1 h. Methyl trifluoromethanesulfonate (3.9 g, 23.63 mmol) diluted in THF (10 mL) was then added dropwise. The reaction was continued for 30 min. LC-MS confirmed the reaction was complete. The reaction was stopped and quenched with saturated aqueous NH4Cl. The reaction system was extracted with EA. The organic phase was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 30%-80% MeCN, eluted over 20 min) to afford the target intermediate, int 16-8 (2 g, yield: 76.6%). LC-MS:ESI-MS(m / z):[M+H] + =332.

[0293] Step 6: Under nitrogen, int 16-8 (2.0 g, 6.03 mmol) was dissolved in DCM (20 mL), and m-CPBA (2.3 g, 13.28 mmol) was added portionwise. The mixture was stirred at room temperature for 1.5 h. After completion of the reaction as monitored by LC-MS, the reaction was stopped and quenched with a saturated aqueous solution of sodium thiosulfate. The reaction system was extracted with DCM. The organic phase was concentrated to obtain a crude product, which was purified by silica gel column chromatography (elution with PE / EA = 3:1) to obtain the target intermediate int 16-9 (1.48 g, yield: 67.5%). LC-MS: ESI-MS (m / z): [M+H] + =364.

[0294] Step 7: Under nitrogen, int 16-9 (1.5 g, 4.07 mmol) was dissolved in methanol (20 mL), and K₂CO₃ (1.1 g, 8.14 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated, and H₂O (29.6 mL) was added to the crude product, followed by potassium acetate (0.8 g, 8.14 mmol) and sulfamic acid (0.4 g, 4.07 mmol). The mixture was stirred at room temperature for 4.5 h. LC-MS confirmed the reaction was complete and the reaction was stopped. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with DCM. The organic phase was concentrated to obtain the crude product, which was purified by C₁8 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 2%-10% MeCN, elution over 20 min) to afford the target intermediate, int 16 (540 mg, yield: 54.1%). LC-MS:ESI-MS(m / z):[M+H] + =246.

[0295] Synthesis of intermediate int 17

[0296] Step 1: Under nitrogen, int 17-1 (10.0 g, 43.09 mmol) and int 17-2 (9.9 g, 64.64 mmol) were dissolved in DMF (300 mL) and H₂O (30 mL). Sodium carbonate (13.7 g, 129.29 mmol) and Pd(PPh₃)₄ (4.9 g, 4.31 mmol) were added. The reaction system was heated to 100°C for 16 h. LC-MS confirmed the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The product was extracted with EA and purified by silica gel column chromatography (PE / EA = 3:1) to obtain the target compound int 17-3 (4.8 g, yield: 62.1%). LC-MS: ESI-MS (m / z): [M+H] +=180.

[0297] Step 2: Under nitrogen, int 17-3 (1.0 g, 5.58 mmol) was dissolved in THF (5 mL) and H₂O (5 mL). NCS (745.2 mg, 5.58 mmol) was added and the reaction system was allowed to react at 5°C overnight. TEA (1.7 g, 16.74 mmol) was then added, and the reaction system was heated to 60°C for 4 h. The reaction was stopped upon completion of the reaction as monitored by LC-MS. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was extracted with EA and concentrated, and purified by C₁8 reverse-phase column chromatography (mobile phase: MeCN and H₂O, 20%-50% MeCN, elution over 20 min) to obtain the target compound int 17-4 (300 mg, yield: 27.5%). LC-MS: ESI-MS (m / z): [M+H] + =196.

[0298] Step 3: Under nitrogen, int 17-4 (300.0 mg, 1.54 mmol) was dissolved in acetic acid (3 mL), and acetic anhydride (313.8 mg, 3.07 mmol) was added. The reaction system was heated to reflux for 2 h. LC-MS monitored the reaction completion and stopped the reaction. The reaction solution was cooled to room temperature, and the filtrate was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 20%-60% MeCN, elution over 10 min) to obtain the target compound int 17-5 (200 mg, yield: 54.8%). LC-MS: ESI-MS (m / z): [M+H] + =238.

[0299] Step 4: Dissolve int 17-5 (200.0 mg, 0.84 mmol) in EA (2 mL) and add Pd / C (40% wt, 80 mg). The reaction system is allowed to react at room temperature under a hydrogen atmosphere for 3 h. LC-MS monitoring indicates that the reaction is complete and the reaction is stopped. The reaction solution is filtered and the filtrate is concentrated to obtain the crude product. After extraction with EA, the crude product is purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 10%-60% MeCN, elution over 15 min) to obtain the target compound int 17-6 (90 mg, yield: 59.5%). LC-MS: ESI-MS (m / z): [M+H] + =180.

[0300] Step 5: Under nitrogen, int 17-6 (90.0 mg, 0.50 mmol) was dissolved in ethanol (0.45 mL), and hydrazine hydrate (50.3 mg, 80 mg) was added. The reaction system was heated to 100°C for 3 h. LC-MS monitoring confirmed the completion of the reaction, and the reaction was stopped. The reaction solution was concentrated to obtain the crude product, yielding the target compound int 17 (70 mg, yield: 77.7%). LC-MS: ESI-MS (m / z): [M+H] + =180.

[0301] Synthesis of intermediate int 18

[0302] Compound int 18-1 (0.2 g, 1.18 mmol) was dissolved in DCM (3 mL), and int 3-3 (411.8 mg, 1.78 mmol) was added. The reaction mixture was allowed to react at room temperature under nitrogen for 15 h. TLC confirmed the reaction was complete, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluting with 0-10% EA / PE) to afford liquid compound int 18 (145 mg) in a yield of 58.2%.

[0303] Synthesis of intermediate int 19

[0304] Step 1: Under nitrogen, compound int 19-1 (811.0 mg, 5.00 mmol) was dissolved in dichloromethane (10 mL). t-Butyl carbazate (990 mg, 7.50 mmol), triethylamine (1000 mg, 10.00 mmol), and HATU (2.85 g, 7.50 mmol) were added sequentially to the reaction mixture. The reaction system was stirred at room temperature for 3 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction mixture was washed with aqueous solution and extracted with dichloromethane. The organic phases were combined and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluted with 0-30% EA / PE) to obtain compound int 19-2 (930.0 mg) as a colorless oil in a yield of 67.39%. LC-MS: ESI-MS (m / z): [M+H] + =277.

[0305] Step 2: Dissolve compound int 19-2 (300.0 mg, 1.09 mmol) in dichloromethane (5 mL). Add HCl-dioxane (4 M, 2 mL) to the reaction mixture, and stir at room temperature for 3 h. LC-MS monitoring indicates that the reaction is complete, and the reaction is stopped. The reaction mixture is evaporated under reduced pressure to obtain compound int 19 (190.0 mg) as a white solid in a yield of 98.96%. LC-MS: ESI-MS (m / z): [M+H] + =177.

[0306] Synthesis of intermediate int 20

[0307] Under nitrogen, compound int 20-1 (0.5 g, 2.58 mmol) was dissolved in EtOH (5 mL), hydrazine hydrate (1.0 mL) was added, and the mixture was heated to 80°C and refluxed for 15 h under nitrogen. TLC monitored the reaction until complete, and the reaction was stopped. The reaction solution was cooled to room temperature and concentrated under reduced pressure to afford compound int 20 (0.47 g) as a white solid in a 94.0% yield. LC-MS: ESI-MS (m / z): [M+H] + =195.

[0308] Synthesis of intermediate int 21

[0309] Step 1: Under nitrogen, int 21-1 (10.5 g, 55.5 mmol) and ICD3 (24.1 g, 167 mmol) were dissolved in DMF (210 mL). Potassium carbonate (19.1 g, 139 mmol) was added, and the reaction system was allowed to react at room temperature for 1 h. LC-MS monitored the reaction completion and stopped the reaction. The reaction solution was concentrated to obtain a crude product, which was extracted with EA and purified by silica gel column chromatography (PE / EA = 5:1) to obtain the target compound int 21-2 (12.1 g, yield: 97.6%). LC-MS: ESI-MS (m / z): [M+H] + =223.

[0310] Step 2: Under nitrogen, int 21-2 (5.5 g, 24.7 mmol) and trifluoroacetamide (5.5 g, 49.3 mmol) were dissolved in CH3CN (210 mL). N,N'-dimethyl-1,2-cyclohexanediamine (1.4 g, 9.86 mmol), K2CO3 (13.6 g, 98.6 mmol), and CuI (0.94 g, 4.93 mmol) were added, and the reaction system was incubated at 80°C for 1 h. LC-MS monitoring confirmed the reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, and methanol (27.5 mL) and H2O (27.5 mL) were added. The reaction system was continued at 65°C for 12 h. After completion, the reaction was concentrated to obtain a crude product, which was extracted with DCM and purified by silica gel column chromatography (PE / EA = 5:1) to obtain the target compound int 21-3 (980 mg, yield: 24.9%). LC-MS:ESI-MS(m / z):[M+H] + =160.

[0311] Step 3: Under nitrogen, int 21-3 (880 mg, 5.52 mmol) was dissolved in DCM (26.4 mL). Br2 (883 mg, 5.52 mmol) was added at -10°C, and the reaction system was allowed to react for 2 h at room temperature. LC-MS monitored the reaction completion and stopped the reaction. The reaction was quenched with sodium thiosulfate, extracted with DCM, and the organic layer was concentrated to obtain a crude product that was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 min) to obtain the target compound int 21-4 (832 mg, yield: 63.2%). LC-MS: ESI-MS (m / z): [M+H] + =238.

[0312] Step 4: Under nitrogen, int 21-4 (830 mg, 3.48 mmol) and cyclopropylboronic acid (1.2 g, 13.9 mmol) were dissolved in toluene (8.3 mL) and water (3.3 mL). K₃PO₄ (2.9 g, 13.9 mmol), Pd(OAc)₂ (156 mg, 0.69 mmol, 0.2 eq.), and tricyclohexylphosphine (195 mg, 0.69 mmol) were added. The reaction system was incubated at 100°C for 1 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature and concentrated to obtain a crude product. The crude product was extracted with EA, and the organic layer was concentrated and purified by C₁8 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 30%-80% MeCN, eluted over 20 min) to obtain the target compound, int 21-5 (430 mg, yield: 61.9%). LC-MS:ESI-MS(m / z):[M+H] + =200.

[0313] Step 5: Dissolve compound int 25-1 (0.2 g, 1.00 mmol) in DCM (4 mL) and add int 3-3 (280 mg, 1.2 mmol). The reaction mixture was allowed to react at room temperature under nitrogen for 1 h. TLC monitored the reaction completion and stopped the reaction. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified using a C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 40%-90% MeCN, elution over 20 min) to obtain the target compound int 21 (258 mg, yield: 94.1%). LC-MS: ESI-MS (m / z): [M+H] + =242.

[0314] Synthesis of intermediate int 22

[0315] Step 1: Under nitrogen, int 22-1 (10.0 g, 66.60 mmol) and I2 (6.7 g, 26.64 mmol) were dissolved in ethanol (100 mL). HIO3 (2.3 g, 13.32 mmol) dissolved in H2O (60 mL) was added dropwise. The reaction system was allowed to react at room temperature for 2 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. Water (830 mL) and aqueous sodium thiosulfate solution (100 mL) were added to the reaction system to quench the reaction. After filtration, the target compound int 22-2 was obtained. LC-MS: ESI-MS (m / z): [M+H] + =277.

[0316] Step 2: Under nitrogen, int 22-2 (15.0 g, 54.34 mmol) was dissolved in DMF (225 mL). K2CO3 (9.0 g, 65.21 mmol) and CH3I (9.2 g, 65.21 mmol) were added, and the reaction system was reacted at 40°C for 2 h. LC-MS monitoring showed that the reaction was complete and the reaction was stopped. Water (2 L) was added to the reaction system to quench the reaction, and the system was adjusted to pH = 4 with HCl (6 M). The precipitated solid was filtered to obtain the target compound int 22-3. LC-MS: ESI-MS (m / z): [M+H] + =291.

[0317] Step 3: Under nitrogen, int 22-4 (27.1 g, 75.86 mmol) was dissolved in THF (154 mL). t-BuOK (1.8 M in THF, 50.5 mL, 91.01 mmol) was added and stirred at room temperature for 1 h. Then, int 22-3 (11.0 g, 37.92 mmol) dissolved in THF (77 mL) was added dropwise. The reaction system was allowed to react at room temperature for 12 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction system was quenched by the addition of aqueous sodium thiosulfate (100 mL). The mixture was then extracted with EA. The organic layer was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 45%-75% MeCN, elution over 15 min) to afford the target compound, int 22-5 (1.8 g, yield: 16.4%). LC-MS:ESI-MS(m / z):[M+H] + =289.

[0318] Step 4: Under nitrogen, ZnEt2 (1.0 g, 8.33 mmol) dissolved in DCM (9.6 mL) and diiodoethane (1.0 g, 8.33 mmol) dissolved in DCM (9.6 mL) were stirred at -40°C for 1 h. Trichloroacetic acid (1.3 g, 8.33 mmol) dissolved in DCM (9.6 mL) was then added dropwise. The mixture was stirred at -15°C for 1 h. Int 22-5 (1.2 g, 4.16 mmol) was then added portionwise to the reaction system. The reaction was continued at room temperature for 12 h. The reaction was stopped upon completion of the reaction as monitored by LC-MS. Saturated aqueous ammonium chloride (50 mL) was added to the reaction system to quench the reaction, followed by extraction with DCM. The organic layer was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 45%-70% MeCN, elution over 10 min) to obtain the target compound int 22-6 (180 mg, yield: 14.3%). LC-MS: ESI-MS (m / z): [M+H]+ =303.

[0319] Step 5: Under nitrogen, int 22-6 (180.0 mg, 0.59 mmol) was dissolved in toluene (3.6 mL). Benzophenone imine (215.9 mg, 1.19 mmol), Pd(OAc)2 (13.3 mg, 0.06 mmol), BINAP (74.2 mg, 0.11 mmol), and Cs2CO3 (388.2 mg, 1.19 mmol) were added. The reaction system was reacted at 110°C for 2 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. Water (100 mL) was added to the reaction system, followed by extraction with EA. The organic layer was concentrated to obtain the crude product. THF (3.6 mL) and HCl (6 M, 1.08 mL) were then added to the crude product, and the mixture was reacted at room temperature for 2 h. The solvent was evaporated, and the resulting crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 35%-50% MeCN, elution over 10 min) to afford the target compound int22-7 (50 mg, yield: 43.8%). LC-MS: ESI-MS (m / z): [M+H] + =192.

[0320] Step 6: Dissolve compound int 22-7 (50 mg, 0.26 mmol) in DCM (1.5 mL) and add int 3-3 (72.8 mg, 0.31 mmol). The reaction mixture was allowed to react at room temperature under nitrogen for 6 h. LC-MS monitored the reaction completion and stopped the reaction. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified using C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 50%-100% MeCN, elution over 10 min) to obtain the target compound int 22 (43 mg, yield: 70.5%). LC-MS: ESI-MS (m / z): [M+H] + =234.

[0321] Synthesis of intermediate int 23

[0322] Step 1: Dissolve compound int 23-1 (3.0 g, 12.9 mmol) in DCM (60 mL) and add int 3-3 (3.0 g, 12.9 mmol). The reaction mixture was allowed to react at room temperature under nitrogen for 1 hour. LC-MS monitored the reaction completion and stopped the reaction. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 minutes) to obtain the target compound int 23-2 (3.3 g, yield: 93.1%). LC-MS: ESI-MS (m / z): [M+H] + =274.

[0323] Step 2: Under nitrogen, compound int 1 (85.0 mg, 0.37 mmol) was dissolved in CH3CN (1.7 mL), and int23-2 (122 mg, 0.45 mmol) and Cs2CO3 (121 mg, 0.37 mmol) were added. The reaction mixture was allowed to react at room temperature for 12 h. LC-MS monitored the reaction completion and stopped the reaction. The resulting reaction mixture of int 23-3 was used directly in the next reaction. LC-MS: ESI-MS (m / z): [M+H] + =503.

[0324] Step 3: Under nitrogen, 5-methylpyridine-3-carbohydrazide (43.2 mg, 0.29 mmol) and AgNO₃ (81.0 mg, 0.48 mmol) were added to the reaction mixture from the previous step and stirred at room temperature for 30 min. The reaction was stopped after completion of the reaction as monitored by LC-MS. The reaction was quenched by adding water (10 mL) and extracted with EA. The organic layer was concentrated to obtain the crude product, which was then purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 10%-50% MeCN, eluted over 20 min) to afford the target compound int 23-4 (110 mg, yield: 74.4%). LC-MS: ESI-MS (m / z): [M+H] + =620.

[0325] Step 4: Under nitrogen, int 23-4 (110 mg, 0.18 mmol) was dissolved in 1,4-dioxane (2.2 mL). Methanesulfonic acid (68.1 mg, 0.71 mmol) was added and stirred at 100°C for 1 h. The reaction was stopped upon completion of the reaction as monitored by LC-MS. The reaction was cooled to room temperature and the pH of the reaction system was adjusted to 8 with aqueous ammonia. The product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃), 20%-70% MeCN, elution over 18 min) to afford the target compound int 23 (60 mg, yield: 56.2%). LC-MS: ESI-MS (m / z): [M+H] + =602.

[0326] Synthesis of intermediate int 24

[0327] Step 1: Under nitrogen, int 24-1 (11.0 g, 58.2 mmol) and Cs2CO3 (37.9 g, 116 mmol) were dissolved in DMF (137.5 mL). Sodium difluorochloroacetate (35.4 g, 233 mmol) was added at room temperature, and the reaction system was incubated at 105°C for 3 h. LC-MS monitoring confirmed the completion of the reaction, and the reaction was stopped. Ice water (280 mL) was added to the reaction system to quench the reaction. Extraction with EA was performed, and the organic layer was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100:1) to obtain the target compound int 24-2 (10.0 g, yield: 59.4%). LC-MS: ESI-MS (m / z): [M+H] + =289.

[0328] Step 2: Under nitrogen, int 24-2 (5.5 g, 19.03 mmol) and trifluoroacetamide (4.3 g, 38.1 mmol) were dissolved in CH3CN (55 mL). N,N'-dimethyl-1,2-cyclohexanediamine (1.1 g, 7.61 mmol), K2CO3 (10.5 g, 76.12 mmol), and CuI (0.7 g, 3.81 mmol) were added. The reaction system was reacted at 80°C for 72 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature, H2O (100 mL) was added, the reaction system was filtered, and the filtrate was extracted with DCM (3 x 40 mL). The organic layer was concentrated to obtain the target compound int 24-3. LC-MS: ESI-MS (m / z): [M+H] + =322.

[0329] Step 3: Under nitrogen, int 24-3 (4.2 g, 13.1 mmol) was added to methanol (21 mL) and H2O (21 mL). The reaction system was continued at 65°C for 12 h. After completion of the reaction, the crude product was concentrated and extracted with DCM. The concentrated crude product was purified by silica gel column chromatography (PE / EA = 25:1 elution) to obtain the target compound int 24-4 (1 g, yield: 33.9%). LC-MS: ESI-MS (m / z): [M+H] + =226.

[0330] Step 4: Under nitrogen, int 24-4 (1.0 g, 4.44 mmol) was dissolved in chloroform (20 mL). Br2 (0.7 g, 4.44 mmol) was added at -10°C, and the reaction system was allowed to react for 2 h at room temperature. LC-MS monitored the reaction completion and stopped the reaction. The reaction was quenched with sodium thiosulfate, extracted with DCM, and the organic layer was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 10:1) to obtain the target compound int 24-5 (1.1 g, yield: 81.4%). LC-MS: ESI-MS (m / z): [M+H] + =304.

[0331] Step 5: Under nitrogen, int 24-5 (1.1 g, 3.61 mmol) and cyclopropylboronic acid (1.0 g, 14.4 mmol) were dissolved in toluene (11 mL) and water (4.4 mL). K3PO4 (3.1 g, 14.4 mmol), Pd(OAc)2 (0.16 g, 0.72 mmol, 0.2 eq.), and tricyclohexylphosphine (0.2 g, 0.72 mmol) were added. The reaction system was reacted at 100°C for 1 h. LC-MS monitored the reaction completion and stopped the reaction. The reaction solution was cooled to room temperature and concentrated to obtain the crude product. The organic layer was extracted with EA, and the resulting crude product was purified by silica gel column chromatography (PE / EA = 25:1) to obtain the target compound int 24-6 (500 mg, yield: 52.1%). LC-MS: ESI-MS (m / z): [M+H] + =266.

[0332] Step 6: Dissolve compound int 24-6 (250.0 mg, 0.94 mmol) in DCM (7.5 mL) and add int 3-3 (262.7 mg, 1.13 mmol). The reaction mixture was allowed to react at room temperature under nitrogen for 1 h. TLC confirmed the reaction was complete and the reaction was stopped. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified using C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 20%-50% MeCN, elution over 15 min) to obtain the target compound int 24 (200 mg, yield: 69%). LC-MS: ESI-MS (m / z): [M+H] + =308.

[0333] Synthesis of intermediate int 25

[0334] Step 1: Dissolve int 25-1 (5.0 g, 2.08 mmol) in toluene (50 mL). Add cyclopropylboronic acid (1.85 g, 2.20 mmol), potassium phosphate (12.5 g, 6.24 mmol), Pd(OAc)2 (75.0 mg, 0.20 mmol), and water (5 mL). Heat to 100°C under nitrogen for 16 h. LC-MS monitoring confirmed the reaction was complete and stopped. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. Purification of the crude product by prep-TLC (PE / EA = 20:1) afforded int 25-2 (50.0 mg, 0.25 mmol) as a pale yellow solid. LC-MS: ESI-MS (m / z): [M+H] + =202.

[0335] Step 2: Dissolve compound int 25-2 (50.0 mg, 0.25 mmol) and compound int 3-3 (85.0 mg, 0.38 mmol) in DCM (5 mL) and react at room temperature for 3 h under nitrogen. TLC monitors the reaction until complete and stops the reaction. Cool to room temperature, dilute with water, and extract three times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (0-10% EA / PE) to obtain compound int 25 (50.0 mg, 0.21 mmol) as a white solid. LC-MS: ESI-MS (m / z): [M+H] + =244.

[0336] Synthesis of intermediate int 26

[0337] Step 1: Dissolve compound int 26-1 (10.0 g, 121.88 mmol) in tetrahydrofuran (100 mL). Under nitrogen protection, NaH (9.75 g, 243.76 mmol) was added to the reaction solution under an ice bath. The reaction system was stirred at room temperature for 30 min. Subsequently, int 26-2 (19.38 g, 182.82 mmol) was added under an ice bath. The reaction solution was stirred at room temperature for 2 h. LC-MS monitoring showed that the reaction was complete and the reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by silica gel column chromatography (0-10% EA / PE) to obtain int 26-3 (11.2 g) as a yellow oil in a yield of 60.42%. LCMS: ESI-MS (m / z): [M+H] + =153.

[0338] Step 2: Compound int 26-3 (11.2 g, 73.64 mmol) was dissolved in tetrahydrofuran (100 mL). LiAlH₄ (5.59 g, 147.28 mmol) was added to the reaction mixture under nitrogen at zero degrees Celsius. The reaction system was stirred at room temperature for 6 hours. LC-MS monitored the reaction completion and stopped the reaction. Sodium sulfate decahydrate was slowly added to the reaction mixture under ice-cooling to quench the reaction. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (0-5% MeOH / DCM) to afford int 26-4 (530.0 mg) as a white solid in a yield of 4.67%. LCMS: ESI-MS (m / z): [M+H] + =155.

[0339] Step 3: Compound int 26-4 (530.0 mg, 3.44 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen, int 26-5 (862.0 mg, 5.16 mmol) and triphenylphosphine (1.35 g, 5.16 mmol) were added to the reaction mixture. The reaction system was stirred at room temperature for 10 min. DIAD (696 mg, 3.44 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. LC-MS analysis confirmed the reaction was complete and the reaction was stopped. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (0-20% EA / PE) to afford int 26-6 (660.0 mg) as a white solid in a yield of 63.30%. LCMS: ESI-MS (m / z): [M+H] + =304.

[0340] Step 4: Dissolve compound int 26-6 (660.0 mg, 2.18 mmol) in dichloromethane (10 mL). Add m-CPBA (1.13 g, 6.54 mmol) to the reaction mixture, and stir at room temperature for 16 h. LC-MS monitoring indicates that the reaction is complete, and the reaction is stopped. The reaction mixture is quenched with sodium thiosulfate and extracted with dichloromethane. The organic phase is evaporated under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (0-5% MeOH / DCM) to afford compound int 26-7 (610.0 mg) as a white solid in an 83.20% yield. LCMS: ESI-MS (m / z): [M+H] + =336.

[0341] Step 5: Dissolve compound int 26-7 (610.0 mg, 1.82 mmol) in methanol (10 mL). Add potassium carbonate (902 mg, 6.54 mmol) to the reaction solution, and stir the reaction system at room temperature for 16 h. LC-MS monitoring shows that the reaction is complete, and the reaction is stopped. The reaction solution is evaporated under reduced pressure to obtain a crude product, which is dissolved in ethyl acetate and filtered. The filter cake is washed with ethyl acetate and collected to obtain int 26-8 (370.0 mg). LCMS: ESI-MS (m / z): [M+H] + =203.

[0342] Step 6: Dissolve compound int 26-8 (370.0 mg, 1.82 mmol) in water (10 mL). Add sulfamic acid (411 mg, 3.64 mmol) to the reaction mixture, and stir at room temperature for 16 h. LC-MS monitoring indicates that the reaction is complete, and the reaction is stopped. The reaction mixture is extracted with ethyl acetate, and the organic phase is evaporated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (0-5% MeOH / DCM) to obtain compound int 26 (160.0 mg) as a white solid in a yield of 40.50%. LCMS: ESI-MS (m / z): [M+H] + =218.

[0343] Synthesis of intermediate int 27

[0344] Step 1: Dissolve int 13-3 (0.18 g, 0.84 mmol) in methanol (10 mL), add palladium on carbon (0.1 g), replace the hydrogen atmosphere three times, and stir at room temperature for 2 h. LC-MS monitoring indicates that the reaction is complete, and the reaction is stopped. The reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated to obtain the crude product. The crude product is purified by column chromatography (0-5% DCM / MeOH) to obtain int 27-1 (0.12 g, 0.54 mmol) as a pale yellow solid in a yield of 31.8%. LCMS: ESI-MS (m / z): [M+H] + =222.

[0345] Step 2: Dissolve compound int 27-1 (0.12 g, 0.54 mmol) and compound int 3-3 (0.18 g, 0.81 mmol) in DCM (5 mL) and react at room temperature under nitrogen for 3 h. Stop the reaction after TLC monitoring of reaction completion. Cool to room temperature, dilute with water, and extract three times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (0-10% EA / PE) to obtain compound int 27 (0.12 g, 0.45 mmol) as a white solid in a yield of 84.3%. LCMS: ESI-MS (m / z): [M+H] + =264.

[0346] Synthesis of intermediate int 28

[0347] Intermediate int 28 was synthesized using a method similar to that of int 1, where int 28-1 replaced int 1-1.

[0348] Synthesis of intermediate int 29

[0349] Step 1: Dissolve int 29-1 (0.6 g, 3.16 mmol) in toluene (8.5 mL). Add cyclopropylboronic acid (0.4 g, 4.74 mmol), potassium phosphate (2.0 g, 9.49 mmol), PCy3 (0.17 g, 0.63 mmol), Pd(OAc)2 (0.14 g, 0.63 mmol), and water (3.4 mL). Heat to 100°C under nitrogen for 1 h. After completion of the reaction, monitor the reaction by LC-MS. The reaction mixture is cooled to room temperature, filtered, and the filtrate is concentrated to obtain the crude product, which is then purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 30%-80% MeCN, elution over 20 min) to afford the target compound, int 29-2 (486 mg, yield: 78.6%). LC-MS:ESI-MS(m / z):[M+H] + =196.

[0350] Step 2: Dissolve compound int 29-2 (486 mg, 2.48 mmol) and compound int 3-3 (693 mg, 2.98 mmol) in DCM (10 mL). Under nitrogen, react at room temperature for 1 h. After TLC monitoring, the reaction is stopped. Cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 min) to obtain the target compound int 29 (268 mg, yield: 45.3%). LC-MS: ESI-MS (m / z): [M+H] + =238.

[0351] Synthesis of intermediate int 30

[0352] Step 1: Under nitrogen, int 30-1 (2.5 g, 12.02 mmol) and pyridine (1.9 g, 24.04 mmol) were dissolved in DCM (50 mL). Trifluoroacetic acid (5.1 g, 24.04 mmol) was added at 0°C, and the reaction system was allowed to react at room temperature for 12 h. LC-MS monitored the reaction completion and stopped the reaction. Ice water (50 mL) was added to the reaction system to quench the reaction. The system was adjusted to pH 7 with saturated sodium bicarbonate, extracted with DCM, and the organic layer was concentrated to obtain the target compound int 30-2 (2.5 g, yield: 68.4%). LC-MS: ESI-MS (m / z): [M+H] + =304.

[0353] Step 2: Under nitrogen, int 30-2 (2.5 g, 8.22 mmol) was added to THF (37.5 mL). n-BuLi (2.5 M in n-hexane, 6.9 mL, 17.27 mmol) was added dropwise at -78°C. After the addition was complete, the reaction was continued for 30 min. Cyclobutanone (0.6 g, 8.22 mmol) was added to the reaction system. After the addition was complete, the reaction was continued at -78°C for 1 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. Saturated aqueous ammonium chloride was added to the reaction system to quench the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain the target compound int 30-3 (2.0 g, yield: 82.4%). LC-MS: ESI-MS (m / z): [M+H] + =296.

[0354] Step 3: Under nitrogen, int 30-3 (2.0 g, 6.78 mmol) was added to methanol (12 mL) and NaOH (1 N, 6 mL). The reaction system was incubated at 80°C for 12 h. LC-MS monitoring confirmed the completion of the reaction and stopped the reaction. Ice water (30 mL) was added to the reaction system to quench the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 10%-50% MeCN, elution over 10 min) to obtain the target compound int 30-4 (600 mg, yield: 44.5%). LC-MS: ESI-MS (m / z): [M+H] + =200.

[0355] Step 4: Under nitrogen, int 30-4 (600 mg, 3.01 mmol) was dissolved in THF (9 mL). NaBH4 (649.5 mg, 17.17 mmol) and AlCl3 (1.4 g, 9.03 mmol) were added portionwise. The reaction system was heated to 70°C for 3 h. LC-MS monitored the reaction completion and stopped the reaction. Ice water (30 mL) was added to the reaction system to quench the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The concentrated crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 30%-80% MeCN, elution over 10 min) to obtain the target compound int 30-5 (200 mg, yield: 36.2%). LC-MS: ESI-MS (m / z): [M+H] + =184.

[0356] Step 5: Dissolve compound int 30-5 (200 mg, 1.63 mmol) and compound int 3-3 (456 mg, 1.96 mmol) in DCM (6 mL). Under nitrogen, react at room temperature for 1 h. TLC monitors the reaction until complete, then stop the reaction. Cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution over 20 min) to obtain the target compound int 30 (290 mg, yield: 78.6%). LC-MS: ESI-MS (m / z): [M+H] + =226.

[0357] Synthesis of intermediates int 31 and int 32

[0358] Step 1: Under nitrogen, int 22-7 (120.0 mg, 0.63 mmol) was dissolved in DCM (3.6 mL). Br2 (100.3 mg, 0.63 mmol) was added dropwise at room temperature and the reaction was allowed to react for 1 h. LC-MS monitoring confirmed the completion of the reaction and stopped the reaction. Saturated sodium thiosulfate (3 mL) was added to the reaction system to quench the reaction. The system was extracted with DCM, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 40%-80% MeCN, elution over 20 min) to obtain the target compound int 31-1 (140 mg, yield: 82.6%). LC-MS: ESI-MS (m / z): [M+H] + =270.

[0359] Step 2: Under nitrogen, int 31-1 (60.0 mg, 0.22 mmol) was added to dioxane (0.96 mL) and H₂O (0.24 mL). Methylboronic acid (19.9 mg, 0.33 mmol), K₂CO₃ (61.4 mg, 0.44 mmol), and Pd(dppf)Cl₂ (16.2 mg, 0.022 mmol) were then added. The reaction system was then heated to 100°C for 1 h. LC-MS monitored the reaction completion and the reaction was stopped. The solvent was evaporated, the system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H₂O (0.1% FA), 20%-60% MeCN, elution over 20 min) to afford the target compound, int 31-2 (40 mg, yield: 87.7%). LC-MS: ESI-MS (m / z): [M+H] + =206.

[0360] Step 3: Dissolve compound int 31-2 (40.0 mg, 0.20 mmol) and compound int 3-3 (54.3 mg, 0.24 mmol) in DCM (1.2 mL). Under nitrogen, react at room temperature for 1 h. After TLC monitoring, the reaction is complete and the reaction is stopped. Cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 40%-70% MeCN, elution over 20 min) to obtain the target compound int 31 (40 mg, yield: 83%). LC-MS: ESI-MS (m / z): [M+H] + =248.

[0361] Using a similar synthesis method to int 31, in the second step, methylboronic acid is replaced with cyclopropylboronic acid to synthesize intermediate int 32 (as shown below).

[0362] Synthesis of intermediate int 33

[0363] Step 1: Under nitrogen, int 33-1 (3.7 g, 16.81 mmol) and cyclopropylboronic acid (3.7 g, 16.81 mmol) were added to toluene (30 mL) and H₂O (6 mL). PCy₃ (0.94 g, 3.36 mmol), K₃PO₄ (10.7 g, 50.44 mmol), and Pd(OAc)₂ (0.76 g, 3.36 mmol) were then added. The reaction system was then heated to 100°C for 1 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The solvent was evaporated, the system was extracted with DCM, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C₁8 reverse-phase column chromatography (mobile phase: MeCN and H₂O (0.1% FA), 20%-75% MeCN, elution over 20 min) to afford the target compound, int 33-2 (776 mg, yield: 25.4%). LC-MS:ESI-MS(m / z):[M+H] + =182.

[0364] Step 2: Under nitrogen protection, compound int 33-2 (530 mg, 2.92 mmol) and compound int 3-3 (815 mg, 3.51 mmol) were dissolved in DCM (10.6 mL) and reacted at room temperature for 1 hour. TLC monitored the reaction to be complete and the reaction was stopped. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 30%-80% MeCN, elution time: 20 min) to obtain the target compound int 33 (396 mg, yield: 60.6%). LC-MS: ESI-MS (m / z): [M+H] + =224.

[0365] Synthesis of intermediate int 34

[0366] Under nitrogen protection, compound int 33-2 (0.6 g, 3.63 mmol) and compound int 3-3 (1.0 g, 4.35 mmol) were dissolved in DCM (10.6 mL) and reacted at room temperature for 1 hour. TLC monitored the reaction completion and stopped the reaction. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 50%-100% MeCN, elution over 10 minutes) to obtain the target compound int 33 (600 mg, yield 79.7%). LC-MS: ESI-MS (m / z): [M+H] + =208.

[0367] Synthesis of intermediate int 35

[0368] Under nitrogen, compound int 35-1 (0.4 g, 2.83 mmol) and compound int 3-3 (0.8 g, 3.41 mmol) were dissolved in DCM (12 mL) and allowed to react at room temperature for 1 h. The reaction was stopped upon completion of the reaction as monitored by TLC. The mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product, which was then purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 50%-100% MeCN, elution over 20 min) to afford the target compound int 33 (400 mg, 66.7% yield). LC-MS: ESI-MS (m / z): [M+H] + =212.

[0369] Synthesis of intermediates int 36, int 37, int38, and int39

[0370] The following intermediate was synthesized using a method similar to that of int 1.

[0371] Synthesis of intermediate int 41

[0372] Under nitrogen, int 38 (50 mg, 0.20 mmol) and cyclopropylboronic acid (86 mg, 1.00 mmol) were added to toluene (0.83 mL) and H₂O (0.17 mL). PCy₃ (11.2 mg, 0.04 mmol), K₃PO₄ (170 mg, 0.80 mmol), and Pd(OAc)₂ (8.9 mg, 0.04 mmol) were then added. The reaction system was then heated to 100°C for 1 h. The reaction was stopped after completion as monitored by LC-MS. The solvent was evaporated, the system was extracted with DCM, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C₁8 reverse-phase column chromatography (mobile phase: MeCN and H₂O (0.1% FA), 30%-80% MeCN, elution over 20 min) to afford the target compound int 41 (14 mg, yield: 27.3%). LC-MS: ESI-MS (m / z): [M+H] + =256.

[0373] Synthesis of intermediates int 42, int43, int44, int 45, and int48

[0374] The following intermediate was synthesized using a method similar to that used to synthesize int 35.

[0375] Synthesis of intermediate int 46

[0376] Int 46 is synthesized using a method similar to that used to synthesize int 30.

[0377] Synthesis of intermediate int 49

[0378] Step 1: Under nitrogen, int 49-1 (70.0 g, 251.76 mmol) was dissolved in DCM (1.4 L). Imidazole (34.3 g, 503.52 mmol) and tert-butyldimethylsilyl chloride (56.9 g, 377.64 mmol) were added at room temperature. The reaction system was allowed to react for 2 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. Distilled water (500 mL) was added to the reaction system to quench the reaction. The system was extracted with DCM, and the organic layer was concentrated to obtain the target compound int 49-2 (95 g, yield: 96.2%). LC-MS: ESI-MS (m / z): [M+H] + =393.

[0379] Step 2: Under nitrogen, int 49-2 (95 g, 242.16 mmol) was dissolved in DCM (1.9 L). m-CPBA (83.6 g, 484.31 mmol) was added at 0°C, and the reaction was incubated at 45°C for 24 h. LC-MS monitoring confirmed the completion of the reaction, and the reaction was stopped. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, extracted with DCM, and the organic layer concentrated to obtain the crude product. KCO (40% in H2O) (0.95 L) and methanol (0.95 L) were added to the crude product, and the reaction was stirred at room temperature for 5 h. Distilled water (500 mL) was added to the reaction system, extracted with EA, and the organic layer concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to yield the target compound, int 49-3 (30 g, yield: 32.6%). LC-MS: ESI-MS (m / z): [M+H] + =381.

[0380] Step 3: Under nitrogen, int 49-3 (30 g, 78.89 mmol) was dissolved in acetone (600 mL) and dimethyl sulfate (19.9 g, 157.77 mmol) was added dropwise at room temperature. The reaction system was allowed to react for 12 h. LC-MS monitored the reaction completion and stopped the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography to obtain the target compound int 49-4 (22 g, yield: 70.7%). LC-MS: ESI-MS (m / z): [M+H] + =395.

[0381] Step 4: Under nitrogen, int 49-4 (22.0 g, 55.79 mmol) was dissolved in THF (600 mL). TBAF (111 mL, 1 M in THF, 111.58 mmol) was added dropwise at 0°C. The reaction was incubated at 0°C for 1 h. LC-MS monitored the reaction completion and stopped the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target compound int 49-5 (10.7 g, yield: 68.5%). LC-MS: ESI-MS (m / z): [M+H] + =281.

[0382] Step 5: Under nitrogen, vinyl bromide (6.9 g, 57.31 mmol), tetrabutylammonium bromide (1.2 g, 3.82 mmol), and NaOH (3.1 g, 76.41 mmol) were dissolved in 2-methyltetrahydrofuran (53 mL) and H₂O (107 mL). Int 49-5 (10.7 g, 38.21 mmol) dissolved in 2-methyltetrahydrofuran (53 mL) was added dropwise at room temperature. The reaction system was allowed to react for 2 h at room temperature. LC-MS monitored the reaction completion and stopped the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography to yield the target compound, int 49-6 (3.6 g, yield: 29.4%). LC-MS: ESI-MS (m / z): [M+H] + =321.

[0383] Step 6: Under nitrogen, int 49-6 (3.6 g, 11.25 mmol) and silver carbonate (6.2 g, 22.49 mmol) were dissolved in DMF (72 mL). Pd(PPh3)4 (0.65 g, 0.56 mmol, 0.05 eq.) was added, and the reaction system was incubated at 80°C for 3 h. LC-MS monitored the reaction completion and stopped the reaction. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 10%-50% MeCN, elution over 20 min) to obtain the target compound int49-7 (600 mg, yield: 27.8%). LC-MS: ESI-MS (m / z): [M+H] + =193.

[0384] Step 7: Under nitrogen, CH2I2 (1.7 g, 6.24 mmol) was dissolved in DCM (6.4 mL). ZnEt2 (6.2 mL, 6.24 mmol) was added at -40°C, and the reaction was incubated at -40°C for 1 h. Trifluoroacetic acid (1.0 g, 6.24 mmol, 2.0 eq.) dissolved in DCM (6.4 mL) was then added at -10°C. The reaction was continued at -10°C for 1 h. Int 49-7 (0.6 g, 3.12 mmol) dissolved in DCM (6.4 mL) was then added dropwise at -10°C. The reaction was then warmed to room temperature for 2 h. Upon completion of the reaction, the reaction was stopped by LC-MS and quenched by the addition of MeOH (0.5 mL). The system was extracted with EA, and the organic layer was concentrated to obtain a crude product, which was then purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 30%-80% MeCN, elution over 20 min) to obtain the target compound int 49-8 (400 mg, yield: 62.1%). LC-MS: ESI-MS (m / z): [M+H] + =207.

[0385] Step 8: Under nitrogen, int 49-8 (400 mg, 1.94 mmol) and tetramethylethylenediamine (450.8 mg, 3.88 mmol) were dissolved in THF (8 mL). n-BuLi (1.2 mL, 2.91 mmol) was added dropwise at -78°C, and the reaction system was allowed to react at -78°C for 30 min. LC-MS monitored the reaction completion, and the reaction was stopped and quenched by adding saturated aqueous ammonium chloride. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 30%-80% MeCN, elution over 20 min) to obtain the target compound int 49-9 (500 mg, yield: 77.6%). LC-MS: ESI-MS (m / z): [M+H] + =333.

[0386] Step 9: Under nitrogen, int 49-9 (500 mg, 1.51 mmol) and benzophenone imine (545.7 mg, 3.01 mmol) were dissolved in toluene (10 mL). BINAP (187.5 mg, 0.30 mmol), Pd(OAc)2 (34.0 mg, 0.15 mmol), and Cs2CO3 (981 mg, 3.01 mmol) were added, and the reaction system was reacted at 110°C for 12 h. After completion of the reaction as monitored by LC-MS, the reaction was stopped and the system was concentrated. The system was extracted with EA, and the organic layer was concentrated to obtain the crude product. HCl (6 M, 5 mL) and THF (5 mL) were added to the crude product, and the reaction was continued at room temperature for 12 h. The pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate, and the system was extracted with EA. The crude product was purified by C18 reverse phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 30%-80% MeCN, elution over 20 min) to afford the target compound int 49-10 (200 mg, yield: 60.1%). LC-MS: ESI-MS (m / z): [M+H] + =222.

[0387] Step 10: Dissolve compound int 49-10 (60 mg, 0.27 mmol) and compound int 3-3 (71.7 mg, 0.33 mmol) in DCM (1.2 mL). Under nitrogen, react at room temperature for 1 h. TLC monitors the reaction until complete, then stop the reaction. Cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O, 50%-100% MeCN, elution over 20 min) to obtain the target compound int 49 (60 mg, yield: 84%). LC-MS: ESI-MS (m / z): [M+H] + =264.

[0388] Example 2 Preparation of target compound

[0389] Preparation of target molecule P1

[0390] Step 1: Under nitrogen, compound P1-1 (70.0 mg, 0.35 mmol) and compound int 1 (82.2 mg, 0.36 mmol) were dissolved in ACN (2 mL). Cs2CO3 (233.6 mg, 0.70 mmol) was added and the reaction system was allowed to react at room temperature for 3 h. LC-MS analysis confirmed complete consumption of the starting material. Compound int 2 (75.3 mg, 0.43 mmol) and AgNO3 (121.8 mg, 0.70 mmol) were then added to the reaction system and the reaction continued at room temperature for 30 min. LC-MS analysis confirmed complete consumption of the starting material. The solvent was evaporated, the mixture was extracted with EA, and the crude product was concentrated to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3), 10%-60% MeCN, elution over 20 min) to obtain the target compound P1-2 (26 mg, yield: 12.8%). LC-MS:ESI-MS(m / z):[M+H] + =575.

[0391] Step 2: Under nitrogen, compound P1-2 (26 mg, 0.04 mmol) and methanesulfonic acid (17.6 mg, 0.18 mmol) were dissolved in 1,4-dioxane (520 μL). The reaction system was heated to 100°C for 1 hour. LC-MS analysis confirmed complete consumption of the starting material. The solvent was evaporated, and the crude product was purified using a C18 reverse-phase column (mobile phase: MeCN and H₂O (10 mmol / L NH₄HCO₃ + 0.05% NH₃H₂O), 13%-43% MeCN, elution over 10 minutes) to obtain the target compound P1 (6.3 mg, yield: 25.0%). LC-MS: ESI-MS (m / z): [M+H] + =548.

[0392] 1 H NMR(300MHz,DMSO-d6,ppm)δ8.59(s,2H),8.55(s,1H),8.35(s,1H),7.60(s,1H),7.48(t,J=8.7Hz,1H),6.8 2(dd,J=8.4,4.5Hz,2H),3.83-3.64(m,8H),2.24(s,3H),2.06(s,3H),1.28-1.24(m,3H),1.10-1.05(m,3H).

[0393] Referring to the synthetic route of compound P1, similar intermediate structures and methods were used to synthesize the following target molecules or key intermediates:

[0394] P88-0A / 0B SFC splitting method:

[0395] Chromatographic column: CHIRALPAK IK 2*25cm, 5μm;

[0396] Mobile Phase A: HEX (0.5% 2M NH3-MeOH) , Mobile Phase B:EtOH:DCM=1:1;

[0397] Flow rate: 20 mL / min; Gradient: 30% B;

[0398] Detection wavelength: 254 / 220nm;

[0399] Retention time: RT1 (min): 20.82; RT2 (min): 24.22;

[0400] P89-0A / 0B SFC splitting method:

[0401] Chromatographic column: CHIRALPAK IK 2*25cm, 5μm;

[0402] Mobile phase: HEX (0.5% 2M NH3-MeOH) , Mobile Phase B:EtOH:DCM=1:1;

[0403] Flow rate: 20 mL / min; Gradient: 40% B;

[0404] Detection wavelength: 220nm;

[0405] Retention time: RT1 (min): 13.97; RT2 (min): 17.89;

[0406] P90-0A / 0B SFC splitting method:

[0407] Chromatographic column: CHIRALPAK IK 2*25cm, 5μm;

[0408] Mobile phase: HEX (0.5% 2M NH3-MeOH), Mobile Phase B:EtOH:DCM=1:1;

[0409] Flow rate: 20 mL / min; Gradient: 40% B;

[0410] Detection wavelength: 254 / 220nm;

[0411] Retention time: RT1 (min): 10.34; RT2 (min): 13.11;

[0412] Preparation of target molecule P30

[0413] Under nitrogen, int 23 (30.0 mg, 0.05 mmol) and P 30-1 (8.5 mg, 0.15 mmol) were dissolved in 1,4-dioxane (0.6 mL). XPhos (7.1 mg, 0.015 mmol), Cs2CO3 (48.9 mg, 0.15 mmol), and Pd2(dba)3 (4.6 mg, 0.005 mmol) were added. The reaction system was incubated at 90°C for 12 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature and concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (10 mmol / L NH4HCO3 + 0.05% NH3-H2O), elution: 10%-40% MeCN, 20 min) to afford the target compound P30 (6.5 mg, yield: 22.6%). LC-MS:ESI-MS(m / z):[M+H] + =579.

[0414] 1 H NMR (300MHz, DMSO-d6, ppm) δ12.16(brs,1H),8.60(s,2H),8.45(d,J=2.1Hz,1H),8.21(d,J=2.1Hz,1H),7.67(d,J=2.1Hz,1H),5.69(q,J=2.1Hz,2H),3. 90(t,J=7.2Hz,4H),3.76–3.65(m,2H),3.62(d,J=2.7Hz,6H),2.31(t,J=7.2 Hz, 2H), 2.26 (d, J = 9.0Hz, 6H), 1.28 (d, J = 6.9Hz, 3H), 1.10 (d, J = 6.9Hz, 3H).

[0415] Referring to the synthetic route of compound P30, similar intermediate structures and methods were used to synthesize the following target molecules or key intermediates:

[0416] Preparation of target molecule P 96

[0417] Under nitrogen, int 23 (30.0 mg, 0.05 mmol), P 96-1 (13.6 mg, 0.10 mmol), and P 96-2 (1.4 mg, 0.01 mmol, 0.1 eq.) were dissolved in DMA (0.6 mL). Zn (6.5 mg, 0.10 mmol), TFA (1.1 mg, 0.01 mmol), NiCl (0.6 mg, 0.005 mmol), and NaI (3.7 mg, 0.02 mmol) were added. The reaction was incubated at 90°C for 12 h. LC-MS monitoring confirmed the reaction was complete and the reaction was stopped. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was then purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 19%-49% MeCN, elution over 12 min) to obtain the target compound P 96 (3.3 mg, yield: 11.4%). LC-MS: ESI-MS (m / z): [M+H] + =580.

[0418] 1 H NMR (300MHz, DMSO-d6, ppm) δ8.59(s,2H),8.46(s,1H),8.19(s,1H),7.65(s,1H),6.84(s,2H),4.93(dd,J=8.4,5.9Hz,2H),4.71(td,J=6.4,3. 2Hz, 2H), 4.37–4.28 (m, 1H), 3.72 (d, J = 2.7Hz, 6H), 3.67 (t, J = 2.7Hz, 2H), 2.25 (d, J = 5.7Hz, 6H), 1.25 (d, J = 6.9Hz, 3H), 1.11 (d, J = 6.9Hz, 3H).

[0419] Compound P97 was synthesized using a similar synthetic method to P96.

[0420] Preparation of target molecule P98

[0421] Under nitrogen, int 23 (30.0 mg, 0.05 mmol) and P 98-1 (9.2 mg, 0.08 mmol) were dissolved in 1,4-dioxane (0.48 mL) and water (0.12 mL). K2CO3 (20.6 mg, 0.15 mmol) and Pd(dppf)Cl2 (3.6 mg, 0.005 mmol) were added. The reaction system was incubated at 90°C for 30 min. LC-MS monitored the reaction completion and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by C18 reverse-phase column chromatography (mobile phase: MeCN and H2O (0.1% FA), 5%-35% MeCN, elution over 12 min) to obtain the target compound P98 (9.0 mg, yield: 30.1%). LC-MS: ESI-MS (m / z): [M+H] + =601.

[0422] 1 H NMR (300MHz, DMSO-d6, ppm) δ13.39(brs,1H),8.69(d,J=5.1Hz,2H),8.58(s,2H),8.46(d,J=2.1Hz,1H),8.22(d,J=2.1Hz,1H),7.93–7.82(d,J=6.0H z,2H),7.69(s,1H),7.19(d,J=2.4Hz,2H),3.81(d,J=3.6Hz,6H),3.71(m, 2H), 2.25 (d, J = 10.5Hz, 6H), 1.26 (d, J = 6.9Hz, 3H), 1.11 (d, J = 6.9Hz, 3H).

[0423] Compounds P99 and P100 were synthesized using a similar synthetic method to P98.

[0424] Example 3 HTRF Detection of cAMP Accumulation by Compounds

[0425] Upon activation, the APJ target can bind to the Gαi subunit, which inhibits adenylate cyclase from converting ATP, leading to a decrease in cAMP. This experiment uses forskolin to elevate intracellular cAMP production. HTRF assays are then used to measure changes in cAMP after APJ stimulation to assess the compound's effect on the APJ target. This assay uses the Cisbio kit #62AM4PEJ.

[0426] CHO cells stably expressing the hAPJ gene were cultured at 37°C in the presence of 5% CO₂ (medium: Ham's F-12, 10% FBS, 1% penicillin / streptomycin, 400 μg / mL G418) until logarithmic growth phase. 5 μL (5 x 10⁵ cells / mL) of CHO-K1 / APJ cells were plated per well in a 384-well plate. The supernatant was removed by centrifugation, and the cells were redispersed in 1x stimulation buffer (containing 500 μM IBMX) for later use. Test compounds were serially diluted three-fold starting from a 1 μM solution in 1x stimulation buffer (containing 500 μM IBMX) to create 11 assay concentrations. 10 nL of the test sample was pipetted onto the cells and assayed in duplicate. A blank control was treated with DMSO to a final concentration of 0.1%, and a positive control was treated with apelin-13 serially diluted three-fold starting from 1 μM. Add 5 μL of forskolin dissolved in 1x stimulation buffer (containing 500 μM IBMX), seal the plate, and incubate at 37°C for 30 min. For the blank control, add cell lysis buffer and detection reagent. For the test control, add 5 μL of 1x cAMP-d2 reagent dissolved in lysis buffer and detection buffer to each well of cells, followed by 5 μL of anti-cAMP chelate antibody coupling reagent. Seal the plate and incubate at room temperature for 60 min.

[0427] The fluorescence ratio of 665 nm to 620 nm was read by using an Envision plate reader (PerkinElmer) on a 384-well plate at a height of 6.5 mm for 0.5 s. 样品 -Ratio 空白 ) / (Ratio 阳参 -Ratio 空白 )*100% value for curve fitting and calculate EC 50 The specific experimental results are shown in Table 1.

[0428] Example 4 Compound recruitment test for β-arrestin

[0429] The APJ target site recruits β-arrestin upon phosphorylation. This assay constructs a short β-gal ProLink peptide at the intracellular end of the APJ protein. The EA carried by the β-arrestin in the kit binds to the recombinant APJ ProLink, generating a complementary β-gal and luminescent substrate. The substrate's luminescence intensity is then measured to assess β-arrestin binding. The kit used for this assay is DiscoverX #93-0001.

[0430] U2OS cells stably expressing the hAPJ gene were cultured at 37°C with 5% CO2 (culture medium: McCoy's 5A, 10% FBS, 1% penicillin / streptomycin, 500μg / mL G418) until the logarithmic growth phase. 20μL (1x 106 / mL) of U2OS-APJ cells were transferred to each well of a 384-well plate, the supernatant was centrifuged, and the cells were redispersed with fresh culture medium for later use. 20nL of the test sample with a serial dilution (starting at 1μM and then 3-fold dilutions, 11 concentrations) was added, mixed, and incubated at 37°C for 2h. The blank group was treated with 0.1% DMSO, and the positive control group was treated with Apelin-13. 10μL of 1x Detection reagent, mix well, and incubate at 37°C for 30 min.

[0431] The luminescence intensity at a wavelength of 400-700 nm was measured by an enzyme-labeled instrument at a height of 6.5 mm in a 384-well plate for 0.5 s. 样品 -ZPE 空白 ) / (HPE 阳参 -ZPE 空白 )*100% to calculate the ratio of different concentrations for curve fitting and calculate the EC 50 The specific experimental results are shown in Table 1.

[0432] Table 1. Activity data of compounds against cAMP and β-arrestin

[0433] Apelin-13 is an endogenous peptide ligand for APJ. The structure of AMG986 is shown below (derived from patent WO2016187308A1 Example 263.0):

[0434] The above test results show that some molecules of the present invention have excellent agonist effects on hAPJ, while some molecules have poor recruitment activity for β-arrestin, proving that the patented compounds have significant G protein bias for activation of the hAPJ target.

[0435] It was unexpectedly discovered that the replacement of substituents on some benzene rings in the molecules of the present invention was significantly better than H substitution, and the substitution of cyclopropyl or cyclobutyl (such as P2, P7, P23, P25, P28, P37, P43, P74, P75, P83, P88, P89, P90, etc.) significantly improved the preference for cAMP compared with the control molecule AMG986.

[0436] It was unexpectedly discovered that replacement of substituents on some benzene rings in the molecules of the present invention was significantly better than replacement with heterocyclic groups. Substitution with cyclopropyl or cyclobutyl (such as P2, P7, P23, P25, P28, P37, P43, P74, P75, P83, P88, P89, P90, etc.) significantly improved the preference for cAMP compared with substituents such as heterocyclic groups and heteroaryl groups (such as molecules P31, P32, P33, P34, P93, P94, P98, etc.), indicating that only specific substituents have a preference for cAMP.

[0437] In addition, some of the tricyclic molecules (P60, P61, P92) of the present invention have excellent agonist effects on hAPJ, while having poor recruitment activity for β-arrestin and having significant cAMP bias compared to the control molecule AMG986.

[0438] Example 5 Liver microsome stability test of the compound

[0439] The experimental plan is as follows:

[0440] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 15, 30, 45, and 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0441] The remaining percentage of the test compound was plotted against the reaction time, T 1 / 2 =0.693 / k, as the half-life of the compound.

[0442] Table 2: Results of the compound stability test on human liver microsomes in vitro.

[0443] An unexpected discovery was made that some of the molecules of the present invention have good metabolic stability in human liver microsomes and are significantly better than the control molecule AMG986.

[0444] Pharmacokinetic evaluation of the compound of Example 6 in mice

[0445] CD1 female mice were used as test animals and the drug was administered orally / intravenously (oral dosage: 10 mg / kg, intravenous dosage: 2 mg / kg).

[0446] Experimental plan: Oral group, 3 mice per group; intravenous group, 3 mice per group. Oral: Collect plasma samples before (0h) and after (0.25, 0.5, 1, 2.48, 24h) administration; intravenous: Collect plasma samples before (0h) and after (0.083, 0.25, 0.5, 1, 2.4, 8, 24h) administration. LC / MS / MS was used to determine the drug concentration in the plasma of mice after oral and intravenous administration. The collected data were calculated using AB Sciex OTRAP6500 software. The experimental results are as follows:

[0447] *: PO (dose: 50 mg / kg)

[0448] The above experimental results show that the compounds of the present invention have good oral absorption effect, have a higher in vivo exposure, and some compounds have better metabolic kinetic properties than the control compounds.

Claims

1. A compound of formula (I), or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof: in, R 1 -(L1) n -R 11 ; L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens; R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace; R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated; R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic or cycloalkyl group may be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated; R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2; R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1- 6-haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O; A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1- 6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace; Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace; R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa or-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated; R 3 Independently selected from C 6-10 Aryl, 5-12 membered heteroaryl and 4-12 membered heterocyclic radical, wherein said aryl, heteroaryl or heterocyclic radical is substituted by 1, 2, 3, 4 or 5 R 3a replace; R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 Alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group, 5-6 membered heteroaryl group, halogen group, cyano group, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa Or =O, where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl substitution; The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Or when R 3 When it is a bicyclic group, the two R 3a Together with the ring atoms to which they are attached, they form a 3-8 membered cycloalkyl or a 4-8 membered heterocyclic group; 3a Each group defined in may be optionally deuterated, up to fully deuterated; m is selected from 0, 1, 2, or 3; and n is selected from 0, 1, 2, or 3.

2. The compound of claim 1, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 for where R 3a1 and R 3a5 Each is independent of -OC 1-6 Alkyl or halogen, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3- 6 cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or R 3a1 and R 3a5 One of them is C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, R 3a1 and R 3a5 The other one is -OC 1-6 Alkyl, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, and R 3a2 、R 3a4 and R 3a3 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2; Preferably, R 3 for where R 3a1 and R 3a5 Each is independent of -OC 1-6 Alkyl or halogen, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or R 3a1 and R 3a5 One of them is C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, R 3a1 and R 3a5 The other one is -OC 1-6 Alkyl, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, C 1-6 alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group or 5-6 membered heteroaryl group, and R 3a2 、R 3a4 and R 3a3 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2; Preferably, R 3 for where R 3a1 and R 3a5 is methoxy, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, C 1-6 Alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Preferably, R 3 for where R 3a1 and R 3a5 is halogen, R 3a2 and R 3a4 is hydrogen, and R 3a3 C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, C 1-6 Alkyl or halogen-substituted 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Preferably, R 3 for 3. The compound of claim 1, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following general structure: in, R 1 -(L1) n -R 11 ; L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens; R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace; R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated; R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic or cycloalkyl group may be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated; R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2; R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1- 6-haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2d and R 2e independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1- 6-haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O; A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1- 6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace; Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace; R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated; R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 Alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group, 5-6 membered heteroaryl group, halogen group, cyano group, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O, where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated; The premise is that the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, 4 or 5.

4. The compound of claim 1, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following general structure: in, R 1 -(L1) n -R 11 ; L1 is C 1-6 Alkylene, said L1 is optionally substituted by 0-3 halogens; R 11 Selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic group, said R 11 Optionally R 1a replace; R 1a Independently selected from halogen, cyano, hydroxy, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R 1a Each group defined in may be optionally deuterated, up to fully deuterated; R 2 Selected from C 1-6 Alkyl, -(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A、-(CR 2b R 2c )-(NR 2d )-A, -5-7 membered heterocyclyl-A and -C 5-8 Cycloalkyl-A, wherein the C 1-6 The alkyl group may be optionally replaced by R 2a Substituted, the heterocyclic group, cycloalkyl group can be optionally replaced by R 2f Replacement; R 2 Each group defined in may be optionally deuterated, up to fully deuterated; R 2a Independently selected from halogen, cyano, hydroxy, amino, C 3-8 Cycloalkyl, C 3-7 Heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, phenyl, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl) and -CON-(C 1-6 Alkyl)2; R 2b and R 2c independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1- 6-haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2d and R 2e independently selected from hydrogen, deuterium halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2; R 2f Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, amino, -OC 1-6 Alkyl-OH, -OC 1-6 Alkyl-OC 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2 and =O; A is -(CH2) m C 6-10 Aryl, -(CH2) m -5-12 membered heteroaryl, -(CH2) m -C 3-8 Cycloalkyl, -(CH2) m -4-10 membered heterocyclic group or C 1- 6 alkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl group may be optionally replaced by R A replace; Alternatively, the substituents on A may be 2d or R 2e To form a phenyl group, a 5-6 membered heteroaryl group, a 5-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group, wherein the phenyl group, heteroaryl group, cycloalkyl group or heterocyclyl group may be optionally replaced by R A replace; R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, amino, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 1aa 、-S(O)(NR 1ab )-R 1aa and-P(O)-R 1ab R 1aa , where R 1aa and R 1ab Selected from H and C 1-6 Alkyl; R A Each group defined in may be optionally deuterated, up to fully deuterated; Ring B and Ring C together form a bicyclic heteroaryl group or a bicyclic heterocyclic group; R 3a Independently selected from C 3-6 Cycloalkyl, C 1-6 Alkyl or halogen substituted C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic group, C 1-6 Alkyl or halogen-substituted 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group, phenyl group, 5-6 membered heteroaryl group, halogen group, cyano group, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, C 2-6 Alkenyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -CONH2, -CONH-(C 1-6 alkyl), -CON-(C 1-6 Alkyl)2, -S(O)2-R 3aa 、-S(O)(NR 3ab )-R 3aa 、-P(O)-R 3ab R 3aa and = O, where R 3aa and R 3ab Selected from H and C 1-6 Alkyl; the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl may be optionally substituted with halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl substitution; R 3a Each group defined in may be optionally deuterated, up to fully deuterated; And the substituent R 3a At least one of them is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-8 membered heterocyclyl, 4-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Or 2 R 3a Together with the ring atoms to which they are attached, they form a 3-8 membered cycloalkyl or a 4-8 membered heterocyclyl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, 4 or 5.

5. The compound of claim 1 or 3, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following general structure: in, R 1 、R 2 and R 3a The scope is the same as claim 3, and p is selected from 0, 1, 2 or 3.

6. The compound of claim 1 or 4, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following general structure: in, R 1 、R 2 、R 3a and p has the same scope as claim 4; t is selected from 1, 2, 3 or 4.

7. The compound of claim 1 or 4, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following general structure: in, R 1 、R 2 、R 3a and p has the same scope as claim 1; X and Y are each independently selected from N or CH, and at least one of X and Y is N.

8. The compound of any one of claims 1 to 7, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 0.

9. The compound of any one of claims 1 to 8, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, 5-6 membered monocyclic heteroaryl, 7-12 membered bicyclic heteroaryl, 5-6 membered monocyclic heterocyclic group, 7-12 membered bicyclic heterocyclic group or C 3-8 Cycloalkyl, wherein the R 1 Optionally R 1a Replacement, R 1a Independently selected from halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2, R 1a Each group defined in may be optionally deuterated, up to fully deuterated; Preferably, R 1 is a 5-6 membered monocyclic heteroaryl group, which is R 1a Replacement, R 1a Independently selected from halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 2-6 Alkynyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2, R 1a Each group defined in may be optionally deuterated, up to fully deuterated; Preferably, R 1 is phenyl; pyridyl, thienyl, furyl, pyridazinyl, pyrazinyl, pyrimidinyl; tetrahydrofuranyl, 1,4-dioxane; or spiro[2.2]pentyl, spiro[3.3]heptyl, spiro[3.4]octyl or spiro[2.2.1]heptyl, wherein R 1 Optionally R 1a Replacement, R 1a independently selected from halogen, methyl, ethyl, propyl, deuterated methyl (methyl-d3), hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 1,1,1-trifluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, C 1-6 haloalkyl, methoxy, ethoxy, isopropoxy, propoxy, ethynyl, dimethylamino or methylamino; Preferably, R 1 is pyridin-3-yl, which is R 1a Replacement, R 1a independently selected from halogen, methyl, ethyl, propyl, deuterated methyl (methyl-d3), hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 1,1,1-trifluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, C 1-6 haloalkyl, methoxy, ethoxy, isopropoxy, propoxy, ethynyl, dimethylamino or methylamino; Preferably, R 1 for 10. The compound of any one of claims 1 to 9, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2 For-(CR 2b R 2c )-(CR 2d R 2e )-A、-(NR 2b )-(CR 2d R 2e )-A or -(CR 2b R 2c )-(NR 2d )-A, wherein A is pyrimidinyl, pyridazinyl, pyridinyl (eg, pyridin-3-yl), pyrazolyl, thiazolyl or phenyl, said A being optionally replaced by R A Substituted, where R A Independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 2b and R 2c independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl; and R 2d and R 2e independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 alkyl halide; Preferably, R 2 for where R 2d For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or -OC 1-6 haloalkyl; and R A Halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl or C 3-6 Cycloalkyl; Preferably, R 2 for 11. A compound, or an isotopic variant, tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally together with other therapeutic agents.

13. Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in the preparation of a medicament for treating and / or preventing diseases associated with APJ receptor activity.

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