Compound for inhibiting IRAK4 activity and application thereof

Abstract

Relates to a compound for inhibiting IRAK4 activity and application thereof, and particularly provides a compound as shown in a formula A, or enantiomers, diastereoisomers, racemate, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope labeled compounds (preferably deuterated compounds) or prodrugs of the compounds. # imgabs0 #

Description

A compound for inhibiting IRAK4 activity and its application Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound for inhibiting IRAK4 activity and application thereof. Background Art

[0002] IRAK4 is a serine / threonine protein kinase that belongs to the interleukin-1 receptor-associated kinase (IRAK) family, which includes four subtypes: IRAK1, IRAK2, IRAK3 (or IRAKM), and IRAK4. IRAK1, IRAK2, and IRAK4 promote the release of inflammatory factors, while IRAK3 is involved in suppressing inflammation. Among the four subtypes, the biological function of IRAK4 has been clearly elucidated. When TLRs or IL-1Rs perceive external signaling, the Myddosome complex formed by IRAK4 activates the MAPK and NF-κB pathways, leading to the release of multiple inflammatory factors.

[0003] Research has confirmed that IRAK4 is highly expressed in various tumor cells and inflammatory models. The development of inhibitors targeting IRAK4 is becoming an increasingly important approach in the treatment of autoimmune diseases and tumors. IRAK4 has both kinase and scaffold activities, both of which play a crucial role in downstream signaling regulation.

[0004] In addition, the protein degradation targeting chimera (PROTAC) technology is a new technology that has emerged in recent years. Since its advent in 2001, the technology has attracted much attention. At present, many drug developments based on this technology have entered the clinical research stage, and some have entered clinical phase 2. PROTAC, as a heterogeneous bifunctional molecule, consists of three parts: a small molecule inhibitor that can recognize the target protein at one end, a connecting chain, and a ligand that can recognize E3 ubiquitin ligase at the other end. This bifunctional molecule recognizes and brings the target protein and E3 ubiquitin ligase together in the body to form a ternary complex, and then ubiquitin-tags the target protein, thereby initiating a degradation pathway that depends on ubiquitin-proteasome. Compared with conventional small molecule inhibitors, PROTAC technology achieves simultaneous inhibition of the two functions of IRAK4 by degrading the IRAK4 protein, which can effectively solve the problem of insufficient small molecule activity or mutation.

[0005] Therefore, the development of new small molecule IRAK4 kinase inhibitors is of great significance, and PROTAC molecules targeting IRAK4 can be obtained based on new small molecule IRAK4 kinase inhibitors.

[0006] Summary of the Invention

[0007] Through in-depth research and creative discoveries, the inventors of this application have obtained a new small molecule IRAK4 kinase inhibitor, which can be used to treat a variety of diseases. The new small molecule IRAK4 kinase inhibitor can also lay the foundation for the subsequent further development of PROTAC molecules targeting IRAK4.

[0008] To this end, in a first aspect of the present invention, the present invention provides a compound of formula A, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof,

[0009] in:

[0010] A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k replaced by;

[0011] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclyl (e.g., 5-6 membered saturated heterocyclyl), 6-10 membered aryl, 5-10 membered heteroaryl;

[0012] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl;

[0013] B is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B is optionally substituted by R a 、R b Preferably, B is substituted by at least one of the substituents R a 、R b replaced by at least one of;

[0014] R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NRNa R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxy), wherein the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl are optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0015] R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo;

[0016] R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0017] Or, R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl);

[0018] L 1 Selected from direct bond, C1-C6 alkyl,

[0019] R 1 Selected from

[0020] C is selected from 5-6 membered heteroaryl, and C is optionally substituted by Rd 、R e 、R f replaced by at least one of;

[0021] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclic group are each independently optionally substituted by C1-C6 alkyl, 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0022] Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl;

[0023] R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly connected, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms.

[0024] In some embodiments, A is selected from a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is optionally substituted with R k replaced.

[0025] In some embodiments, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k replaced.

[0026] In some embodiments, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted with R k replaced.

[0027] In some embodiments, A is selected from and Optionally substituted R k Replaced by, where #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 connection site.

[0028] In some embodiments, A is selected from Among them #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 connection site.

[0029] In some embodiments, A is selected from Among them #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 connection site.

[0030] In some embodiments, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g., 5-6 membered saturated heterocyclic group).

[0031] In some embodiments, R k Selected from C1-C6 alkyl, 5-6 membered saturated heterocyclic group.

[0032] In some embodiments, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl.

[0033] In some embodiments, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0034] In some embodiments, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0035] In some embodiments, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl.

[0036] In some embodiments, B is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B is substituted with R a 、R b replaced.

[0037] In some embodiments, B is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B is substituted by R a 、R b substituted by at least one of; preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms.

[0038] In some embodiments, B is selected from 9-membered heteroaryl, pyridyl, phenyl, and B is substituted by R a 、R b substituted by at least one of; preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms.

[0039] In some embodiments, B is selected from Pyridyl, phenyl, pyrimidinyl, and B is substituted by R a 、R b is replaced by at least one of .

[0040] In some embodiments, B is selected from Pyridyl, phenyl, and B is substituted by R a 、R b is replaced by at least one of .

[0041] In some embodiments, B is selected from and B is substituted with R a 、R b replaced.

[0042] In some embodiments, B is selected from and B is substituted with R a 、R b replaced.

[0043] In some embodiments, R a Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, 4-7 membered heterocyclyl), the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0044] In some embodiments, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), wherein m is selected from 0, 1, 2, 3, n is selected from 0, 1, 2, 3, and p is selected from 0, 1, 2, 3.

[0045] In some embodiments, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), wherein m is selected from 0, 1, 2, 3, n is selected from 0, 1, 2, 3, and p is selected from 0, 1, 2, 3.

[0046] In some embodiments, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), F, Cl, Br, wherein m is selected from 0, 1, 2, 3, and n is selected from 0, 1, 2, 3.

[0047] In some embodiments, R a Selected from hydrogen, cyano, carboxyl,

[0048] In some embodiments, R a Selected from hydrogen, cyano, carboxyl,

[0049] In some embodiments, R a Selected from hydrogen, cyano,

[0050] In some embodiments, R a Selected from hydrogen, cyano,

[0051] In some embodiments, m is selected from 0, 1. In some embodiments, n is selected from 0, 1, 2, 3. In some embodiments, n is selected from 0, 1. In some embodiments, p is selected from 0, 1. In some embodiments, m is 0 and n is 0.

[0052] In some embodiments, Cy1 is optionally replaced by R cy1 and R cy2 More preferably, Cy1 is a 5-7 membered heterocyclic group optionally substituted by R cy1 and R cy2 substituted 6-membered heterocyclic group, further preferably, Cy1 is optionally replaced by R cy1 and R cy2 Substituted morpholine, piperazine, thiomorpholine.

[0053] In some embodiments, Cy2 is a 5-7 membered heterocyclyl, which is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy.

[0054] In some embodiments, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-3 substituents selected from halogen and C1-C6 alkyl.

[0055] In some embodiments, Cy2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl are optionally substituted with 1-3 substituents selected from F, Cl, Br, and methyl.

[0056] In some embodiments, Cy2 is selected from pyrrolidinyl, which is optionally substituted with 1-3 (eg, 1 or 2 or 3) F groups.

[0057] In some embodiments, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo.

[0058] In some embodiments, R b Selected from hydrogen, cyano,

[0059] In some embodiments, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl.

[0060] In some embodiments, R a 、R b Together with the carbon atoms to which they are attached, they form where R c Selected from hydrogen, C1-C6 alkyl.

[0061] In some embodiments, R c Selected from C1-C6 alkyl.

[0062] In some embodiments, B, as a whole, is selected from:

[0063] In some embodiments, B as a whole is selected from

[0064] In some embodiments, B as a whole is selected from

[0065] In some embodiments, B as a whole is selected from

[0066] In some embodiments, L 1 Select from direct keys, In some embodiments, L 1 Selected from direct bond, methylene, In some embodiments, L 1 Select from direct keys, In some embodiments, L 1 Select from Direct Key.

[0067] In some embodiments, C is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms, and C is optionally substituted with R d 、R e 、R f is replaced by at least one of .

[0068] In some embodiments, C is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, oxazolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C is optionally substituted with R d 、R e 、R f is replaced by at least one of .

[0069] In some embodiments, C is selected from pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, oxazolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C is optionally substituted with R d 、R e 、R f is replaced by at least one of .

[0070] In some embodiments, R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclic group are each independently optionally substituted by 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl.

[0071] In some embodiments, R dSelected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, morpholinyl, piperazinyl, piperidinyl, said C3-C6 cycloalkyl, phenyl, pyridyl, morpholinyl, piperazinyl, piperidinyl are each independently optionally substituted with 1-2 substituents selected from C1-C6 alkyl, halogen, alkoxy (e.g. C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g. hydroxymethyl), aminoC1-C6 alkyl, formyl.

[0072] In some embodiments, R d Selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperidinyl, and the C3-C6 cycloalkyl, phenyl, morpholinyl, piperidinyl are each independently optionally substituted by 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl.

[0073] In some embodiments, R d Selected from C1-C6 alkyl, Phenyl, morpholinyl, piperazinyl, piperidinyl, the Phenyl, morpholinyl, piperazinyl, piperidinyl are optionally substituted by C1-C6 alkyl (preferably methyl), wherein p is selected from 0, 1, 2, R g Selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl.

[0074] In some embodiments, R d Selected from Phenyl, morpholinyl, piperidinyl, wherein p is selected from 0, 1, 2, R g Selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl.

[0075] In some embodiments, R d Selected from methyl, ethyl, isopropyl, Piperazinyl, piperidinyl,

[0076] In some embodiments, R d Selected from Piperazinyl.

[0077] In some embodiments, R d Selected from

[0078] In some embodiments, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

[0079] In some embodiments, R e Selected from hydrogen, methyl, F3C-、 -NHCH3.

[0080] In some embodiments, R e Selected from hydrogen, methyl, F3C-、

[0081] In some embodiments, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (for example C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl.

[0082] In some embodiments, R e 、R f Together with the carbon atoms to which they are attached, they form Among them, each R j Independently selected from hydrogen, C1-C6 alkyl, alkoxy (eg C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy.

[0083] In some embodiments, R e 、R f Together with the carbon atoms to which they are attached, they form

[0084] In some embodiments, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl,

[0085] In some embodiments, R 2 、R 3 Together with the N atoms they are connected to, they form

[0086] In some embodiments, R 1 As a whole, selected from:

[0087] In some embodiments, R 1 As a whole, selected from:

[0088] In some embodiments, R 1 As a whole, selected from:

[0089] In some embodiments, R 1 As a whole, selected

[0090] In the second aspect of the present invention, the present invention provides a compound of formula I, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug,

[0091] in:

[0092] A 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by R k Preferably, A 1 is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A 1 Selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring;

[0093] More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 The attachment site;

[0094] More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 The attachment site;

[0095] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, Rp R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0096] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0097] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0098] B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 Optionally substituted R a 、R b Preferably, B 1 Substituted group R a 、R b Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms;

[0099] More preferably, B 1 Selected from Pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b More preferably, B 1 Selected from Pyridyl, phenyl, and B 1 Substituted group Ra 、R b More preferably, B 1 Selected from And B 1 Substituted group R a 、R b replaced by;

[0100] More preferably, B 1 Selected from And B 1 Substituted group R a 、R b Replaced by; R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl, the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl is optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted with C1-C6 alkyl, halogen, hydroxy, or cyano;

[0101] Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is morpholine, piperazine, or thiomorpholine;

[0102] R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo;

[0103] Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; further preferably, Cy2 is selected from pyrrolidinyl, and the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F groups;

[0104] Preferably, R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0105] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0106] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0107] Preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);

[0108] m is selected from 0, 1, 2, 3; preferably, m is selected from 0, 1; n is selected from 0, 1, 2, 3; preferably, n is selected from 0, 1; p is selected from 0, 1, 2, 3; preferably, p is selected from 0, 1;

[0109] More preferably, R a Selected from hydrogen, cyano, carboxyl,

[0110] More preferably, R a Selected from hydrogen, cyano,

[0111] R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl),

[0112] Preferably, R b Selected from hydrogen, cyano,

[0113] R l 、Rm Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0114] Or, R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl); preferably, R a 、R b Together with the carbon atoms to which they are attached, they form

[0115] R c is selected from hydrogen, C1-C6 alkyl; preferably, R c Selected from C1-C6 alkyl;

[0116] Most preferably, B 1 As a whole, selected from:

[0117] Most preferably, B 1 As a whole, selected from:

[0118] Most preferably, B 1 As a whole, selected

[0119] L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Selected from direct bond, methylene, Preferably, L 1 Select from direct keys,

[0120] R 11 Selected from

[0121] C 1 is selected from 5-6 membered heteroaryl, and C 1 Optionally substituted R d 、R e 、R f Preferably, C 1is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f replaced by at least one of;

[0122] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl and 4-7 membered saturated heterocyclic group are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0123] R d 、R e 、R f Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, The C3-C7 cycloalkyl group is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0124] Preferably, R d is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl;

[0125] Preferably, R dis selected from 4-7 membered saturated heterocyclic groups, wherein the 4-7 membered saturated heterocyclic groups are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0126] More preferably, R d Selected from C1-C6 alkyl, Or more preferably, R d is selected from pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl, wherein the pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl is optionally substituted by 1-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl); more preferably, R d Selected from

[0127] p is selected from 0, 1, 2;

[0128] Or more preferably, R d Selected from pyrrolyl and piperidinyl, wherein the pyrrolyl and piperidinyl are optionally substituted by 1-2 groups selected from halogen and C1-C6 alkyl (preferably methyl);

[0129] R g is selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl;

[0130] More preferably, R d Selected from methyl, ethyl, isopropyl, Piperidinyl,

[0131] More preferably, R d Selected from

[0132] More preferably, R d Selected from

[0133] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;

[0134] Preferably, R e Selected from hydrogen, methyl, F3C-、 -NHCH3; preferably, R e Selected from hydrogen, methyl, F3C-、

[0135] Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl;

[0136] Preferably, R e 、R f Together with the carbon atoms to which they are attached, they form

[0137] Each R j Independently selected from hydrogen, C1-C6 alkyl, alkoxy (e.g., C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy;

[0138] More preferably, R e 、R f Together with the carbon atoms to which they are attached, they form

[0139] R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly connected, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms. Preferably, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl,

[0140] Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form

[0141] Most preferably, R 11 As a whole, selected from:

[0142] Most preferably, R 11 As a whole, selected from:

[0143] Most preferably, R 11 As a whole,

[0144] In the third aspect of the present invention, the present invention provides a compound of formula i-1, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs,

[0145] in:

[0146] A 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by R k Preferably, A 1 is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A 1 is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring; further preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 The attachment site;

[0147] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0148] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0149] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0150] B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 Optionally substituted R a 、R b Preferably, B 1 Substituted group R a 、R b Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms;

[0151] More preferably, B 1 Selected from Pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b More preferably, B 1 Selected from Pyridyl, phenyl, and B 1 Substituted group R a 、R b replaced by at least one of;

[0152] More preferably, B 1 Selected from And B 1 Substituted group R a 、R b Further preferably, B1 Selected from And B 1 Substituted group R a 、R b Replaced by; R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl, the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl is optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted with C1-C6 alkyl, halogen, hydroxy, or cyano;

[0153] Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is morpholine, piperazine, or thiomorpholine;

[0154] R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo;

[0155] Preferably, R cy1 and Rcy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo;

[0156] Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; further preferably, Cy2 is selected from pyrrolidinyl, and the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F groups;

[0157] Preferably, R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0158] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0159] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0160] Preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);

[0161] m is selected from 0, 1, 2, 3; preferably, m is selected from 0, 1; n is selected from 0, 1, 2, 3; preferably, n is selected from 0, 1; p is selected from 0, 1, 2, 3; preferably, p is selected from 0, 1;

[0162] More preferably, R a Selected from hydrogen, cyano, carboxyl,

[0163] More preferably, R a Selected from hydrogen, cyano,

[0164] R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl),

[0165] Preferably, R b Selected from hydrogen, cyano,

[0166] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0167] Or, R a 、Rb Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl);

[0168] Preferably, R a 、R b Together with the carbon atoms to which they are attached, they form

[0169] R c is selected from hydrogen, C1-C6 alkyl; preferably, R c Selected from C1-C6 alkyl;

[0170] Most preferably, B 1 As a whole, selected from:

[0171] Most preferably, B 1 As a whole, selected from:

[0172] Most preferably, B 1 As a whole, selected

[0173] L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Selected from direct bond, methylene, Preferably, L 1 Select from direct keys,

[0174] R 11 Selected from

[0175] C 1 is selected from 5-6 membered heteroaryl, and C 1 Optionally substituted R d 、R e 、R f Preferably, C 1 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f replaced by at least one of;

[0176] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl and 4-7 membered saturated heterocyclic group are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0177] R d 、R e 、R f Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, The C3-C7 cycloalkyl group is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0178] Preferably, R d is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl;

[0179] Preferably, R d is selected from 4-7 membered saturated heterocyclic groups, wherein the 4-7 membered saturated heterocyclic groups are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0180] More preferably, R d Selected from C1-C6 alkyl,

[0181] Or more preferably, R d Selected from pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl, wherein the pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl is optionally substituted by 1-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl);

[0182] More preferably, R d Selected from p is selected from 0, 1, 2;

[0183] Or more preferably, R d Selected from pyrrolyl and piperidinyl, wherein the pyrrolyl and piperidinyl are optionally substituted by 1-2 groups selected from halogen and C1-C6 alkyl (preferably methyl);

[0184] R g is selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl;

[0185] More preferably, R d Selected from methyl, ethyl, isopropyl, Piperidinyl, More preferably, R d Selected from More preferably, R d Selected from

[0186] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;

[0187] Preferably, R e Selected from hydrogen, methyl, F3C-、 -NHCH3; preferably, R e Selected from hydrogen, methyl, F3C-、

[0188] Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl;

[0189] Preferably, R e 、R fTogether with the carbon atoms to which they are attached, they form Each R j Independently selected from hydrogen, C1-C6 alkyl, alkoxy (e.g., C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy;

[0190] More preferably, R e 、R f Together with the carbon atoms to which they are attached, they form

[0191] R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly connected, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms. Preferably, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl,

[0192] Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form

[0193] Most preferably, R 11 As a whole, selected from:

[0194] Most preferably, R 11 As a whole, selected from:

[0195] Most preferably, R 11 As a whole,

[0196] In the fourth aspect of the present invention, the present invention provides a compound of formula i-1-1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug,

[0197] in:

[0198] A 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by R k Preferably, A1 is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A 1 Selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring;

[0199] More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 The attachment site;

[0200] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g., 5-6 membered saturated heterocyclic group);

[0201] More preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0202] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0203] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0204] B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 Optionally substituted R a 、R b Preferably, B 1 Substituted group R a 、R b Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; More preferably, B 1 Selected from Pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b More preferably, B 1 Selected from Pyridyl, phenyl, and B 1 Substituted group R a 、R b replaced by at least one of;

[0205] More preferably, B 1 Selected from And B 1 Substituted group R a 、R b replaced by;

[0206] More preferably, B 1 Selected from And B 1 Substituted group R a 、R b Replaced by; R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl, the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl is optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted with C1-C6 alkyl, halogen, hydroxy, or cyano;

[0207] Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is morpholine, piperazine, or thiomorpholine;

[0208] R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo;

[0209] Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; further preferably, Cy2 is selected from pyrrolidinyl, and the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F groups;

[0210] Preferably, R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0211] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0212] Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0213] Preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);

[0214] m is selected from 0, 1, 2, 3; preferably, m is selected from 0, 1; n is selected from 0, 1, 2, 3; preferably, n is selected from 0, 1; p is selected from 0, 1, 2, 3; preferably, p is selected from 0, 1;

[0215] More preferably, R a Selected from hydrogen, cyano, carboxyl,

[0216] More preferably, R a Selected from hydrogen, cyano,

[0217] R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), Preferably, R b Selected from hydrogen, cyano,

[0218] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0219] Or, R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl);

[0220] Preferably, R a 、R b Together with the carbon atoms to which they are attached, they form Rc is selected from hydrogen, C1-C6 alkyl; preferably, R c Selected from C1-C6 alkyl;

[0221] Most preferably, B 1 As a whole, selected from:

[0222] Most preferably, B 1 As a whole, selected from:

[0223] Most preferably, B 1 As a whole, selected

[0224] L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Selected from direct bond, methylene, Preferably, L 1 Select from direct keys,

[0225] R 11 Selected from

[0226] C 1 is selected from 5-6 membered heteroaryl, and C 1 Optionally substituted R d 、R e 、R f Preferably, C 1 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted Rd 、R e 、R f replaced by at least one of;

[0227] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl and 4-7 membered saturated heterocyclic group are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0228] R d 、R e 、R f Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, The C3-C7 cycloalkyl group is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0229] Preferably, R d is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl;

[0230] Preferably, R d is selected from 4-7 membered saturated heterocyclic groups, wherein the 4-7 membered saturated heterocyclic groups are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl;

[0231] More preferably, R d Selected from C1-C6 alkyl,

[0232] Or more preferably, R d Selected from pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl, wherein the pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl is optionally substituted by 1-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl);

[0233] More preferably, Rd Selected from p is selected from 0, 1, 2;

[0234] Or more preferably, R d Selected from pyrrolyl and piperidinyl, wherein the pyrrolyl and piperidinyl are optionally substituted by 1-2 groups selected from halogen and C1-C6 alkyl (preferably methyl);

[0235] R g is selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl;

[0236] More preferably, R d Selected from methyl, ethyl, isopropyl, Piperidinyl,

[0237] More preferably, R d Selected from

[0238] More preferably, R d Selected from

[0239] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;

[0240] Preferably, R e Selected from hydrogen, methyl, F3C-、 -NHCH3;

[0241] Preferably, R e Selected from hydrogen, methyl, F3C-、

[0242] Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl;

[0243] Preferably, R e 、R f Together with the carbon atoms to which they are attached, they form

[0244] Each R jIndependently selected from hydrogen, C1-C6 alkyl, alkoxy (e.g., C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy;

[0245] More preferably, R e 、R f Together with the carbon atoms to which they are attached, they form

[0246] R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms;

[0247] Preferably, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl,

[0248] Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form

[0249] Most preferably, R 11 As a whole, selected from:

[0250] Most preferably, R 11 As a whole, selected from:

[0251] Most preferably, R 11 As a whole,

[0252] In a fifth aspect of the present invention, the present invention provides a compound of formula II, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0253] in:

[0254] A 2 is selected from a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is optionally substituted by R k Preferably, A 2is selected from a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least one heteroatom is a nitrogen atom, and the 6-membered heteroaromatic ring is optionally substituted by R k More preferably, A 2 is selected from 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k Further preferably, A 2 Selected from and Optionally substituted R k Replaced by, where #R 12 Indicates connection R 12 The connection site, $B 2 Indicates connection B 2 More preferably, A 2 Selected from Among them #R 12 Indicates connection R 12 The connection site, $B 2 Indicates connection B 2 The attachment site;

[0255] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclyl (e.g., 5-6 membered saturated heterocyclyl), 6-10 membered aryl, 5-10 membered heteroaryl;

[0256] Preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0257] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0258] More preferably, R kSelected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0259] B 2 is selected from 6-10 membered heteroaryl, and B 2 Optionally substituted R a 、R b Preferably, B 2 Substituted group R a 、R b Preferably, B 2 is selected from 9-membered heteroaryl groups, and B 2 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; More preferably, B 2 Selected from And B 2 Substituted group R a 、R b replaced by at least one of;

[0260] R a Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl); preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl); more preferably, R a Selected from hydrogen, cyano,

[0261] R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), Preferably, R b Selected from hydrogen, cyano,

[0262] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0263] Most preferably, B 2 As a whole, selected

[0264] R 12 Selected from

[0265] C 2 is selected from 5-6 membered heteroaryl, and C 2 Optionally substituted R d 、R e 、R f Preferably, C 2 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 2 Optionally substituted R d 、R e 、R f More preferably, C 2 is selected from pyrrolyl, oxazolyl, furyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C 2 Optionally substituted R d 、R e 、R f replaced by at least one of;

[0266] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, and the C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group is each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl;

[0267] Preferably, R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl, wherein the C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl are each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, formyl; more preferably, R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl; further preferably, R d Selected from piperazinyl;

[0268] Preferably, R e Selected from hydrogen, methyl, F3C-、

[0269] Most preferably, R 12 As a whole, selected from:

[0270] In a sixth aspect of the present invention, the present invention provides a compound of formula I, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0271] in:

[0272] A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k Further preferably, A is selected from and Optionally substituted R k Replaced by, where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site of; Further preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site;

[0273] More preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site;

[0274] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R qN-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0275] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0276] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0277] B is selected from any one of the groups (1) to (7):

[0278] (1) in:

[0279] R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0280] Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0281] m1 is selected from 0, 1, 2, 3; m1 is preferably 0; n1 is selected from 0, 1, 2, 3; n1 is preferably 0, 1;

[0282] More preferably, R 4 Selected from hydrogen,

[0283] R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano,

[0284] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0285] Preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0286] Preferably, R 5 is selected from hydrogen, cyano;

[0287] Most preferably, As a whole, selected

[0288] Most preferably, As a whole, selected

[0289] (2) in:

[0290] R 6 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl;

[0291] Preferably, R 6 Selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3;

[0292] More preferably, R 6 for

[0293] R 7 Selected from hydrogen, C1-C6 alkyl;

[0294] Most preferably, As a whole,

[0295] (3) in:

[0296] R 8 、R 9 、R 10 、R 11 Among them, any one is selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and the rest are hydrogen;

[0297] Preferably, R 8 、R 9 、R 10 、R 11 In, R 8 、R 9 or R 11 Selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), The rest are hydrogen; m3 is selected from 0, 1, 2, 3; n3 is selected from 0, 1, 2, 3;

[0298] Most preferably, As a whole, selected

[0299] (4) in:

[0300] R 12 Selected from hydrogen, C1-C6 alkyl;

[0301] Preferably, R 12 Selected from C1-C6 alkyl;

[0302] (5) in:

[0303] R 22 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 22Selected from hydrogen, m4 is selected from 0, 1, 2, 3; n4 is selected from 0, 1, 2, 3;

[0304] More preferably, R 22 Selected from hydrogen,

[0305] R 23 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl,

[0306] Preferably, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 Selected from hydrogen, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, cyano,

[0307] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0308] Most preferably, As a whole, selected

[0309] Most preferably, As a whole, selected Most preferably, As a whole, selected

[0310] (6) in:

[0311] R 24 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl;

[0312] Preferably, R 24 Selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3;

[0313] More preferably, R 24 for

[0314] (7) in:

[0315] R 25 Selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl;

[0316] Preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; n6 is selected from 0, 1, 2, 3;

[0317] More preferably, R 25 Selected from hydrogen, Preferably, R 25 is hydrogen;

[0318] R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl,

[0319] Most preferably, As a whole, selected

[0320] Most preferably, As a whole, selected

[0321] L 1 Selected from direct bond, C1-C6 alkyl,

[0322] Preferably, L 1 Select from direct keys, Preferably, L 1 Select from direct keys;

[0323] C is selected from any one of the groups (1) to (10):

[0324] (1) in:

[0325] R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl),

[0326] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, Rh 、R i Each is independently selected from hydrogen, methyl, isopropyl;

[0327] Preferably, R 13 Selected from trifluoromethyl, Preferably, R 13 Selected from More preferably, R 13 Selected from

[0328] R 14 Selected from C3-C6 cycloalkyl, piperidinyl, wherein the C3-C6 cycloalkyl and piperidinyl are optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl;

[0329] Preferably, R 14 is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (such as hydroxymethyl) and formyl; preferably, R 14 Selected from p is selected from 0, 1, 2; R g Selected from hydrogen, hydroxy C1-C6 alkyl, formyl;

[0330] Or, preferably, R 14 Selected from piperidinyl, the piperidinyl is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl);

[0331] More preferably, R 14 Selected from

[0332] Most preferably, As a whole, selected

[0333] Most preferably, As a whole, selected

[0334] Most preferably, As a whole, selected

[0335] (2) Where: R 15 Selected from C1-C6 haloalkyl; R 16 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0336] (3) Where: R 17 Selected from hydrogen, C1-C6 alkyl; preferably, As a whole,

[0337] (4) Where: R 18 is selected from hydrogen, C1-C6 alkyl; preferably, R 18 Selected from C1-C6 alkyl; most preferably, As a whole,

[0338] (5) Where: R 19 is selected from hydrogen, C1-C6 alkyl; preferably, R 19 Selected from C1-C6 alkyl; most preferably, As a whole,

[0339] (6) Where: R 20 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0340] (7) Where: R 27 Selected from phenyl, C3-C6 cycloalkyl; most preferably, As a whole, selected

[0341] (8) Where: R 28 is selected from 6-membered saturated heterocyclic groups; preferably, R 28 is morpholinyl; most preferably, As a whole,

[0342] (9) Where: R 29 Selected from C3-C6 alkyl; most preferably, As a whole,

[0343] (10) Where: R 30 Selected from C3-C6 cycloalkyl; R 31 Selected from C1-C6 alkyl; most preferably, As a whole,

[0344] In a seventh aspect of the present invention, the present invention provides a compound represented by formula I-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0345] in:

[0346] A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k replaced by;

[0347] More preferably, A is selected from and Optionally substituted R k Replaced by, where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site;

[0348] More preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site;

[0349] More preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site;

[0350] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R qN-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0351] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0352] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0353] B is selected from any one of the groups (1) to (7):

[0354] (1) in:

[0355] R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0356] Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3; m1 is preferably 0; n1 is selected from 0, 1, 2, 3; n1 is preferably 0, 1;

[0357] More preferably, R 4 Selected from hydrogen,

[0358] R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano,

[0359] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0360] Preferably, R 5 is selected from hydrogen, cyano;

[0361] Most preferably, As a whole, selected

[0362] Most preferably, As a whole, selected

[0363] (2) Where: R 6 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 6 Selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 for

[0364] R 7 Selected from hydrogen, C1-C6 alkyl;

[0365] Most preferably, As a whole,

[0366] (3) Where: R 8 、R 9 、R 10 、R 11 wherein any one is selected from cyano, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and the rest are hydrogen; preferably, R 8 、R 9 、R 10 、R 11 In, R 8 、R 9 or R 11 Selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), The rest are hydrogen; m3 is selected from 0, 1, 2, 3; n3 is selected from 0, 1, 2, 3;

[0367] Most preferably, As a whole, selected

[0368] (4) Where: R 12 is selected from hydrogen, C1-C6 alkyl; preferably, R 12 Selected from C1-C6 alkyl; (5) Where: R 22 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 22 Selected from hydrogen, m4 is selected from 0, 1, 2, 3; n4 is selected from 0, 1, 2, 3;

[0369] More preferably, R 22 Selected from hydrogen,

[0370] R 23 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 Selected from hydrogen, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, cyano,

[0371] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0372] Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected

[0373] (6) Where: R 24 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 24 Selected from m5 is selected from 0, 1, 2, 3;

[0374] n5 is selected from 0, 1, 2, 3; more preferably, R 24 for

[0375] (7) Where: R 25 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; n6 is selected from 0, 1, 2, 3;

[0376] More preferably, R 25 Selected from hydrogen, Preferably, R 25 is hydrogen;

[0377] R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl,

[0378] Most preferably, As a whole, selected Most preferably, As a whole, selected

[0379] L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Select from direct keys;

[0380] C is selected from any one of the groups (1) to (10):

[0381] (1) Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl),

[0382] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl;

[0383] Preferably, R 13 Selected from trifluoromethyl, Preferably, R 13 Selected from More preferably, R 13 Selected from

[0384] R 14 Selected from C3-C6 cycloalkyl, piperidinyl, wherein the C3-C6 cycloalkyl and piperidinyl are optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl;

[0385] Preferably, R 14 is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl) and formyl;

[0386] Preferably, R 14 Selected from p is selected from 0, 1, 2; R g Selected from hydrogen, hydroxy C1-C6 alkyl, formyl;

[0387] Or, preferably, R 14Selected from piperidinyl, the piperidinyl is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl);

[0388] More preferably, R 14 Selected from

[0389] Most preferably, As a whole, selected

[0390] Most preferably, As a whole, selected

[0391] Most preferably, As a whole, selected

[0392] (2) Where: R 15 Selected from C1-C6 haloalkyl; R 16 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0393] (3) Where: R 17 Selected from hydrogen, C1-C6 alkyl; preferably, As a whole,

[0394] (4) Where: R 18 is selected from hydrogen, C1-C6 alkyl; preferably, R 18 Selected from C1-C6 alkyl; most preferably, As a whole,

[0395] (5) Where: R 19 is selected from hydrogen, C1-C6 alkyl; preferably, R 19 Selected from C1-C6 alkyl; most preferably, As a whole,

[0396] (6) Where: R 20 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0397] (7) Where: R 27 Selected from phenyl, C3-C6 cycloalkyl; most preferably, As a whole, selected

[0398] (8) Where: R 28 is selected from 6-membered saturated heterocyclic groups; preferably, R 28 is morpholinyl; most preferably, As a whole,

[0399] (9) Where: R 29 Selected from C3-C6 alkyl; most preferably, As a whole,

[0400] (10) Where: R 30 Selected from C3-C6 cycloalkyl; R 31 Selected from C1-C6 alkyl; most preferably, As a whole,

[0401] In the eighth aspect of the present invention, the present invention provides a compound represented by formula I-1-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0402] in:

[0403] A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine, and the 2-pyridone is optionally substituted by R k Further preferably, A is selected from and Optionally substituted R k substituted, wherein #C represents the connection site for connecting C, $B represents the connection site for connecting B; further preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0404] More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0405] R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclyl (e.g., 5-6 membered saturated heterocyclyl), 6-10 membered aryl, 5-10 membered heteroaryl;

[0406] Preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;

[0407] R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl;

[0408] More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0409] B is selected from any one of the groups (1) to (7):

[0410] (1) Where: R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclic group, -NR Na R Nb (where R Na and RNb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl group may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl group and 4-9 membered saturated heterocyclyl group may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0411] Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); n1 is selected from 0, 1, 2, 3;

[0412] More preferably, R 4 Selected from hydrogen,

[0413] R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano, Preferably, R 5 Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0414] Most preferably, As a whole, selected

[0415] Most preferably, As a whole, selected

[0416] Most preferably, As a whole, selected

[0417] Most preferably, As a whole, selected

[0418] (2) Where: R 6 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 6 Selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 for

[0419] R 7 Selected from hydrogen, C1-C6 alkyl; most preferably, As a whole,

[0420] (3) Where: R 8 、R 9 、R 10 、R 11 wherein any one is selected from cyano, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and the rest are hydrogen; preferably, R 8 、R 9 、R 10 、R 11 In, R 8 、R 9 or R 11 Selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), The rest are hydrogen; m3 is selected from 0, 1, 2, 3; n3 is selected from 0, 1, 2, 3;

[0421] Most preferably, As a whole, selected

[0422] (4) Where: R 12 is selected from hydrogen, C1-C6 alkyl; preferably, R 12 Selected from C1-C6 alkyl;

[0423] (5) Where: R 22 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 22 Selected from hydrogen, m4 is selected from 0, 1, 2, 3; m4 is preferably 0; n4 is selected from 0, 1, 2, 3; n4 is preferably 0, 1; more preferably, R 22 Selected from hydrogen,

[0424] R 23 Selected from hydrogen, C1-C6 alkyl, cyano, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, and the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl);

[0425] Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is morpholine, piperazine, or thiomorpholine;

[0426] R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo;

[0427] Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and the pyrrolidinyl, imidazolidinyl, piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; preferably, R 23 Selected from hydrogen, C1-C6 alkyl, cyano,

[0428] Preferably, R 23 Selected from hydrogen, cyano, Preferably, R 23 Selected from hydrogen, cyano,

[0429] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0430] Most preferably, As a whole, selected

[0431] Most preferably, As a whole, selected

[0432] Most preferably, As a whole, selected

[0433] (6) in:

[0434] R 24 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 24 Selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3; more preferably, R 24 for

[0435] (7) Where: R 25 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; m6 is preferably 0; n6 is selected from 0, 1, 2, 3; n6 is preferably 0, 1; more preferably, R 25 Selected from hydrogen,

[0436] R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 Selected from hydrogen, cyano,

[0437] Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected

[0438] C is selected from any one of the groups (1) to (11):

[0439] (1) Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl;

[0440] Preferably, R 13 Selected from More preferably, R 13 Selected from

[0441] R 14 is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (eg hydroxymethyl), formyl; or R 14is selected from phenyl, morpholinyl, piperazinyl, piperidinyl, wherein the phenyl, morpholinyl, piperazinyl, piperidinyl is optionally substituted with 1-2 substituents selected from C1-C6 alkyl, halogen, alkoxy (e.g. C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g. hydroxymethyl), amino C1-C6 alkyl, formyl. Preferably, R 14 Selected from p is selected from 0, 1, 2; or preferably, R 14 Selected from piperidinyl, the piperidinyl is optionally substituted by 1-2 substituents selected from C1-C6 alkyl (preferably methyl), halogen, hydroxyl, amino

[0442] R g Selected from hydrogen, hydroxy C1-C6 alkyl, formyl;

[0443] More preferably, R 14 Selected from

[0444] More preferably, R 14 Selected from

[0445] Most preferably, As a whole, selected

[0446] Most preferably, As a whole, selected

[0447] Most preferably, As a whole, selected

[0448] (2) Where: R 15 Selected from C1-C6 haloalkyl; R 16 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0449] (3) Where: R 17 Selected from hydrogen, C1-C6 alkyl; preferably, As a whole,

[0450] (4) Where: R 18 is selected from hydrogen, C1-C6 alkyl; preferably, R 18 Selected from C1-C6 alkyl; most preferably, As a whole,

[0451] (5) Where: R 19 is selected from hydrogen, C1-C6 alkyl; preferably, R 19 Selected from C1-C6 alkyl; most preferably, As a whole,

[0452] (6) Where: R 20 Selected from C3-C6 cycloalkyl; most preferably, As a whole,

[0453] (7) Where: R 27 Selected from phenyl, C3-C6 cycloalkyl; most preferably, As a whole, selected

[0454] (8) Where: R 28 is selected from 6-membered saturated heterocyclic groups; preferably, R 28 is morpholinyl; most preferably, As a whole,

[0455] (9) Where: R 29 Selected from C3-C6 alkyl; most preferably, As a whole,

[0456] (10) Where: R 30 Selected from C3-C6 cycloalkyl; R 31 Selected from C1-C6 alkyl; most preferably, As a whole,

[0457] (11) Where: R 32 is selected from phenyl, C3-C6 cycloalkyl; R 33 is selected from C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl, difluoromethyl); most preferably, As a whole, selected

[0458] In the ninth aspect of the present invention, the present invention provides a compound of formula II, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0459] in:

[0460] A is selected from a 5-membered heteroaromatic ring; preferably, A is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A is selected from a 1,2,3-triazole ring, an imidazole ring; most preferably, A is selected from Among them #R 31 Indicates the attachment site of the carbonyl group, $B 11 represents the attachment site for joining the fused-ring bicyclic ring;

[0461] R 2 、R 3 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0462] Or, R 2 、R 3 Together with the nitrogen atom to which they are connected, they form a 6-membered saturated heterocyclic group. Preferably, the 6-membered saturated heterocyclic group contains 2 heteroatoms, and the heteroatoms are nitrogen atoms. Preferably, R 2 、R 3 are each independently selected from hydrogen, methyl, ethyl, isopropyl,

[0463] Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form

[0464] Most preferably, Overall selection

[0465] R 21 Selected from C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl;

[0466] Preferably, R 21 Selected from m7 is selected from 0, 1, 2, 3; n7 is selected from 0, 1, 2, 3;

[0467] More preferably, R 21 Selected from

[0468] In the tenth aspect of the present invention, the present invention provides a compound of formula III, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula III,

[0469] in:

[0470] A is selected from wherein #C represents the connection site for connecting C, $B represents the connection site for connecting B; further preferably, A is selected from wherein #C represents the attachment site for connecting C, $B represents the attachment site for connecting B; most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0471] B is Where: R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclic group, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl);

[0472] Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3; n1 is selected from 0, 1, 2, 3; preferably n1 is 0; more preferably, R 4 Selected from hydrogen,

[0473] More preferably, R 4 Selected from hydrogen,

[0474] R 5 Selected from hydrogen, cyano, C1-C6 alkyl, R m 、R I Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R m 、R I are independently selected from hydrogen, methyl, isopropyl; preferably, R 5 is selected from hydrogen, cyano;

[0475] Preferably, As a whole, selected

[0476] More preferably, As a whole, selected

[0477] More preferably, As a whole, selected

[0478] C is Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl),

[0479] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i are independently selected from hydrogen, methyl, isopropyl; preferably, R 13 Selected from C1-C6 haloalkyl (e.g. difluoromethyl);

[0480] Preferably, R 13 Selected from More preferably, R 13 Selected from

[0481] R 14Selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);

[0482] Preferably, R 14 Selected from Piperidinyl, the piperidinyl is optionally substituted with 1-2 C1-C6 alkyl (preferably methyl) substituents; p is selected from 0, 1, 2; preferably, p is 2;

[0483] R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen;

[0484] More preferably, R 14 Selected from

[0485] More preferably, R 14 Selected from

[0486] Most preferably, As a whole, selected

[0487] Most preferably, As a whole, selected

[0488] In the eleventh aspect of the present invention, the present invention provides a compound of formula IV, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula IV,

[0489] in:

[0490] A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0491] More preferably, A is selected from wherein #C represents the attachment site for connecting C, $B represents the attachment site for connecting B; most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0492] B is Where: R 22 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 22 Selected from hydrogen,

[0493] m4 is selected from 0, 1, 2, 3; preferably, m4 is selected from 0; n4 is selected from 0, 1, 2, 3; preferably, n4 is selected from 0, 1;

[0494] More preferably, R 22 Selected from hydrogen,

[0495] R 23 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, carboxyl,

[0496] R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0497] Most preferably, As a whole, selected

[0498] C is Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl),

[0499] R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl;

[0500] Preferably, R 13 is selected from C1-C6 haloalkyl (eg difluoromethyl); preferably, R 13 Selected from More preferably, R 13 Selected from

[0501] R 14 Selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);

[0502] Preferably, R 14 Selected from Piperidinyl, the piperidinyl is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl) substituents; p is selected from 0, 1, 2; preferably, p is 2; R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen;

[0503] More preferably, R 14 Selected from

[0504] More preferably, R 14 Selected from

[0505] Most preferably, As a whole, selected

[0506] Most preferably, As a whole, selected

[0507] In the twelfth aspect of the present invention, the present invention provides a compound of formula V, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound (deuterated compound), metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein the structural formula of the compound is formula V,

[0508] in:

[0509] A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0510] More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0511] Most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B;

[0512] B is Where: R 25 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 25 Selected from hydrogen,

[0513] m6 is selected from 0, 1, 2, 3; preferably, m6 is 0; n6 is selected from 0, 1, 2, 3; preferably, n6 is 0, 1;

[0514] More preferably, R 25 Selected from hydrogen,

[0515] R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, cyano, carboxyl,

[0516] Most preferably, As a whole, selected

[0517] Most preferably, As a whole, selected

[0518] C is Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl;

[0519] Preferably, R 13 is selected from C1-C6 haloalkyl (eg difluoromethyl); preferably, R 13 Selected from

[0520] More preferably, R 13 Selected from

[0521] R 14Selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);

[0522] Preferably, R 14 Selected from Piperidinyl, which is optionally substituted with 1-2 C1-C6 alkyl (preferably methyl) substituents;

[0523] p is selected from 0, 1, 2; preferably, p is 2;

[0524] R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen;

[0525] More preferably, R 14 Selected from

[0526] More preferably, R 14 Selected from

[0527] Most preferably, As a whole, selected

[0528] Most preferably, As a whole, selected

[0529] In the thirteenth aspect of the present invention, the present invention provides a compound represented by formula VI-1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VI-1,

[0530] wherein B and C are as defined in any one of the first to twelfth aspects of the present invention.

[0531] In the fourteenth aspect of the present invention, the present invention provides a compound represented by formula VI-2 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VI-2,

[0532] wherein B and C are as defined in any one of the first to twelfth aspects of the present invention.

[0533] In the fifteenth aspect of the present invention, the present invention provides a compound of formula VII-1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-1,

[0534] Among them, A, B, R d 、R e 、R f is as defined in any one of the first to twelfth aspects of the present invention.

[0535] In the sixteenth aspect of the present invention, the present invention provides a compound of formula VII-1-1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-1-1,

[0536] Among them, A, B, R e 、R f 、R g , and p are defined as in the fifteenth aspect of the present invention.

[0537] In the seventeenth aspect of the present invention, the present invention provides a compound of formula VII-1-2 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VII-1-2,

[0538] Each R x independently selected from halogen, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkyl, cyano, s is selected from 0, 1, 2, 3, or two R x The C atom to which it can be connected forms a C1-C6 cycloalkyl group, R y Selected from H, C1-C6 alkyl, A, B, R e 、R f is defined as in the fifteenth aspect of the present invention.

[0539] In the eighteenth aspect of the present invention, the present invention provides a compound of formula VII-2-1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-2-1,

[0540] Among them, B, R e 、R f 、R g , and p are defined as in the sixteenth aspect of the present invention.

[0541] In the nineteenth aspect of the present invention, the present invention provides a compound of formula VII-2-2 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-2-2,

[0542] Among them, B, R e 、R f 、R x 、R y The definitions of s are as defined in the seventeenth aspect of the present invention.

[0543] In the twentieth aspect of the present invention, the present invention provides a compound of formula VII-3-1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-3-1,

[0544] Among them, A, R d 、R e 、R f 、R a 、R b is defined as in the fifteenth aspect of the present invention.

[0545] In the twenty-first aspect of the present invention, the present invention provides a compound of formula VII-3-2 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-3-2,

[0546] Among them, A, R d 、R e 、R f 、R a 、R b The definition is as defined in the fifteenth aspect of the present invention.

[0547] In the twenty-second aspect of the present invention, the present invention provides a compound of formula VII-3-3 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is formula VII-3-3,

[0548] Among them, A, R d 、R e 、R f 、R a 、R b is defined as in the fifteenth aspect of the present invention.

[0549] In the twenty-third aspect of the present invention, the present invention provides a compound of formula VIII-1 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is the compound of formula VIII-1,

[0550] where R d 、R e 、R f 、R a 、R b The definition of is as defined in any one of the first to twelfth aspects of the present invention.

[0551] In the twenty-fourth aspect of the present invention, the present invention provides a compound of formula VIII-2 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is the compound of formula VIII-2,

[0552] where R d 、R e 、R f 、R a 、R b is as defined in any one of the first to twelfth aspects of the present invention.

[0553] In the twenty-fifth aspect of the present invention, the present invention provides a compound of formula VIII-3 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is the compound of formula VIII-3,

[0554] where R d 、R e 、R f 、R a 、R b is as defined in any one of the first to twelfth aspects of the present invention.

[0555] In some embodiments, the compound is selected from:

[0556] In some embodiments, the compound is selected from:

[0557] In the twenty-sixth aspect of the present invention, the present invention provides a method for preparing a compound of formula A as described in any one of the above aspects of the present invention, wherein A in formula A is The method comprises:

[0558] Compound A-1-B1 undergoes a halogenation reaction to obtain compound A-1-B2, compound A-1-B2 undergoes a substitution reaction to obtain compound A-1-B3, and compound A-1-B3 and compound A-1-C1 undergo a cyclization reaction to obtain compound A-1;

[0559] Wherein X1 is halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, and C are as described in any one of the first to twenty-fifth aspects of the present invention.

[0560] In the twenty-seventh aspect of the present invention, the present invention provides a method for preparing compound AC-1, comprising:

[0561] Compound A-1-C1 is subjected to nitration reaction to obtain compound A-1-C2, compound A-1-C2 is subjected to reduction reaction to obtain compound A-1-C3, and compound A-1-C3 is subjected to azidation reaction to obtain compound AC-1, R d 、R e 、R f The ranges of and C are as described in any one of the first to twenty-fifth aspects of the present invention.

[0562] In the twenty-eighth aspect of the present invention, the present invention provides a method for preparing the compound of formula A according to any one of the above aspects of the present invention, wherein A is The method comprises:

[0563] Compound A-2-B1 is subjected to coupling reaction to obtain compound A-2-B2, and compound A-2-B2 and compound A-2-C2 are subjected to coupling reaction to obtain compound A-2, wherein X2 and X3 are each independently halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, and C are as described in any one of the first to twenty-fifth aspects of the present invention.

[0564] In the twenty-ninth aspect of the present invention, the present invention provides a method for preparing compound A-2-C2, comprising:

[0565] Compound A-2-C1 is subjected to halogenation reaction to obtain compound A-2-C2, wherein X3 is halogen (such as Cl, Br, I), R d 、R e 、R f, C as described in any one of the first to twenty-fifth aspects of the present invention.

[0566] In the thirtieth aspect of the present invention, the present invention provides a method for preparing the compound of formula A according to any one of the first to twenty-fifth aspects of the present invention, characterized in that: in formula A, A is The method comprises:

[0567] Compound A-3-C1 is subjected to cyanation reaction to obtain compound A-3-C2, which is then subjected to cyclization reaction with A-3-B2 to obtain A-3

[0568] Wherein X4 is halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, and C are as described in any one of the first to twenty-fifth aspects of the present invention.

[0569] In the thirty-first aspect of the present invention, the present invention provides a method for preparing compound A-3-B2, comprising:

[0570] Compound A-3-B1 is acylated to obtain compound A-3-B2, wherein R a 、R b , B as described in claims 1-27.

[0571] In the thirty-second aspect of the present invention, the present invention provides a pharmaceutical composition comprising the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, and optional pharmaceutically acceptable excipients.

[0572] In the thirty-third aspect of the present invention, the present invention provides a PROTAC molecule comprising: a warhead portion, a ligase binding portion and a linker, wherein the warhead portion is divided into the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, and the linker is covalently linked to the warhead portion and the ligase binding portion, respectively.

[0573] In some embodiments, the ligase binding moiety is an E3 ubiquitin ligase binding moiety.

[0574] In the thirty-fourth aspect of the present invention, the present invention provides the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, or the aforementioned pharmaceutical composition, or the use of the aforementioned PROTAC molecule in the preparation of a medicament for treating and / or preventing a disease associated with IRAK4 kinase.

[0575] In some embodiments, the disease associated with IRAK4 kinase is cancer or an autoimmune disease.

[0576] In some embodiments, the autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, ulcerative colitis, irritable bowel syndrome, or any combination thereof.

[0577] In some embodiments, the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.

[0578] In the thirty-fifth aspect of the present invention, the present invention provides the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, or the aforementioned pharmaceutical composition, or the aforementioned PROTAC molecule, for treating and / or preventing diseases associated with IRAK4 kinase.

[0579] In some embodiments, the disease associated with IRAK4 kinase is cancer or an autoimmune disease.

[0580] In some embodiments, the autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, ulcerative colitis, irritable bowel syndrome, or any combination thereof.

[0581] In some embodiments, the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.

[0582] In the thirty-sixth aspect of the present invention, the present invention provides a method for treating and / or preventing a disease associated with IRAK4 kinase, comprising: administering to a subject an effective amount of the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, or the aforementioned pharmaceutical composition, or the aforementioned PROTAC molecule.

[0583] In some embodiments, the disease associated with IRAK4 kinase is cancer or an autoimmune disease.

[0584] In some embodiments, the autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, ulcerative colitis, irritable bowel syndrome, or any combination thereof.

[0585] In some embodiments, the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof. DETAILED DESCRIPTION

[0586] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[0587] In the present invention, unless otherwise explicitly stated, the description method "... are independently selected from" used throughout this document can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0588] The substituents of the compounds of the present invention are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0589] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including both branched and straight-chain groups, having a specified number of carbon atoms. For example, a "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably a "C1-C4 alkyl," and more preferably a "C1-C3 alkyl." Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0590] The term "cycloalkyl" refers to a saturated hydrocarbon monovalent ring containing 3-15 ring carbon atoms or 3-10 ring carbon atoms, for example, "C3-C7 cycloalkyl", "C4-C9 cycloalkyl", "C3-C6 cycloalkyl", etc. The cycloalkyl group may be in the form of a single ring, a fused ring, a bridged ring, or a spiro ring. Exemplary cycloalkyl groups include, but are not limited to, the following:

[0591] etc. Examples of the term "C3-C6 cycloalkyl" include

[0592] Halogen refers to fluorine, chlorine, bromine or iodine.

[0593] The term "heteroalkyl" refers to a group formed by replacing one or more backbone carbon atoms of any alkyl group described above (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) with a heteroatom (N, O or S).

[0594] The term "alkoxy" refers to any alkyl group as described above (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) connected to the remaining structural part of the molecule through an O atom, examples of which are C1-C6 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, and specific examples are methoxy, ethoxy, etc.

[0595] The term "C1-C6 haloalkyl" refers to a group in which one or more hydrogen atoms in any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) are replaced by halogen (preferably fluorine or chlorine), for example, monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, etc.

[0596] The terms "6-10 membered aryl" and "6-10 membered aromatic ring" are used interchangeably and refer to an aromatic 6-10 membered monocyclic or bicyclic group, with specific examples being phenyl and naphthyl, preferably phenyl.

[0597] The heteroatom refers to N, O or S.

[0598] The terms "heteroaryl" and "heteroaromatic ring" are used interchangeably and refer to substituted and unsubstituted aromatic 5- or 6-membered monocyclic radicals, 8-, 9- or 10-membered bicyclic radicals, and 11- to 14-membered tricyclic radicals having at least one heteroatom (N, O, or S) in at least one ring, the heteroatom-containing ring optionally further having 1, 2, or 3 heteroatoms selected from N, O, or S. Among them, substituted and unsubstituted aromatic 8-, 9- or 10-membered bicyclic radicals and 11- to 14-membered tricyclic radicals having at least one heteroatom (N, O, or S) in at least one ring are "fused heteroaryls" or "fused heteroaromatic rings." Heteroaromatic radicals or heteroaromatic rings that are bicyclic or tricyclic require a bicyclic or tricyclic overall structure to form an aromatic system. The heteroaryl radical or heteroaromatic ring may be attached at any available nitrogen or carbon atom of either ring. It will be understood by those skilled in the art that two adjacent atoms (preferably carbon atoms) are shared between each two rings in the fused ring.

[0599] Exemplary monocyclic heteroaryl groups or monocyclic heteroaromatic rings include, but are not limited to, pyrrolyl / ring, pyrazolyl / ring, imidazolyl / ring, oxazolyl / ring, isoxazolyl / ring, thiazolyl / ring, thiadiazolyl / ring, isothiazolyl / ring, furanyl / ring, thienyl / ring, oxadiazolyl / ring, pyridinyl / ring, pyrazinyl / ring, pyrimidinyl / ring, pyridazinyl / ring, triazinyl / ring, triazolyl / ring, pyridazinyl / ring, 2-pyridone, and the like.

[0600] Exemplary bicyclic heteroaryl groups include, but are not limited to, indolyl, 5-azaindolyl, pyrrolo[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridinyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridinyl, isoindolyl, and the like, preferably as benzothiazolyl.

[0601] Exemplary "9-membered heteroaryl" include, but are not limited to wait.

[0602] The terms "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered (preferably 4-7 members, more preferably 5-6 members) monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, which may contain one or more double bonds but do not constitute aromatic rings; wherein at least one ring has at least one heteroatom (N, O, or S). The fused, bridged, or spirocyclic rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated or partially saturated but do not constitute aromatic rings. The heterocyclic group may be attached at any available nitrogen or carbon atom. Exemplary heterocyclic examples include, but are not limited to, the following:

[0603] Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepanyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, and the like, preferably as

[0604] Wherein, "saturated heterocyclic group" refers to the heterocyclic ring defined above that does not contain unsaturated bonds, such as double bonds. For example, examples of "4-9 membered saturated heterocyclic rings" include but are not limited to hexahydropyrimidine, hexahydropyrazine,

[0605] For example, examples of "6-membered saturated heterocyclic group" include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, hexahydropyrimidinyl, and hexahydropyrazinyl.

[0606] From all of the above descriptions, it is obvious to those skilled in the art that any group whose name is a composite name, such as "hydroxy C1-C6 alkyl," should refer to a group conventionally constructed from its derived portion from left to right, such as "C1-C6 alkyl" substituted with a hydroxy group, where "C1-C6 alkyl" is as defined above. Specifically, "hydroxy C1-C6 alkyl" can be, for example, a hydroxymethyl group. Other similar composite groups can be understood with reference to the above.

[0607] The term "direct bond" refers to the direct connection of the groups on both sides. For example, the structure shown in formula A In, if L 1 is a direct bond, then the structural formula shown in formula A is

[0608] The term "substituted" or "substituted with a substituent" means that any one or more hydrogens on the designated atom or group are replaced with the selection of the designated group, provided that the normal valence of the designated atom is not exceeded.

[0609] "B is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B is substituted by R a 、R b "Substituted" means that B may be a 6-10 membered heteroaryl group, and the 6-10 membered heteroaryl group is substituted by two substituents, namely, substituents R a 、R b B can also be a 6-10 membered aryl group, and the 6-10 membered aryl group is substituted by two substituents, namely, substituents R a 、R b and the substituents of the 6-10 membered heteroaryl and the 6-10 membered aryl are independent of each other and do not affect each other, that is, the substituents of the 6-10 membered heteroaryl and the substituents of the 6-10 membered aryl can be the same or different. a 、R b If all are hydrogen, then those skilled in the art will understand that the 6-10 membered heteroaryl or the 6-10 membered aryl is not substituted. Other similar definitions can be understood with reference to the above content.

[0610] “R d "C3-C6 cycloalkyl group is optionally substituted with a substituent selected from hydroxyC1-C6 alkyl group (e.g., hydroxymethyl group) and formyl group" means that the C3-C6 cycloalkyl group may be unsubstituted or substituted with a substituent selected from hydroxyC1-C6 alkyl group (e.g., hydroxymethyl group) and formyl group. Other similar definitions can be understood with reference to the above content.

[0611] "B is phenyl, and B is substituted by R a 、R b Replaced by", and "R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituent is selected from C1-C6 alkyl (such as tert-butyl)". a 、R b and R a 、R b The two adjacent carbon atoms on the benzene rings connected together form a 5-membered heterocyclic ring, and the 5-membered heterocyclic ring may be unsubstituted or substituted at any position by a substituent selected from C1-C6 alkyl (such as tert-butyl). For example, if B is phenyl, B is substituted by R a 、R b Replaced by, and R a、R b Together with the carbon atoms to which they are attached, they form substituted or unsubstituted When the substituent is tert-butyl, it means that B as a whole can be Can also be etc., among which, The dotted double bond in represents the site where the 5-membered heterocycle is fused to the benzene ring. Other similar definitions can be understood with reference to the above content.

[0612] "C is selected from 5-6 membered heteroaryl, and C is optionally substituted by R d 、R e 、R f "Replaced by at least one of" means that C may be unsubstituted or substituted. When substituted, the substituent may be only R d 、R e or R f , the substituent can also be R d 、R e 、R f The combination of any two of the substituents can also be R d 、R e and R f Other similar definitions can be understood by referring to the above content.

[0613] “R 1 for And "R 2 、R 3 Together with the nitrogen atoms to which they are attached, they form a 6-membered saturated heterocyclic group”, which means that R 2 、R 3 and R 2 、R 3 The N atoms connected together form a 6-membered saturated heterocyclic group. For example, if the 6-membered saturated heterocyclic group is Then the 1st N atom is the same as R 2 、R 3 Commonly connected N atoms.

[0614] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0615] In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0616] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the individual's disease state, age, sex and weight, and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Usually, but not necessarily, since a prophylactic dose is used for a subject before the onset of the disease or in the early stages of the disease, the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0617] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[0618] The pharmaceutical composition of the present invention can be prepared into various forms according to different routes of administration. For example, the pharmaceutical composition can be administered by any of the following methods: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or administration via an explanted reservoir. Oral and intravenous administration are preferred.

[0619] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, and the dosage and ratio of each can be adjusted by those skilled in the art according to the specific disease and patient conditions and clinical needs.

[0620] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only through this reaction under biological conditions, or they have no or only low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0621] When the stereoisomers in the compounds described herein are specifically designated as (R)- or (S)-isomers in the chemical name, it should be understood that the predominant configuration is the (R)-isomer or the (S)-isomer, respectively. Any asymmetric carbon atom may be present in the (R)-, (S)-, or (R, S)-configuration, preferably in the (R)- or (S)-configuration.

[0622] The compounds described herein include all possible tautomers of all compounds described herein. The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions, such as the very typical enol-keto tautomers.

[0623] The compounds described herein include all possible isotopically labeled compounds of all compounds described herein. The term "isotopically labeled compound" refers to a compound wherein any atom in the compound is replaced by an isotope thereof.

[0624] "Solvate" or "solvate" are used interchangeably to refer to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate" such as a monohydrate or dihydrate is formed, or it may include any amount of water; for example, when the solvent is an alcohol such as methanol or ethanol, an "alcoholate" may be formed, which may also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e., a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.

[0625] As used herein, the term "metabolite" refers to a derivative of a compound formed when the compound is metabolized. The term "metabolism" refers to the sum of processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions).

[0626] As used herein, the term "ester" refers to an ester formed between the -COOH group present in the compounds provided herein and a suitable alcohol, or an ester formed between the -OH group present in the compounds provided herein and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearic acid esters, or palmitates. Esters can undergo hydrolysis in the presence of an acid or base to produce the corresponding acid or alcohol.

[0627] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided herein with a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. and (ii) salts formed by basic functional groups (e.g., -NH2) present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), including but not limited to hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0628] As used herein, the term "crystalline form" refers to the crystal structure of a substance. During crystallization, various factors may alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms within the crystal lattice space, forming different crystal structures. The compounds of the present invention may exist in a single crystal structure or in multiple crystal structures, i.e., they may exhibit "polymorphism." The compounds of the present invention may exist in different crystalline forms.

[0629] Example

[0630] The present invention also provides methods for preparing corresponding compounds. A variety of synthetic methods can be used to prepare the compounds described herein, including the following methods. The compounds of the present invention or pharmaceutically acceptable salts, isomers or hydrates thereof can be synthesized using the following methods in combination with synthetic methods known in the field of organic chemical synthesis, or by variations of these methods understood by those skilled in the art. Preferred methods include but are not limited to the following methods.

[0631] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail with reference to specific examples below. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention. If the specific technology or conditions are not specified in the examples, they shall be carried out in accordance with the technology or conditions described in the literature in this field or in accordance with the product instructions. The reagents or instruments used without indicating the manufacturer are all conventional products that can be obtained commercially. The term "and / or" used herein includes any and all combinations of one or more related listed items. The examples provided below can better illustrate the present invention. Unless otherwise specified, all temperatures are ℃. The naming of some compounds in this application is obtained according to the chemdraw naming translation.

[0632] Example 1:

[0633] Synthesis of (1R,4R)-5-(3-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1A)

[0634] 1) Preparation of compound 1-2 in the first step

[0635] At room temperature, compound 1-1 (5.00 g, 52.04 mmol) and N,N-dimethylformamide (100 mL) were added to a three-necked flask and stirred until dissolved. Bromocyclohexane (12.7 g, 78.1 mmol) and potassium carbonate (14.4 g, 104 mmol) were added sequentially, and the reaction solution was stirred at 100°C for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate (300 mL × 3), washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to obtain compound 1-2 (1.3 g). LC-MS: m / z: 179.0 (M+H) +

[0636] 2) Preparation of the second step compound 1-3

[0637] At room temperature, compound 1-2 (1.30 g, 7.29 mmol) and dichloromethane (20 mL) were added to a three-necked flask and stirred thoroughly. Diethylaminosulfur trifluoride (10.58 g, 65.65 mmol) was added dropwise under an ice bath. The reaction solution was stirred for 16 hours and slowly returned to room temperature. The reaction solution was slowly added to ice water, the acidity and base were adjusted to neutral with sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (20 mL × 1), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by column chromatography (0-30% dichloromethane / petroleum ether) to obtain compound 1-3 (1 g). LC-MS: m / z: 201.0 (M+H) +

[0638] 3) Preparation of the third step compound 1-4

[0639] Under ice bath cooling, compound 1-3 (1.00 g, 4.99 mmol) was added to a single-necked flask, concentrated sulfuric acid (5 mL) was added and stirred evenly, and concentrated nitric acid was added to the reaction solution. The reaction solution was stirred at 0°C for 5 minutes, heated to 120°C and reacted for 2 hours. The reaction solution was slowly added to ice water, the acidity and base were adjusted to neutral with sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (10 mL × 1), and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure, and the residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain compound 1-4 (700 mg). LC-MS: m / z: 246.0 (M+H) + .

[0640] 4) Preparation of the fourth step compound 1-5

[0641] At room temperature, compound 1-4 (700 mg, 2.85 mmol) was added to a single-necked flask, and ethanol (10 mL) was added and stirred until dissolved. 100 mg of palladium on carbon (10%) was added to the reaction solution, and the system was replaced with hydrogen three times. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filter cake was rinsed with ethyl acetate (10 mL × 3). The filtrate was concentrated under reduced pressure, and the product 1-5 (600 mg) was directly used in the next reaction. LC-MS: m / z: 216.0 (M+H) + .

[0642] 5) Step 5: Preparation of Compound 1-6

[0643] Under ice bath, compound 1-5 (600 mg, 2.79 mmol) and acetonitrile (5 mL) were added to a three-necked flask and stirred evenly. The system was replaced with nitrogen three times, tert-butyl nitrite (431.18 mg, 4.18 mmol) was added, and the reaction solution was stirred under ice bath for 0.5 hours. Azide trimethylsilane (642.30 mg, 5.58 mmol) was added. The reaction solution was stirred for 16 hours and slowly returned to room temperature. Water was added to the reaction solution, extracted with dichloromethane (20 mL × 3), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by column chromatography (0-5% ethyl acetate / petroleum ether) to obtain compound 1-6 (400 mg). LC-MS: m / z: 241.9 (M+H) + .

[0644] 6) Step 6 Preparation of Compound 1-8

[0645] At room temperature, compound 1-7 (3.02 g, 19.54 mmol) was added to a single-necked flask, followed by acetonitrile (30 mL) and stirring until dissolved. N,N-diisopropylethylamine (6.89 g, 53.28 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.41 g, 17.76 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 60°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (30-60% ethyl acetate / petroleum ether) to afford compound 1-8 (3.84 g).

[0646] LC-MS: m / z: 217.1 (M+H) + .

[0647] 7) Step 7 Preparation of Compound 1-9

[0648] At room temperature, compound 1-8 (1.02 g, 4.62 mmol) and acetonitrile (10 mL) were added to a single-necked flask and stirred until dissolved. N-iodosuccinimide (1.56 g, 6.94 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction solution was quenched by adding a saturated aqueous sodium thiosulfate solution (20 ml), it was extracted twice with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (30-80% ethyl acetate / petroleum ether) to obtain compound 1-9 (1.4 g). LC-MS: m / z: 343.0 (M+H) + .

[0649] 8) Step 8 Preparation of Compound 1-10

[0650] At room temperature, compound 1-9 (1.00 g, 2.93 mmol) was added to a single-necked flask, and tetrahydrofuran (10 mL) was added and stirred until dissolved. Trimethylethynylsilane (285 mg, 2.93 mmol), triethylamine (1.25 mL, 8.77 mmol), cuprous iodide (55.1 mg, 0.29 mmol), and bistriphenylphosphine palladium dichloride (205 mg, 0.29 mmol) were added, and the nitrogen atmosphere was purged three times. The reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (200 mL). The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was dissolved in methanol (10 ml), and potassium carbonate (810 mg, 5.85 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to obtain compound 1-10 (800 mg). LC-MS: m / z: 241.1 (M+H) + .

[0651] 9) Step 9: Preparation of Compound 1A

[0652] At room temperature, compound 1-10 (100 mg, 0.41 mmol) and compound 1-6 (100.41 mg, 0.41 mmol) were added to a single-necked flask, and ethanol (5 mL) and water (2 mL) were added and stirred until dissolved. Sodium ascorbyl palmitate (8.21 mg, 0.04 mmol) and copper sulfate pentahydrate (10.35 mg, 0.04 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 18 hours. Water was added to the reaction solution, extracted twice with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%-95%, flow rate: 25mL / min) to prepare compound 1A (7mg). 1H NMR(400MHz,DMSO-d6)δ8.72(d,J=7.7Hz,1H),8.66(s,1H),8.35(s,1H),7.21(t,J=53 .2Hz,1H),6.57(d,J=152.0Hz,1H),5.13(d,J=102.1Hz,1H),4.74(s,1H),4.39–4.22( m,1H),3.74(dd,J=68.0,26.5Hz,5H),2.10(d,J=14.7Hz,2H),1.96(d,J=13.7Hz,2H), 1.89–1.63(m,5H),1.43(q,J=12.8Hz,2H),1.33–1.16(m,1H).LC-MS:m / z:482.2(M+H) + .

[0653] Example 2

[0654] Preparation of (1R,4R)-5-(3-(1'-cyclohexyl-3'-(difluoromethyl)-1'-[1,4'-bipyrazol]-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (2A)

[0655] 1) Preparation of compound 2-1

[0656] Under ice bath, compound 1-3 (700 mg, 3.50 mmol) was added to a single-necked flask, and dichloromethane (15 mL) was added and stirred until dissolved. N-bromosuccinimide (933 mg, 5.24 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 24 hours. Water was added to the reaction solution, extracted with dichloromethane (20 mL × 2), washed with saturated brine (10 mL × 1), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by column chromatography (0-2% dichloromethane / petroleum ether) to obtain compound 2-1 (400 mg). LC-MS: m / z: 279.0 (M+H) +

[0657] 2) Preparation of the second step compound 2-3

[0658] To a solution of compound 2-2 (1.00 g, 4.30 mmol) in N,N-dimethylformamide (15 mL) were added N,N-diisopropylethylamine (3.56 mL, 21.51 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.58 g, 4.30 mmol) at room temperature. The resulting mixture was stirred at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound 2-3 (960 mg). LC-MS: m / z: 296.7 (M+H) + .

[0659] 3) Preparation of the third step compound 2-4

[0660] At room temperature, compound 2-3 (250 mg, 0.85 mmol), N,N-dimethylformamide (5 mL) and water (1 mL), 1H-pyrazole-4-boronic acid (94.78 mg, 0.85 mmol), sodium carbonate (270.27 mg, 2.55 mmol) and tetrakis(triphenylphosphine)palladium (98.23 mg, 0.09 mmol) were added to the microwave tube in sequence. After nitrogen purging for 3 minutes, the mixture was sealed and the microwave tube was placed in the microwave instrument. After stirring at 120°C for 1 hour, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-10% ethyl acetate / petroleum ether) to obtain compound 2-4 (100 mg). LC-MS: m / z: 282.8 (M+H) + .

[0661] 4) Preparation of the fourth step compound 2A

[0662] At room temperature, compound 2-4 (100 mg, 0.35 mmol), compound 2-1 (118.65 mg, 0.43 mmol), N,N-dimethylformamide (5 mL), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (10.08 mg, 0.07 mmol), cuprous iodide (10.12 mg, 0.05 mmol), and potassium phosphate (225.56 mg, 1.06 mmol) were added sequentially to a microwave tube. The tube was sealed after a nitrogen purge for 3 minutes. The microwave tube was placed in a microwave instrument and stirred at 120°C for 4 hours before cooling to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%-95%, flow rate: 25mL / min) to obtain compound 2A (29.5mg). 1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.64(s,1H),8.44(s,1H),8.39(s,1H),8.21(s,1H),8.15(s,1H),7. 23(t,J=53.5Hz,1H),6.41(s,1H),4.73(d,J=2.4Hz,1H),4.24(t,J=11.5Hz,1H),3.83(d,J=7.2Hz,1H),3 .74(s,1H),3.59(d,J=9.3Hz,1H),3.30(s,1H),2.07(d,J=11.8Hz,2H),2.03–1.91(m,2H),1.83(d,J=14. 2Hz,2H),1.75(dd,J=12.1,3.7Hz,2H),1.73–1.61(m,2H),1.41(q,J=12.9Hz,2H).LC-MS:m / z:481.3(M+H) +

[0663] Example 3

[0664] Preparation of 3-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (3A)

[0665] 1) Preparation of compound 3-2 in the first step

[0666] At room temperature, compound 3-1 (1.00 g, 5.05 mmol), N,N-dimethylformamide (10 mL), zinc cyanide (0.47 g, 4.04 mmol), tris(dibenzylideneacetone)dipalladium (0.46 g, 0.50 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.15 g, 0.25 mmol) were added to a microwave tube. The atmosphere was purged with nitrogen three times and the reaction was carried out in a microwave reactor at 130°C for 30 minutes. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-50%, petroleum ether / ethyl acetate) to obtain compound 3-2 (350 mg). LC-MS: m / z: 144.8 (M+H) +

[0667] 2) Preparation of the second step compound 3-3

[0668] At room temperature, compound 3-2 (350 mg, 2.43 mmol), N,N-dimethylformamide (5 mL), and N-iodosuccinimide (600 mg, 2.67 mmol) were added to a 50 mL single-necked flask and stirred at 25°C for 3 hours. The reaction solution was poured into a 10% sodium thiosulfate solution (30 mL), extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-50%, petroleum ether / ethyl acetate) to obtain compound 3-3 (210 mg). LC-MS: m / z: 270.8 (M+H) +

[0669] 3) Preparation of the third step compound 3-4

[0670] At room temperature, compound 3-3 (200 mg, 0.740 mmol), tetrahydrofuran (5 mL), cuprous iodide (14.1 mg, 0.07 mmol), triethylamine (0.31 mL, 2.22 mmol), bis(triphenylphosphine)palladium dichloride (51.9 mg, 0.07 mmol), trimethylsilyl acetylene (0.21 mL, 1.48 mmol) were added to a single-necked flask and stirred until dissolved. The system was purged with nitrogen three times, and the reaction was stirred at 25 ° C for 16 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-20%, petroleum ether / ethyl acetate) to obtain compound 3-4 (150 mg). LC-MS: m / z: 240.9 (M + H) +

[0671] 4) Preparation of the fourth step compound 3-5

[0672] At room temperature, compound 3-4 (110 mg, 0.46 mmol), methanol (2 mL), and potassium carbonate (127 mg, 0.92 mmol) were added to a single-necked flask. The reaction was stirred at 25°C for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was directly used in the next reaction.

[0673] LC-MS: m / z: 168.8 (M+H) +

[0674] 5) Step 5: Preparation of Compound 3A

[0675] At room temperature, compound 3-5 (50.0 mg, 0.300 mmol), tert-butyl alcohol (1 mL), water (1 mL), compound 1-6 (86.0 mg, 0.360 mmol), copper sulfate pentahydrate (7.42 mg, 0.30 mmol), and sodium ascorbate (5.89 mg, 0.30 mmol) were added to a single-necked flask and stirred at 25°C for 3 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to prepare compound 3A (70 mg). LC-MS: m / z: 410.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.10(d,J=2.0Hz,1H),8.98(s,1H),8.95(d,J=2.0Hz,1H),8.76(s,1 H),8.73(s,1H),7.24(t,J=53.2Hz,1H),4.26-4.24(m,1H),2.12-2.09(m,2H),1.86-1.67(m, 4H),1.48-1.38(m,2H),1.25-1.21(m,2H).

[0676] Example 4

[0677] Preparation of 4-(3-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (4A)

[0678] 1) Preparation of compound 4-1

[0679] At room temperature, compound 1-7 (5.00 g, 32.56 mmol) and acetonitrile (50 mL) were added to a single-necked flask in sequence and stirred until dissolved. Morpholine (4.25 g, 48.84 mmol) and N,N-diisopropylethylamine (12.63 g, 97.68 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-1% methanol / dichloromethane) to obtain compound 4-1 (6.00 g). LC-MS: m / z: 205.4 (M+H) + .

[0680] 2) Preparation of the second step compound 4-2

[0681] At room temperature, compound 4-1 (2 g, 9.79 mmol) and acetonitrile (25 mL) were added to a single-necked flask and stirred until dissolved. N-iodosuccinimide (3.30 g, 14.69 mmol) was added, and the atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 25°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-1% methanol / dichloromethane) to obtain compound 4-2 (2.0 g). LC-MS: m / z: 330.9 (M+H) + .

[0682] 3) Preparation of the third step compound 4-3

[0683] At room temperature, compound 4-2 (500 mg, 1.51 mmol) and tetrahydrofuran (10 mL) were added to a single-necked flask in sequence and stirred until dissolved. Trimethylethynylsilane (743.80 mg, 7.57 mmol), cuprous iodide (28.84 mg, 0.15 mmol), triethylamine (459.77 mg, 4.54 mmol) and bistriphenylphosphine palladium dichloride (106.31 mg, 0.15 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 30 ° C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-2% dichloromethane / petroleum ether) to obtain compound 4-3 ((340 mg). LC-MS: m / z: 300.8 (M+H) + .

[0684] 4) Preparation of the fourth step compound 4-4

[0685] At room temperature, compound 4-3 (300 mg, 1.00 mmol) and anhydrous methanol (10 mL) were added to a single-necked flask and stirred until dissolved. Potassium carbonate (276.00 mg, 2.00 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain compound 4-4 (250 mg, 0.88 mmol, 87.75%). The product was directly processed into the next step without purification. LC-MS: m / z: 228.9 (M+H) + .

[0686] 5) Step 5: Preparation of Compound 4A

[0687] To a 50 mL single-necked flask at room temperature, compound 4-5 (200 mg, 0.83 mmol), tert-butyl alcohol (8 mL), and water (5 mL) were added sequentially and stirred until dissolved. Copper sulfate pentahydrate (62.2 mg, 0.25 mmol), compound 1-6 (284.17 mg, 1.24 mmol), and sodium ascorbyl palmitate (49.3 mg, 0.25 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Gilson 306-1741, column: Waters-Xbridge-C18-10μm-19*250 mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: 19% to 95% acetonitrile, flow rate: 25 mL / min) to obtain compound 4A (82 mg).

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=7.8Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),7.19(t,J=53.2Hz,1H),6.80(d,J=7.8Hz,1H),4.33-4.32 (m,1H),3.72(s,8H),2.09(dd,J=12.9,3.6Hz,2H),1.88-1.64(m,5H),1.49-1.34(m,2H),1.23(dd,J=12.5,3.6Hz,1H).LC-MS:m / z:470.2(M+H) + .

[0689] Example 5

[0690] Preparation of 2-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)pyridine (11A)

[0691] 1) Preparation of compound 11-2

[0692] At room temperature, compound 11-1 (1.00 g, 4.42 mmol) and triethylamine (10 mL) were added to a single-necked flask in sequence and stirred until dissolved. Cuprous iodide (80.1 mg, 0.44 mmol), ethynyltrimethylsilane (800 mg, 8.85 mmol) and bis(triphenylphosphine)palladium dichloride (310 mg, 0.44 mmol) were added in sequence. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 30°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 11-2 (450 mg). LC-MS: m / z: 244.0 (M+H) +

[0693] 2) Preparation of the second step compound 11A

[0694] At room temperature, compound 11-2 (430 mg, 1.77 mmol), 1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazole (554 mg, 2.30 mmol), potassium carbonate (489 mg, 3.53 mmol), copper sulfate pentahydrate and sodium ascorbate (140 mg, 0.710 mmol) were added to a single-necked flask in a mixed solvent system of water (4 mL) and methanol (4 mL), stirred until dissolved, and the reaction solution was stirred at 30 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%-95%, flow rate: 25mL / min) to give compound 11A (640mg).

[0695] 1 H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.39 (d, J = 8.0Hz, 1H), 7.99-7.94 (m, 2H), 7.62 (d, J = 7.6Hz, 1H), 6.86 (t, J = 53.6Hz, 1H), 4.22-4. 15(m,1H),2.25-2.21(m,2H),1.97-1.92(m,2H),1.78-1.975(m,3H),1.47-1.44(m,2H),1.30-1.24(m,1H).LC-MS:m / z:413.5(M+H) +

[0696] Example 6

[0697] Preparation of (1R,4r)-4-(4-(4-(5-(((1R,4r)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl (25A)

[0698] 1) Preparation of compound 25-2

[0699] Under ice bath, to a solution of compound 25-1 (300 mg, 1.09 mmol) in acetonitrile (8 mL) was added isoamyl nitrite (153 mg, 1.31 mmol). The reaction solution was stirred for 1 hour. Azidotrimethylsilane (188 mg, 1.64 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to give compound 25-2 (325 mg). No purification is required, and the next step is carried out directly. LC-MS: m / z: 300.1 (M+H) +

[0700] 2) Preparation of the second step compound 25-3

[0701] To a mixed solution of compound 25-2 (325 mg, 1.09 mmol) in ethanol (8 mL) and water (5 mL) were added sodium ascorbyl palmitate (40 mg, 0.22 mmol), copper sulfate pentahydrate (50 mg, 0.22 mmol) and compound 1-10 (240 mg, 1.09 mmol) in sequence. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-8% methanol / dichloromethane) to obtain compound 25-3 (320 mg). LC-MS: m / z: 540.2 (M+H) +

[0702] 3) Preparation of the third step compound 25-4

[0703] Compound 25-3 (320 mg, 0.59 mmol) was added to a three-necked flask, and tetrahydrofuran (5 mL) was added and stirred until dissolved. The mixture was replaced with nitrogen three times, cooled to -50 ° C, and a tetrahydrofuran solution of lithium aluminum hydride (0.60 mL, 0.60 mmol, 1.0 M) was added dropwise to the reaction solution. The reaction solution was stirred at -50 ° C for 1 hour. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL × 3). Washed with saturated brine (50 mL × 1) and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by column chromatography (0-10% methanol / dichloromethane) to give compound 25-4 (200 mg). LC-MS: m / z: 512.2 (M + H) +

[0704] Step 4) Preparation of Compound 25A

[0705] To a solution of compound 25-4 (200 mg, 0.39 mmol) in dichloromethane (8 mL) was added Dess-Martin periodinane (250 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Water (15 mL) was added to the reaction mixture and extracted with dichloromethane (15 mL × 3). The mixture was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain compound 25A (180 mg). LC-MS: m / z: 510.1 (M+H) +

[0706] Example 7

[0707] Preparation of 4-(3-(5-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (27A)

[0708] 1) Preparation of compound 27-2

[0709] Compound 27-1 (10.0 g, 44.3 mmol) was added to a single-necked flask, and acetonitrile (100 mL) was added and stirred until dissolved. At room temperature, N,N-diisopropylethylamine (22.0 mL, 133 mmol) and morpholine (7.72 g, 88.6 mmol) were added in sequence. The reaction mixture was refluxed and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography and separated and purified by silica gel column (0-40% ethyl acetate / dichloromethane) to obtain compound 27-2 (9.54 g). LC-MS: m / z: 277 (M+H) + ,

[0710] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=7.9Hz,1H),8.16(s,1H),6.79(d,J=7.9Hz,1H),4.13(q,J=7.1Hz,2H),3.78–3.54(m,8H),1.21(t,J=7.1Hz,3H).

[0711] 2) Preparation of the second step compound 27-3

[0712] Compound 27-2 (2.00 g, 7.24 mmol), hydrazine hydrate (7.25 mL, 145 mmol, 98%), and ethanol (20 mL) were added sequentially to a single-necked flask. The reaction mixture was stirred at 45°C for 30 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized (petroleum ether / ethyl acetate = 1 / 1, 10 mL) to give compound 27-3 (1.5 g). LC-MS: m / z: 263 (M+H) +

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=7.9Hz,1H),8.53(s,1H),8.19(s,1H),6.85(d,J=7.9Hz,1H),4.42(s,1H),3.77–3.70(m,8H),3.33(s,2H).

[0714] 3) Preparation of the third step compound 27-4

[0715] At room temperature, compound 2-1 (1.30 g, 4.66 mmol) and N,N-dimethylformamide (20 mL) were added to a single-necked flask and stirred until dissolved. Zinc powder (0.30 g, 4.66 mmol), zinc cyanide (0.34 g, 4.66 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.34 g, 0.46 mmol) were then added to the reaction solution. The reaction solution was stirred at 120 ° C for 18 hours. Water (30 mL) was added to the reaction solution to dilute it and extracted with ethyl acetate (50 mL) three times. The organic phases were combined, washed once with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-70% ethyl acetate / petroleum ether) to give compound 27-4 (600 mg). LC-MS: m / z: 225.9 (M+H) +

[0716] 4) Preparation of the fourth step compound 27A

[0717] Compound 27-3 (100 mg, 0.38 mmol), compound 27-4 (85.9 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), and n-butanol (2 mL) were added sequentially to a microwave tube. The reaction mixture was heated in a microwave oven at 150°C for 30 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated on a silica gel plate (petroleum ether / ethyl acetate = 1 / 2) and then purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30 x 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain 27A (2 mg).

[0718] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.79(d,J=7.9Hz,1H),8.34(s,2H),7.54(t,J=54.1Hz,1H),6.85(d,J=8.0Hz,1H),4.34-4.24(m,1H) ,3.91-3.80(m,4H),3.75-3.70(m,4H),2.10-2.03(m,2H),1.89-1.80(m,3H),1.46-1.38(m,2H),1.28-1.22(m,3H).LC-MS:m / z:470.2(M+H) +

[0719] Example 8

[0720] Preparation of 4-(3-(5-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (28A)

[0721] 1) Preparation of compound 28-2

[0722] At room temperature, compound 28-1 (3.75 g, 19.71 mmol, Bid) and N,N-dimethylformamide (15 mL) were added to a single-necked flask and stirred until dissolved. Bromocyclohexane (4.93 mL, 39.41 mmol) and potassium carbonate (4.09 g, 29.51 mmol) were then added in sequence. The reaction solution was stirred at 80°C for 18 hours. Water (100 mL) was added to the reaction solution and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain compound 28-2 (1.61 g).

[0723] LC-MS: m / z: 273.2 (M+H) +

[0724] 2) Preparation of the second step compound 28-3

[0725] At room temperature, compound 28-2 (1.79 g, 19.71 mmol), tetrahydrofuran (10 mL), water (10 mL), and methanol (5 mL) were added to a single-necked flask and stirred until dissolved. Lithium hydroxide (0.83 g, 19.7 mmol) was then added to the reaction solution. The reaction solution was stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the aqueous phase was adjusted to pH 2-3 by adding 2.0 M dilute hydrochloric acid. The reaction solution was diluted with water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phase was washed once with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield compound 28-3 (1.51 g).

[0726] LC-MS: m / z: 245.1 (M+H) +

[0727] 3) Preparation of the third step compound 28-4

[0728] Compound 28-3 (190 mg, 0.78 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (444.88 mg, 1.17 mmol) were added to a single-necked flask, and tetrahydrofuran (5 mL) was added and stirred until dissolved. After stirring at room temperature for 2 hours, N,N-diisopropylethylamine (0.39 mL, 2.34 mmol) and compound 28-3 (245.48 mg, 0.94 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 10 hours. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 2). The organic layers were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Compound 28-4 (300 mg) was obtained by column chromatography (0-5% methanol / dichloromethane).

[0729] LC-MS: m / z: 489 (M+H) +

[0730] 1H NMR (400MHz, DMSO-d6) δ10.68(d,J=3.4Hz,1H),9.75(d,J=3.4Hz,1H),8.84(d ,J=7.9Hz,1H),8.54(s,1H),8.25(s,1H),7.27(t,J=54Hz,1H),6.91(d,J=8.0H z,1H),4.27(ddd,J=15.1,7.6,3.8Hz,1H),3.87–3.68(m,8H),2.11–2.06(m,2H ),1.85–1.80(m,2H),1.71–1.65(m,3H),1.46–1.40(m,2H),1.30–1.27(m,1H).

[0731] 4) Preparation of the fourth step compound 28A

[0732] Compound 28-4 (150 mg, 0.31 mmol), Lawesson's reagent (149 mg, 0.37 mmol) and toluene (2.5 mL) were added to a microwave tube. The reaction mixture was stirred at reflux for 6 hours. After completion of the reaction, water (10 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (5 mL × 2). The organic layers were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 28A (70.1 mg). LC-MS: m / z: 487 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=7.9Hz,1H),8.63(s,1H),8.53(s,1H),7.36(t,J=53.6Hz,1H),6.92(d,J=7.9Hz,1H),4.36–4 .25(m,1H),3.91–3.72(m,8H),2.13–2.04(m,2H),1.89–1.74(m,4H),1.73–1.65(m,1H),1.48–1.36(m,2H),1.27–1.22(m,1H).

[0733] Example 9

[0734] Preparation of 1-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (43A)

[0735] 1) Preparation of compound 43-1

[0736] Compound 43-1 (0.500 g, 3.49 mmol, Bid) was added to a single-necked flask at room temperature. Toluene (10 mL) was stirred until dissolved. 43-1a (1.10 g, 4.19 mmol, Bid), 1,10-phenanthroline (0.11 mL, 0.70 mmol), potassium phosphate (1.48 g, 6.98 mmol), and anhydrous copper sulfate (0.060 g, 0.35 mmol) were added in sequence. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled, water (30 mL) was added, and extraction with ethyl acetate (50 mL × 3) was performed. The organic layers were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-30% petroleum ether / ethyl acetate) to give compound 43-2 ((1.0 g). 1 H NMR (400MHz, CDCl3) δ8.68(d,J=1.9Hz,1H),8.19(d,J=1.9Hz,1H),7.46(d,J=3.8Hz,1H),6.62(d,J=3.8Hz,1H),1.30-1.12(m,21H).

[0737] 2) Preparation of the second step compound 43-3

[0738] Under ice-cooling, compound 43-2 (100 mg, 0.31 mmol) was added to a three-necked flask, and tetrahydrofuran (2 mL) was added and stirred. Tetrabutylammonium fluoride-tetrahydrofuran solution (0.15 mL, 0.46 mmol, 3.0 mol / L) was slowly added dropwise to the reaction solution at 0°C. The mixture was stirred at room temperature for 6 hours. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-15% petroleum ether / ethyl acetate) to obtain compound 43-3 (45 mg). LC-MS: m / z: 168.0 (M+H) +

[0739] 3) Preparation of the third step compound 43A

[0740] At room temperature, compound 43-3 (40.0 mg, 0.17 mmol) and compound 1-6 (33.26 mg, 0.20 mmol) were added to a single-necked flask and stirred in ethanol (2 mL). Sodium ascorbate (3.28 mg, 0.02 mmol) and copper sulfate pentahydrate (4.14 mg, 0.02 mmol) were then added. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 43A (20 mg, 0.05 mmol). 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),8.82(d,J=1.7Hz,1H),8.78(s,1H),8.73(d,J=1.8Hz,1H),8.38(d,J=3.7Hz,1H),7.25(t,J=53.3H z,1H),6.99(d,J=3.8Hz,1H),4.35-4.29(m,1H),2.12(d,J=12.6Hz,2H),1.90-1.63(m,4H),1.44(q,J=12.8Hz,2H),1.32-1.17(m,2H).

[0741] Example 10

[0742] Preparation of 4-(1-(1-(1-(cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (45A)

[0743] 1) Preparation of compound 45-2

[0744] To a single-necked flask at 25°C were added compound 45-1 (1.00 g, 5.08 mmol, Bid), toluene (10 mL), 43-1a (1.46 g, 5.58 mmol, Bid), tripotassium phosphate (2.15 g, 10.1 mmol), 1,10-phenanthroline (0.180 g, 1.02 mmol), and copper sulfate pentahydrate (0.080 g, 0.510 mmol). The atmosphere was purged with nitrogen three times and the reaction was stirred at 80°C for 18 hours. The reaction solution was spin-dried, diluted with water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 100 to 1 / 1) to afford compound 45-2 (1.40 g).1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.1Hz,1H),7.30(d,J=8.1Hz,1H),7.26(d,J=3.7Hz,1H),6.47(d,J=3.7Hz,1H),1.17(d,J=1.8Hz,21H).

[0745] 2) Preparation of the second step compound 45-3

[0746] To a single-necked flask at 25°C, compound 45-2 (400 mg, 1.06 mmol), toluene (4 mL), morpholine (0.370 mL, 4.24 mmol), palladium acetate (118 mg, 0.530 mmol), tri-tert-butylphosphine (0.130 mL, 0.530 mmol), and potassium tert-butoxide (356 mg, 3.18 mmol) were added. The reaction was stirred at 80°C for 1 hour. The reaction solution was filtered through celite, and the filtrate was diluted with saturated sodium chloride solution and extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:1) to obtain compound 45-3 (250 mg). 1 HNMR (400MHz, CDCl3) δ7.68(d,J=8.6Hz,1H),7.02(d,J=3.7Hz,1H),6.57(d,J=8.6Hz,1H),6 .33(d,J=3.7Hz,1H),3.85-3.81(m,4H),3.60-3.56(m,4H),1.16(s,18H),1.10-1.00(m,3H).

[0747] 3) Preparation of the third step compound 45-4

[0748] Compound 45-3 (300 mg, 0.780 mmol), tetrahydrofuran (3 mL), and tetrabutylammonium fluoride solution (1 M, 0.940 mL, 0.940 mmol) were added to a single-necked flask at 25°C. The reaction was stirred at 25°C for 30 minutes. The reaction solution was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:100 to 1:1) to obtain compound 45-4 (150 mg). LC-MS: m / z: 228.0 (M+H) +

[0749] 4) Preparation of the fourth step compound 45A

[0750] Compound 45-4 (30.0 mg, 0.130 mmol), tert-butyl alcohol (1 mL), water (1 mL), compound 1-6 (3.18 mg, 0.130 mmol), copper sulfate pentahydrate (3.29 mg, 0.013 mmol), and sodium ascorbate (2.62 mg, 0.013 mmol) were added to a single-necked flask at room temperature and stirred for 18 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (5 mL) and dried. The residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 45A (17.0 mg). LC-MS: m / z: 469.2 (M+H). +

[0751] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.73(s,1H),7.91(d,J=8.7Hz,1H),7.85(d,J=3.7Hz,1H),7 .24(t,J=53.1Hz,1H),6.84(d,J=8.7Hz,1H),6.63(d,J=3.7Hz,1H),4.35–4.29(m,1H),3.80–3.71 (m,4H),3.56–3.48(m,4H),2.16–2.06(m,2H),1.85–1.67(m,4H),1.47–1.41(m,2H),1.25–1.22(m,2H)

[0752] Example 11

[0753] Preparation of (1R,4R)-5-(3-(1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (46A)

[0754] 1) Preparation of compound 46-2

[0755] Compound 46-1 (50 mg, 0.340 mmol, Bid) was added to a three-necked flask under an ice bath. Acetonitrile (2 mL) was stirred until dissolved. The atmosphere was purged with nitrogen three times. Tert-butyl nitrite (0.090 mL, 0.680 mmol) was slowly added dropwise at 0°C. The mixture was stirred under an ice bath for 30 minutes. Azidotrimethylsilane (0.070 mL, 0.510 mmol) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-30% petroleum ether / ethyl acetate) to afford compound 46-2 (45 mg). LC-MS: m / z: 174.0 [M+1] +

[0756] 2) Preparation of the second step compound 46A

[0757] Compound 46-2 (45 mg, 0.260 mmol) was added to a single-necked flask at room temperature. Ethanol (2 mL) and water (1 mL) were added and stirred. Compound 1-10 (74.9 mg, 0.310 mmol), copper sulfate pentahydrate (6.49 mg, 0.030 mmol), and sodium ascorbate (5.15 mg, 0.030 mmol) were then added. The reaction mixture was stirred at room temperature for 3 hours. Water was then added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 46A (5 mg). 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.7Hz,1H),8.59(s,1H),8.35(s,1H),7.21(t,J=53.2Hz,1H),6.81-6.28(m,1H),5. 30-5.10(m,1H),4.74(s,1H),3.99(s,3H),3.83-3.65(m,2H),3.59(s,2H),1.98-1.94(m,2H).LC-MS:m / z:414.4[M+1] + .

[0758] Example 12

[0759] Preparation of 3-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidine (56A)

[0760] 1) Preparation of Compound 56A

[0761] At room temperature, compound 56-1 (60 mg, 0.21 mmol, prepared using the method disclosed for the intermediate 3-ethynylpyrazolo[l,5-a]pyrimidine on page 111 of the specification of patent application "WO2015108490 A2") was added to a single-necked flask. Compound 1-6 (51 mg, 0.21 mmol) was added to tetrahydrofuran (1.5 mL) and stirred until dissolved. Cuprous iodide (12 mg, 0.06 mmol) and triethylamine (64 mg, 0.63 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%-95%, flow rate: 25mL / min) to prepare compound 56A (2.5mg). 1 H NMR(400MHz,DMSO-d6)δ9.24(d,J=6.0Hz,1H),8.72(d,J=10.8Hz,4H),7.45-7.05(m,2H),4.3 2-4.26(m,1H),2.13-2.10(m,2H),1.92-1.60(m,5H),1.51-1.35(m,2H),1.30-1.14(m,1H).MS m / z(ESI):384.8[M+1] + .

[0762] Example 13

[0763] Preparation of 1-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (66A)

[0764] 1) Preparation of Compound 66A

[0765] Compound 43A (50.0 mg, 0.120 mmol), ethanol (1 mL), water (1 mL), and sodium hydroxide (24.0 mg, 0.600 mmol) were added to a single-necked flask at room temperature and reacted at 100°C for 2 hours. The reaction solution was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 66A (23.0 mg). LC-MS: m / z: 428.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),8.92(d,J=1.9Hz,1H),8.75(s,1H),8.66(d,J=2.0Hz,1H),8.27(d,J=3.8Hz,1H),7.22(t,J=5 3.3Hz,1H),6.96(d,J=3.8Hz,1H),4.36-4.26(m,1H),2.12-2.08(m,2H),1.85-1.65(m,4H),1.50-1.30(m,2H),1.25-1.20(m,2H).

[0766] Example 14

[0767] Preparation of 1-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (65A)

[0768] Synthesis route:

[0769] 1) Preparation of Compound 65A

[0770] Compound 43A (50.0 mg, 0.120 mmol), dimethyl sulfoxide (1 mL), and potassium carbonate (33.8 mg, 0.240 mmol) were added to a 25 mL single-necked vial at room temperature and stirred until dissolved. Hydrogen peroxide (30%, 0.05 mL, 0.61 mmol) was then added and allowed to react at room temperature for 5 minutes. The reaction solution was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 65A (20.0 mg, 0.050 mmol). LC-MS: m / z: 427.0 (M+H). + . 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.88(d,J=1.9Hz,1H),8.75(s,1H),8.60(d,J= 2.0Hz,1H),8.25(d,J=3.7Hz,1H),8.13(s,1H),7.48(s,1H),7.22(t,J=53.3Hz,1H), 6.92(d,J=3.7Hz,1H),4.30(d,J=3.8Hz,1H),2.10(d,J=12.4Hz,2H),1.83(d,J=17.3 Hz,2H),1.78-1.74(m,1H),1.70-1.60(m,1H),1.50-1.30(m,2H),1.25-1.20(m,2H).

[0771] Example 15

[0772] Preparation of (7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrrolo[1,2-b]pyridazin-3-yl)(piperazin-1-yl)methanone (64A)

[0773] 1) Preparation of compound 64-1

[0774] Compound 61A (80 mg, 0.19 mmol) was added to a single-necked flask at room temperature and stirred in DCM (5 mL) until dissolved. O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142.34 mg, 0.37 mmol), N,N-diisopropylethylamine (0.05 mL, 0.28 mmol), and 1-tert-butyloxycarbonylpiperazine (41.83 mg, 0.22 mmol) were then added sequentially. The reaction mixture was stirred at 25°C for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-15% dichloromethane / methanol) to give compound 64-1 (90 mg). LC-MS: m / z: 596.7 (M+H). + .

[0775] 2) Preparation of the second step compound 64A

[0776] Compound 64-1 (30 mg, 0.05 mmol) was added to a single-necked flask at room temperature. Dichloromethane (2 mL) and trifluoroacetic acid (1 mL) were added and stirred. The reaction mixture was stirred at room temperature for 0.5 hours and then concentrated under reduced pressure. The crude product was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 64A (20 mg). 1 HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.75(s,1H),8.43(d,J=2.1Hz,1H),8.27( d,J=2.1Hz,2H),7.63(d,J=4.6Hz,1H),7.24(t,J=53.3Hz,1H),6.96(d,J=4.6Hz ,1H),4.36-4.26(m,1H),3.55(s,4H),2.80(s,4H),2.12(d,J=12.3Hz,2H),1.91 -1.70(m,4H),1.44(q,J=12.9Hz,2H),1.33-1.21(m,2H).LC-MS:m / z:496.3(M+H) + Example 16

[0777] Preparation of 7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (29A)

[0778] 1) Preparation of compound 29-2

[0779] At room temperature, compound 29-1 (300 mg, 2.10 mmol, prepared using the method disclosed for the intermediate pyrrolo[1,2-b]pyndazine-3-carbonitrile on page 75 of the specification of patent application "WO2015117563 A1") and N-iodosuccinimide (707 mg, 3.14 mmol) were added to acetonitrile (10 mL). The reaction solution was stirred at 60°C for 1 hour. TLC monitored the reaction completion, and saturated sodium sulfite solution (10 mL) was carefully added to the reaction solution. The mixture was then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 29-2 (270 mg). 1 H NMR (400MHz, CDCl3): δ8.27(d,J=2.1Hz,1H), 8.05(d,J=2.1Hz,1H), 7.24(d,J=4.7Hz,1H), 6.95(d,J=4.7Hz,1H).

[0780] 2) Preparation of the second step compound 29-3

[0781] Compound 29-2 (1.16 g, 4.31 mmol) was added to tetrahydrofuran (10 mL), followed by the addition of cuprous iodide (0.08 g, 0.43 mmol), bistriphenylphosphine palladium dichloride (0.30 g, 0.43 mmol), and triethylamine (1.20 mL, 8.62 mmol). The atmosphere was then purged with nitrogen, and trimethylethynylsilane (6.14 mL, 43.11 mmol) was added. The mixture was stirred at room temperature overnight. The reaction system was added to water, and then extracted with ethyl acetate (15 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Compound 29-3 (816 mg) was obtained by purification via a flash column (petroleum ether / ethyl acetate = 20 / 1). 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.2Hz,1H),8.63(d,J=2.2Hz,1H),7.38(d,J=4.7Hz,1H),6.96(d,J=4.8Hz,1H),0.27(s,9H).

[0782] 3) Preparation of the third step compound 29-4

[0783] Compound 29-3 (816 mg, 3.41 mmol) and potassium carbonate (1413.47 mg, 10.23 mmol) were added to methanol (10 mL) and stirred at room temperature for 2 h. Water was added to the reaction system, followed by extraction with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by Flash forward column chromatography (EA:PE = 5%) afforded product 29-4 (175 mg, 1.05 mmol). 1 H NMR (400MHz, CDCl3) δ8.28(d,J=2.2Hz,1H),8.12(d,J=2.2Hz,1H),7.25(s,1H),6.82(d,J=4.7Hz,1H),3.78(s,1H).

[0784] 4) Preparation of the fourth step compound 29A

[0785] Under nitrogen, compound 29-3 (175 mg, 1.05 mmol) and compound 1-6 (252.55 mg, 1.05 mmol) were added to a mixture of ethanol (8 mL) and water (4 mL). Copper sulfate pentahydrate (0.01 mL, 0.10 mmol) and sodium ascorbyl palmitate (20.74 mg, 0.10 mmol) were then added, and the mixture was stirred at room temperature overnight. The reaction solution was distilled under reduced pressure, and the residue was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain product 29A (230 mg). LC-MS: m / z: 409.0 (M+H) + .

[0786] Example 17

[0787] Preparation of 7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (60A)

[0788] 1) Preparation of Compound 60A

[0789] Compound 29A (100 mg, 0.24 mmol) was added to a mixed solvent of aqueous ammonia (1 mL) and ethanol (1 mL), followed by the dropwise addition of hydrogen peroxide (0.03 mL, 0.98 mmol, 30%), and the reaction was stirred at room temperature for 16 h. The reaction system was quenched by the addition of saturated sodium thiosulfate solution, then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 x 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to afford compound 60A (30 mg, 0.07 mmol). LC-MS: m / z: 427.0 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.84-8.73(m,2H),8.66(d,J=2.3Hz,1H),8.17(s,1H),7.65(d,J=4.6Hz,1H),7.57(s,1H),7.23(t,J=53.3H z,1H),7.05(d,J=4.6Hz,1H),4.30(td,J=9.6,7.7,5.8Hz,1H),2.18-2. 06(m,2H),1.94-1.62(m,5H),1.55-1.37(m,2H),1.24(d,J=11.3Hz,1H).

[0790] Example 18

[0791] Preparation of 7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrrolo[1,2-b]pyridazine-3-carboxylic acid (61A)

[0792] 1) Preparation of Compound 61A

[0793] Compound 29A (50 mg, 0.12 mmol) was added to a mixture of ethanol (2 mL) and water (2 mL), followed by sodium hydroxide (48.97 mg, 1.22 mmol) and reflux with stirring for 2 h. The reaction system was concentrated to remove the organic solvent, and the pH was adjusted to 4-5 with HCl (2N). A large amount of solid precipitated, which was filtered and dried to obtain product 61A (25 mg, 0.06 mmol). 1H NMR (400MHz, DMSO-d6) δ13.20(s,1H),9.05(s,1H),8.75(s,1H),8.73-8.69(m,2H),7.69(d,J=4.7Hz,1H),7.39-7.08(m,2 H),4.34-4.27(m,1H),2.14–2.10(m,2H),1.93-1.64(m,5H),1.53-1.35(m,2H),1.30-1.21(m,1H).LC-MS:m / z:428.2(M+H) + .

[0794] Example 19

[0795] Preparation of 4-(3-(1-(3-(difluoromethyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (69A)

[0796] 1) Preparation of compound 69-2

[0797] Compound 69-1 (1.04 g, 3.29 mmol, prepared using the method disclosed in step 5, product on page 140 of patent application "WO2022161414 A1") was added to a three-necked flask under an ice bath. Acetonitrile (25 mL) was stirred until dissolved. Tert-butyl nitrite (0.47 mL, 3.94 mmol) was slowly added dropwise at 0°C. The mixture was stirred under an ice bath for 30 minutes. Azidotrimethylsilane (0.65 mL, 4.93 mmol) was slowly added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 3), washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This yielded compound 69-2 (1.05 g, 3.07 mmol, 93.29%), which was used directly in the next step without purification.

[0798] LC-MS: m / z: 287.1 (M+H-55) + .

[0799] 2) Preparation of the second step compound 69-3

[0800] At room temperature, compound 69-2 (300 mg, 0.88 mmol) was added to a single-necked flask. Ethanol (4 mL) and water (4 mL) were added and stirred. Compound 69-2a (200 mg, 0.88 mmol), copper sulfate pentahydrate (21.9 mg, 0.09 mmol), and sodium ascorbate (17.36 mg, 0.09 mmol) were then added. The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% dichloromethane / methanol) to obtain compound 69-3 (195 mg, 0.34 mmol, 39.00%). LC-MS: m / z: 571.4 (M+H). + .

[0801] 3) Preparation of the third step compound 69A

[0802] Compound 69-3 (175 mg, 0.31 mmol) and dichloromethane (3 mL) were added to a single-necked vial at room temperature, followed by the dropwise addition of hydrogen chloride / dioxane (4.0 M, 3 mL, 12.00 mmol). The reaction mixture was stirred at 25°C for 1 hour and concentrated under reduced pressure. The residue was purified by HPLC (Waters-SunFire-C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol / L hydrochloric acid) and acetonitrile, gradient ratio: acetonitrile 40%-50%, flow rate: 30 mL / min) to obtain compound 69A (53 mg, 0.11 mmol, 36.73%). 1 H NMR(400MHz,DMSO-d6)δ9.30-9.13(m,1H),8.94(d,J=10.3Hz,1H),8.76(d ,J=7.9Hz,1H),8.71(s,1H),8.55(s,1H),8.38(s,1H),7.23(t,J=53.1Hz,1 H),6.81(d,J=7.9Hz,1H),4.75-4.57(m,1H),3.73(s,8H),3.42(d,J=12.9 Hz,2H),3.10(q,J=11.9Hz,2H),2.39-2.14(m,4H).LC-MS:m / z:471.0(M+H) + .

[0803] Example 20

[0804] Preparation of 7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-N-(pyrrolidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (67A)

[0805] 1) Preparation of compound 67-1

[0806] Compound 61A (100 mg, 0.23 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (52.3 mg, 0.28 mmol, Bid) were dissolved in dichloromethane (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (107 mg, 0.28 mmol) and triethylamine (0.10 mL, 0.70 mmol) were added. After stirring at room temperature for 2 hours, water (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain the title compound 67-1 (145 mg). MS m / z (ESI): 596.5 [M+1]. + .

[0807] 2) Preparation of the second step compound 67A

[0808] Compound 67-1 (125 mg, 0.21 mmol) was dissolved in dioxane (5 mL, 4 M) and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the title compound 67A (30 mg). MS m / z (ESI): 496.2 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ9.11–8.95(m,2H),8.90(d,J=6.2Hz,1H),8.82(d,J=2.3Hz ,1H),8.77–8.70(m,2H),7.68(d,J=4.6Hz,1H),7.23(t,J=53.3Hz,1H),7.09(d,J= 4.6Hz,1H),4.59–4.50(m,1H),4.38–4.30(m,1H),3.50–3.40(m,2H),3.30–3.20(m ,2H),2.29–2.01(m,4H),1.89–1.66(m,5H),1.51–1.37(m,2H),1.31–1.19(m,1H).

[0809] Example 21

[0810] Preparation of 7-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-N-(4,4-difluoropyrrolidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (68A)

[0811] 1) Preparation of compound 68-1

[0812] Compound 64-1 (100 mg, 0.23 mmol) and tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (62.4 mg, 0.28 mmol, Bid) were dissolved in dichloromethane (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (107 mg, 0.28 mmol) and triethylamine (0.10 mL, 0.70 mmol) were added. After stirring at room temperature for 2 hours, 15 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 68-1 (150 mg). MS m / z (ESI): 632.4 [M+1]+.

[0813] 2) Preparation of the second step compound 68A

[0814] Compound 68-1 (130 mg, 0.21 mmol) was dissolved in hydrochloric acid (5 mL, 4 M in 1,4-dioxane) and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 68A (50 mg). MS m / z (ESI): 532.2 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 2H), 9.16 (d, J = 8.4Hz, 1H), 9.02 (s, 1H), 8.81 (dd,J=17.8,2.3Hz,2H),8.75(s,1H),7.70(d,J=4.6Hz,1H),7.37–7.10(m,2H ),5.23–5.00(m,1H),4.38–4.26(m,1H),3.93–3.76(m,3H),3.52–3.48(m,1H) ,2.17–2.07(m,2H),1.90–1.71(m,5H),1.49–1.40(m,2H),1.28–1.22(m,1H).

[0815] Example 22

[0816] Preparation of 4-(3-(1-(3-(difluoromethyl)-1-((2S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (79A)

[0817] 1) Preparation of compound 79-2

[0818] At room temperature, compound 79-1 (9.09 g, 42.6 mmol, Leyan) was added to a single-necked flask, followed by methanol (100 mL), and the reaction system was placed in an ice bath for cooling. Sodium borohydride (3.22 g, 85.2 mmol) was added in batches to the rapidly stirred reaction solution. After the addition, the temperature was naturally restored to 25 ° C and stirring was continued for 30 minutes. Saturated ammonium chloride solution (100 mL) was added dropwise to the reaction system under an ice bath, and extracted with ethyl acetate (80 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 79-2 (9.54 g). MS m / z (ESI): 160.2 [M-55] + .

[0819] 2) Preparation of the second step compound 79-3

[0820] Compound 79-2 (9.54 g, 42.1 mmol) was added to a single-necked flask at room temperature, followed by dichloromethane (100 mL). The reaction system was placed in an ice bath to cool and nitrogen was replaced three times. Triethylamine (17.5 mL, 126 mmol) and methylsulfonyl chloride (3.91 mL, 50.5 mmol) were added in sequence. After the addition, the temperature was naturally restored to 25 ° C and stirring was continued for 2 hours. The reaction system was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (150 mL × 3). The collected dichloromethane layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, compound 79-3 (12.5 g) was obtained. MS m / z (ESI): 238.0 [M-55] + .

[0821] 3) Preparation of the third step compound 79-5

[0822] Compound 79-3 (5.00 g, 8.52 mmol), 79-4 (1.25 g, 7.67 mmol) and cesium carbonate (8.33 g, 25.6 mmol) were added to a single-necked flask at room temperature, followed by N,N-dimethylformamide (50 mL). The reaction atmosphere was replaced with nitrogen three times and the mixture was allowed to react at 80°C for 18 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (eluent: ethyl acetate / petroleum ether = 0%-40%) to obtain compound 79-5 (1.30 g). MS m / z (ESI): 305.2 [M-55] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(d,J=13.9Hz,1H),7.46–7.17(m,1H),4.90–4.14(m,2H),4.02–3 .62(m,2H),2.15–2.06(m,2H),1.49–1.31(m,11H),1.19–1.17(m,2H),1.00(d,J=6.6Hz,1H).

[0823] 4) Preparation of the fourth step compound 79-6

[0824] Compound 79-5 (430 mg, 1.19 mmol) and palladium carbon (100 mg, 0.0900 mmol) were added to a single-necked flask at room temperature, followed by methanol (5 mL). The reaction was purged with hydrogen three times and allowed to react under hydrogen at 25°C for 18 hours. The reaction solution was filtered and concentrated to obtain compound 79-6 (400 mg). MS m / z (ESI): 275.2 [M-55] + .

[0825] 5) Preparation of the fifth step compound 79-7

[0826] Compound 79-6 (400 mg, 1.21 mmol) was added to a single-necked flask at room temperature, followed by acetonitrile (5 mL). The reaction system was placed in an ice bath and tert-butyl nitrite (0.220 mL, 1.82 mmol) was slowly added dropwise and stirred for 1 hour. Azidotrimethylsilane (0.240 mL, 1.82 mmol) was then slowly added dropwise to the reaction system, and the temperature was then naturally restored to 25 ° C and stirred for 1 hour. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title compound 79-7 (431 mg). The crude product can be subjected to the next step without purification. MS m / z (ESI): 301.2 [M-55] + .

[0827] 6) Step 6 Preparation of Compound 79-8

[0828] Compound 79-7 (431 mg, 1.21 mmol), compound 4-5 (304 mg, 1.33 mmol), copper sulfate pentahydrate (30.2 mg, 0.120 mmol), and sodium ascorbyl palmitate (24.0 mg, 0.120 mmol) were added to a single-necked flask at room temperature. Ethanol (6 mL) and water (3 mL) were then added and the mixture was allowed to react at 25°C for 2 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography using an eluent system (eluent: ethyl acetate / petroleum ether = 40%-100%) to obtain compound 79-8 (340 mg). MS m / z (ESI): 585.4 [M+1] + .

[0829] 7) Step 7: Preparation of Compound 79A

[0830] Compound 79-8 (100 mg, 0.170 mmol) was added to a single-necked flask at room temperature, followed by dioxane (2 mL). A 4.00 mol / L dioxane hydrochloride solution (2 mL) was added dropwise under an ice bath, and the mixture was allowed to react at 25°C for 1.5 hours. The reaction solution was concentrated, water (1 mL) was added, and the mixture was neutralized with aqueous ammonia (1 mL). Solid precipitated and was filtered to obtain a crude filter cake. The crude product was purified by HPLC (Gilson 306-1741, column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10.0 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: 19% to 95% acetonitrile, flow rate: 25 mL / min) to afford compound 79A (53.1 mg). MS m / z (ESI): 485.2 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.76(d,J=7.9Hz,1H),8.71–8.65(m,1H),8.53(d,J=6 .3Hz,1H),8.38(d,J=1.2Hz,1H),7.20(td,J=53.2,5.5Hz,1H),6.81(d,J=7.9 Hz,1H),4.68–4.59(m,1H),4.43–4.31(m,1H),3.72(s,8H),3.09–2.98(m,1H) ,2.86–2.63(m,2H),2.24–1.89(m,3H),1.83–1.65(m,1H),1.08–1.04(m,3H).

[0831] Example 23

[0832] Preparation of 4-(3-(3-difluoromethyl)-1-(2R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine hydrochloride (80A)

[0833] 1) Preparation of compound 80-2

[0834] Compound 80-1 (3.00 g, 14.1 mmol) was dissolved in methanol (30 mL), and sodium borohydride (0.55 g, 14.5 mmol) was added to the reaction solution. The reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 80-2 (2.80 g). MS m / z: 160.0 [M-55] + .

[0835] 2) Preparation of the second step compound 80-3

[0836] Compound 80-2 (2.80 g, 13.0 mmol) was dissolved in dichloromethane (40 mL). Triethylamine (4.00 g, 39.5 mmol) and methanesulfonyl chloride (1.80 g, 15.7 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 80-3 (3.20 g).

[0837] 3) Preparation of the third step compound 80-4

[0838] Compound 79-4 (1.70 g, 10.4 mmol) and compound 80-3 (3.20 g, 20.2 mmol) were dissolved in N,N-dimethylformamide (80 mL), and cesium carbonate (10.5 g, 32.2 mmol) was added. The reaction solution was stirred at 80°C for 18 hours. The reaction solution was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 80-4 (1.10 g). MS m / z (ESI): 305.0 [M-55] + .

[0839] 4) Preparation of the fourth step compound 80-5

[0840] Compound 80-4 (1.10 g, 3.05 mmol) was dissolved in methanol (10 mL) and wet palladium on carbon (150 mg, 10%) was added. The reaction solution was purged with a hydrogen balloon three times and stirred at 25°C for 2 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 80-5 (950 mg). MS m / z (ESI): 275.1 [M-55] + .

[0841] 5) Preparation of the fifth step compound 80-6

[0842] Compound 80-5 (900 mg, 2.72 mmol) was dissolved in acetonitrile (20 mL) and isoamyl nitrite (500 mg, 4.27 mmol, Bidler) was added at 0°C. After the reaction solution was stirred for 30 minutes, trimethylsilyl azide (470 mg, 4.08 mmol) was added. The reaction solution was stirred at 25°C for 18 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 80-6 (900 mg). MS m / z (ESI): 301.0 [M-55] + .

[0843] 6) Preparation of the sixth step compound 80-7

[0844] Compound 80-6 (900 mg, 2.53 mmol) was dissolved in ethanol (20 mL) and water (5 mL). Vitamin C sodium (50 mg, 0.25 mmol, Anaiji), copper sulfate pentahydrate (65 mg, 0.26 mmol, Anaiji) and compound 4-5 (650 mg, 2.85 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 25 ° C for 18 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1 to 0 / 1) to give compound 80-7 (520 mg). MS m / z(ESI):585.4[M+H] + .

[0845] 7) Step 7 Preparation of Compound 80A

[0846] Compound 80-7 (80 mg, 0.14 mmol) was dissolved in ethyl acetate (3 mL), and a solution of hydrochloric acid in ethyl acetate (1 mL, 4 M) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain the title compound 80A (20.0 mg). MS m / z (ESI): 485.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.59–8.95(m,2H),8.84–8.66(m,2H),8.56(d,J=4.2Hz,1H),8.39(d,J=1.4Hz,1H),7.39–7.10(m ,1H),6.82(d,J=7.9Hz,1H),4.86–4.69(m,1H),3.73(s,8H),3.56–3.05(m,3H),2.46–1.98(m,4H),1.34(d,J=6.5Hz,3H).

[0847] Example 24

[0848] Preparation of 4-(3-(3-difluoromethyl)-1-(2R,4S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine isomer 1 (72A) and 4-(3-(3-difluoromethyl)-1-(2R,4R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine isomer 2 (73A)

[0849] 1) Preparation of Compounds 72-1 and 73-1

[0850] Compound 80-7 (320 mg, 0.55 mmol) was subjected to chiral separation (WATERS 150 preparative SFC (SFC-26), column: Chiral Cel OX, 250×30 mm, ID, 10 μm; mobile phase: carbon dioxide and ethanol, gradient ratio: ethanol 30-50%, flow rate: 150 mL / min) to give compound 72-1 (120 mg, retention time: 3.345 minutes) and compound 73-1 (160 mg, retention time: 3.661 minutes). MS m / z: 585.3 [M+H] + .

[0851] 2) Preparation of the second step compound 72A

[0852] Compound 72-1 (120 mg, 0.210 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain compound 72A (45 mg). MS m / z (ESI): 485.3 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),6.82(d,J=7.9Hz,1H),4.42–4.32 (m,1H),3.73(s,8H),3.10–3.02(m,1H),2.72–2.61(m,2H),2.10–1.96( m,3H),1.82–1.71(m,1H),1.49(q,J=11.6Hz,1H),1.06(d,J=6.2Hz,3H).

[0853] 3) Preparation of the third step compound 73A

[0854] Compound 73-1 (140 mg, 0.241 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain compound 73A (55 mg). MS m / z (ESI): 485.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.77(d,J=7.9Hz,1H),8.72(s,1H),8.55(s,1H),8.39(s,1H),7.21(t,J=53.2Hz,1H),6.82(d,J=7.9Hz,1H),4.71–4.60(m, 1H),3.73(s,8H),3.04–2.97(m,1H),2.87–2.74(m,2H),2.25–2.08(m,2H),1.97–1.89(m,1H),1.75–1.62(m,1H),1.06(d,J=6.5Hz,3H).

[0855] Example 25

[0856] Preparation of (S)-4-(3-(1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (82A)

[0857] 1) Preparation of compound 82-1

[0858] Compound 1-7 (1.00 g, 6.51 mmol, Bid) was dissolved in acetonitrile (40 mL), and 1-7a (990 mg, 9.77 mmol, Bid) and N,N-diisopropylethylamine (4.32 mL, 26.1 mmol) were added. After stirring at 60°C for 2 hours, water (40 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (40 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 82-1 (642 mg). MS m / z (ESI): 219.2 [M+1] + .

[0859] 2) Preparation of the second step compound 82-2

[0860] Compound 82-1 (642 mg, 2.94 mmol) was dissolved in dichloromethane (30 mL). N-iodosuccinimide (728 mg, 3.24 mmol) was added at 0°C. After stirring for 2 hours at 0°C, the reaction solution was quenched by adding saturated sodium bicarbonate solution (40 mL). The mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain compound 82-2 (700 mg). MS m / z (ESI): 345.1 [M+1]. + .

[0861] 3) Preparation of the third step compound 82-3

[0862] Compound 82-2 (1.10 g, 0.09 mmol) was dissolved in tetrahydrofuran (10 mL), and cuprous iodide (600 mg, 0.32 mmol), bis(triphenylphosphine)palladium dichloride (220 mg, 0.32 mmol), and triethylamine (0.89 mL, 6.39 mmol) were added sequentially. The nitrogen atmosphere was replaced three times, and trimethylethynylsilane (4.55 mL, 31.96 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was added with water (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain compound 82-3 (700 mg). MS m / z (ESI): 315.6 [M+1] + .

[0863] 4) Preparation of the fourth step compound 82-4

[0864] Compound 82-3 (650 mg, 2.07 mmol) was dissolved in methanol (30 mL), and potassium carbonate (571 mg, 4.13 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain compound 82-4 (320 mg). MS m / z (ESI): 243.1 [M+1] + .

[0865] 5) Step 5: Preparation of Compound 82A

[0866] Compound 82-4 (200 mg, 0.83 mmol) and 1-6 (200 mg, 0.83 mmol) were dissolved in a mixed solution of water (4 mL) and ethanol (4 mL). Copper sulfate pentahydrate (20.6 mg, 0.08 mmol) and sodium ascorbate (16.4 mg, 0.08 mmol) were added. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove ethanol. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 82A (75 mg). MS m / z(ESI):484.5[M+1] + . 1 H NMR (400MHz, CDCl3) δ8.62–8.57(m,2H),8.45(d,J=7.7Hz,1H),8.11(s,1H),6.82(t, J=53.7Hz,1H),6.37(d,J=7.3Hz,1H),4.45(d,J=7.3Hz,1H),4.21–4.03(m,3H),3.88 –3.73(m,2H),3.61–3.58(m,1H),3.49–3.40(m,1H),2.27–2.18(m,2H),1.98–1.90(m ,2H),1.80–1.71(m,3H),1.50–1.39(m,2H),1.38(d,J=6.8Hz,3H),1.36–1.25(m,1H).

[0867] Example 26

[0868] Preparation of (2S)-4-(3-{1-[1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl]-1H-1,2,3-triazol-4-yl}pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylmorpholine (83A)

[0869] 1) Preparation of compound 83-1

[0870] At room temperature, compound 1-7 (1.00 g, 6.51 mmol, Shanghai Bidex) and N,N-dimethylformamide (8 mL) were added sequentially to a single-necked flask. After thorough mixing, (2S)-2-methylmorpholine hydrochloride (93.7 mg, 680 umol, Shanghai Haohong) and cesium carbonate (3.18 g, 9.70 mmol) were added. The reaction solution was stirred at 100°C for 16 hours. 20 mL of water was added to the reaction solution, and then extracted twice with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (ethyl acetate / petroleum ether = 0-3 / 2) to obtain compound 83-1 (1.15 g). 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=7.9Hz,1H),7.86(d,J=2.0Hz,1H),6.72(d,J=7.9Hz,1H),6.04(d,J=1.9Hz,1H),4.28–4.25 (m,1H),4.20–4.16(m,1H),3.92–3.88(m,1H),3.58–3.47(m,2H),2.98–2.94(m,1H),2.65–2.59(m,1H),1.16(d,J=6.1Hz,3H)

[0871] 2) Preparation of the second step compound 83-2

[0872] At room temperature, compound 83-1 (1.05 g, 4.81 mmol) and acetonitrile (10 mL) were added sequentially to a single-necked flask and stirred until dissolved. A solution of N-iodosuccinimide (1.62 g, 7.22 mmol) previously dissolved in 10 mL of acetonitrile was then added to the reaction flask. The reaction solution was stirred at 25°C for 6 hours. 20 mL of saturated aqueous sodium sulfite solution was added to the reaction solution, followed by extraction twice with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (ethyl acetate / petroleum ether = 0-3 / 2) to obtain compound 83-2 (1.58 g). MS m / z (ESI): 345.2 [M+1] +

[0873] 3) Preparation of the third step compound 83-3

[0874] At room temperature, compound 83-2 (1.58 g, 4.59 mmol) and tetrahydrofuran (12 mL) were added sequentially to a single-necked flask and stirred until dissolved. Cuprous iodide (90.0 mg, 460 μmol) and bis(triphenylphosphine)palladium dichloride (320 mg, 46 μmol) were then added to the reaction flask, followed by triethylamine (1.91 mL, 13.8 mmol) and ethynyltrimethylsilane (1.31 mL, 9.18 mmol). Nitrogen was bubbled through the reaction solution for approximately 1 minute to expel as much air as possible, and the cap was quickly tightened. The mixture was stirred at 25°C for 6 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (ethyl acetate / petroleum ether = 1 / 4 to 4 / 1) to afford compound 83-3 (830 mg). MS m / z(ESI):315.2[M+1] +

[0875] 4) Preparation of the fourth step compound 83-4

[0876] At room temperature, compound 83-3 (770 mg, 2.45 mmol) and methanol (10 mL) were added sequentially to a single-necked flask and stirred until dissolved. Potassium carbonate (677 mg, 4.90 mmol) was then added to the reaction flask. The reaction solution was stirred at 25°C for 1 hour. 20 mL of water was added to the reaction solution, and then extracted twice with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 83-4 (547 mg).

[0877] MS m / z(ESI):243.3[M+1] +

[0878] 5) Step 5: Preparation of Compound 83

[0879] At room temperature, compound 83-4 (150 mg, 620 μmol), tert-butyl alcohol (1.2 mL), and water (1.2 mL) were added sequentially to a single-necked flask and stirred until uniform. Sodium ascorbate (12.3 mg, 60.0 μmol) and cuprous oxide (39.4 mg, 500 μmol) were then added to the reaction flask, followed by compound 1-6 (149 mg, 620 μmol). The reaction mixture was stirred at 80°C for 2 hours. 10 mL of water was added to the reaction solution, followed by extraction twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (CAS-CD-SEMI-PREP-S, column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: water (containing formic acid) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 25 mL / min) to obtain compound 83 (88.2 mg). MS m / z (ESI): 484.4 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.37(s ,1H),7.22(t,J=53.2Hz,1H),6.82(d,J=7.9Hz,1H),4.44–4.23(m,3H),3.95–3.9 1(m,1H),3.63–3.51(m,2H),3.05–3.02(m,1H),2.75–2.71(m,1H),2.11–2.07(m ,2H),1.88–1.71(m,4H),1.70–1.60(m,1H),1.49–1.35(m,2H),1.30–1.14(m,4H)

[0880] Example 27

[0881] Preparation of 7-(1-(3-(difluoromethyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (84A)

[0882] 1) Preparation of compound 84-1

[0883] Compound 29-3 (300 mg, 1.79 mmol) was dissolved in dimethyl sulfoxide (0.6 mL) and ethanol (3 mL). Sodium hydroxide (86.0 mg, 2.15 mmol) and hydrogen peroxide (0.2 mL, 30% aqueous solution) were added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Water (15 mL) was then added and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford compound 84-1 (254 mg). MS m / z (ESI): 186.1 [M+1] + .

[0884] 2) Preparation of the second step compound 84-2

[0885] Compound 84-1 (200 mg, 1.08 mmol) and 69-2 (555 mg, 1.62 mmol) were dissolved in a mixture of water (4 mL) and ethanol (4 mL). Copper sulfate pentahydrate (27.0 mg, 0.11 mmol) and sodium ascorbyl palmitate (21.4 mg, 0.11 mmol) were added. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove the ethanol. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 84-2 (435 mg). MS m / z (ESI): 528.3 [M+1]. + .

[0886] 3) Step 5: Preparation of Compound 84A

[0887] Compound 84-2 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid (3 mL, 4 M in 1,4-dioxane) was added. After stirring at room temperature for 1 hour, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the title compound 84A (70 mg). MS m / z (ESI): 428.2 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ9.07(s,1H),9.03(s,1H),8.80(s,2H),8.67(d,J=2.2Hz,1H),8.17(s,1H),7.66(d,J=4.6Hz,1H),7.56(s,1H),7.27(t, J=53.2Hz,1H),7.05(d,J=4.6Hz,1H),4.77–4.61(m,1H),3.44(d,J=12.8Hz,2H),3.12(d,J=11.8Hz,2H),2.36–2.32(m,2H),2.27–2.17(m,2H).

[0888] Example 28

[0889] Preparation of 4-(3-(1-(3-(difluoromethyl)-1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (85A)

[0890] 1) Preparation of compound 85-2

[0891] Compound 85-1 (1.88 g, 8.20 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol) were added to a single-necked flask at room temperature, followed by dichloromethane (20 mL). The reaction system was placed in an ice bath to cool and nitrogen was replaced three times. Triethylamine (2.27 mL, 16.4 mmol) and p-toluenesulfonyl chloride (2.34 g, 12.3 mmol) were added in sequence, and the mixture was reacted at 40 ° C for 18 hours after the addition. Dichloromethane (200 mL) was added to the reaction system, and the dichloromethane layer was washed with water (50 mL × 3). The dichloromethane layer was collected and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 85-2 (3.07 g). MS m / z (ESI): 406.2 [M+23] + .

[0892] 2) Preparation of the second step compound 85-3

[0893] Compound 85-2 (3.07 g, 8.01 mmol), 79-4 (1.31 g, 8.01 mmol) and cesium carbonate (7.82 g, 24.0 mmol) were added to a single-necked flask at room temperature, followed by DMF (31 mL). The reaction atmosphere was replaced with nitrogen three times and the mixture was allowed to react at 80°C for 18 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using an eluent system (eluent: ethyl acetate / petroleum ether = 0%-40%) to obtain the title compound 85-3 (830 mg). MS m / z (ESI): 319.2 [M-55] + . 1 H NMR(400MHz, DMSO-d6)δ9.10(s,1H),7.31(t,J=52.9Hz,1H),4.75–4.62(m,1H),3.92–3.80(m,1H),3.26–3.20 (m,1H),2.23–2.12(m,1H),2.05(t,J=12.7Hz,1H),1.97–1.84(m,2H),1.50(s,3H),1.41(s,9H),1.34(s,3H).

[0894] 3) Preparation of the third step compound 85-4

[0895] Compound 85-3 (830 mg, 2.22 mmol) and palladium on carbon (165 mg) were added to a single-necked flask at room temperature, followed by methanol (8 mL). The reaction was purged with hydrogen three times and allowed to react at 25°C under hydrogen for 18 hours. The reaction solution was filtered and concentrated to give the title compound 85-4 (690 mg). MS m / z (ESI): 289.2 [M-55] + .

[0896] 4) Preparation of the fourth step compound 85-5

[0897] Compound 85-4 (200 mg, 0.580 mmol) was added to a single-necked flask at room temperature, followed by acetonitrile (2 mL). The reaction system was placed in an ice bath and tert-butyl nitrite (0.100 mL, 0.870 mmol) was slowly added dropwise and stirred for 1 hour. Azidotrimethylsilane (0.110 mL, 0.870 mmol) was then slowly added dropwise to the reaction system, and then naturally returned to room temperature and stirred for 1 hour. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound 85-5 (215 mg). The crude product was subjected to the next step without purification. MS m / z (ESI): 315.2 [M-55] + .

[0898] 5) Step 5 Preparation of Compound 85-6

[0899] Compound 85-5 (215 mg, 0.580 mmol), 4-5 (146 mg, 0.640 mmol), copper sulfate pentahydrate (14.5 mg, 0.0600 mmol) and sodium ascorbyl palmitate (11.5 mg, 0.060 mmol) were added to a single-necked flask at room temperature. Ethanol (3 mL) and water (1.5 mL) were then added and the mixture was reacted at 25°C for 1.5 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (eluent: ethyl acetate / petroleum ether = 1 / 3-1 / 1) to obtain the title compound 85-6 (145 mg). MS m / z (ESI): 599.4 [M+1] + .

[0900] 6) Step 6: Preparation of Compound 85A

[0901] Compound 85-6 (40 mg, 0.0700 mmol) was added to a single-necked flask at room temperature, followed by dioxane (0.5 mL). A 4.00 mol / L dioxane hydrochloride solution (0.5 mL) was added dropwise under an ice bath. The mixture was allowed to react at 25°C for 1.5 hours. The reaction solution was concentrated, methanol (1 mL) was added, and the system was neutralized with aqueous ammonia (1 mL). Compound 85A (12.7 mg) was obtained by preparative purification. MS m / z (ESI): 499.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.9Hz,1H),8.65(s,1H),8.52(s,1H),8.38(s,1H),7.19(t,J=53.2Hz,1H),6.81(d,J=7.9 Hz,1H),4.64–4.52(m,1H),3.72(s,8H),2.93–2.78(m,2H),2.02–1.88(m,2H),1.81–1.60(m,3H),1.13(s,3H),1.10(s,3H).

[0902] Example 29

[0903] Preparation of (R)-4-(3-(1-(3-(difluoromethyl)-1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)morpholine Isomer 1 Hydrochloride (86A) & (S)-4-(3-(1-(3-(difluoromethyl)-1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)morpholine Isomer 2 Hydrochloride (87A)

[0904] 1) Preparation of Compounds 86-1 and 87-1

[0905] Compound 85-6 (450 mg, 0.750 mmol) was subjected to chiral separation (WATERS 150 preparative SFC (SFC-26), column: ChiralCel OX, 250×30 mm ID, 10 μm; mobile phase: carbon dioxide and ethanol, gradient ratio: 40% ethanol, flow rate: 150 mL / min) to afford compound 86-1 (200 mg, retention time: 3.920 minutes) and compound 87-1 (191 mg, retention time: 4.946 minutes). MS m / z (ESI): 599.3 [M+1] + .

[0906] 2) Preparation of the second step compound 86A

[0907] Compound 86-1 (200 mg, 0.330 mmol) was added to a single-necked flask at room temperature, followed by dichloromethane (2 mL) and a 2.00 mol / L hydrochloric acid in ethyl acetate (4 mL). The mixture was allowed to react at 25°C for 3 hours. The reaction solution was concentrated to yield the title compound 86A (179 mg). MS m / z (ESI): 499.2 [M+1] + .1 HNMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.20 (s, 1H), 8.76 (d, J = 7.9Hz, 1H), 8.69 (s, 1H), 8. 55(s,1H),8.38(s,1H),6.82(d,J=7.9Hz,1H),4.90–4.79(m,1H),3.72(s,8H),3.23(d,J= 12.3Hz,2H),2.35–2.06(m,4H),1.43(d,J=4.3Hz,6H).

[0908] 3) Preparation of the third step compound 87A

[0909] Compound 87-1 (191 mg, 0.320 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in dioxane (4 mL, 4.0 M) was slowly added dropwise. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to give the title compound 87A (169 mg). MS m / z (ESI): 499.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.59(d,J=11.2Hz,1H),9.32(t,J=10.4Hz,1H),8.77(d,J=8.0Hz,1H),8.69(s,1H),8.55(s,1H),8.38(s,1H),7.24 (t,J=53.2Hz,1H),6.82(d,J=8.0Hz,1H),4.92-4.80(m,1H),3.72(s,8H),3.37-3.13(m,2H),2.30-2.06(m,4H),1.44(s,3H),1.43(s,3H).

[0910] Example 30

[0911] Preparation of ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-(3,3-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methanol (88A)

[0912] 1) Preparation of compound 88-2

[0913] Compound 88-1 (3.00 g, 12.2 mmol, prepared by the method disclosed in the intermediate step 6 compound on page 137 of the specification of the patent application "WO2022161414 A1") was dissolved in acetonitrile (35 mL), and isoamyl nitrite (2.10 g, 17.9 mmol, Bid) was added at 0 ° C. After stirring the reaction solution for 30 minutes, azidotrimethylsilane (2.00 g, 17.4 mmol) was added. The reaction solution was stirred at 25 ° C for 18 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 88-2 (3.00 g). MS m / z (ESI): 272.1 [M+H] + .

[0914] 2) Preparation of the second step compound 88-3

[0915] 5-Chloropyrazolo[1,5-a]pyrimidine 1-7 (2.00 g, 13.0 mmol), 3,3-dimethylmorpholine (1.80 g, 15.6 mmol), N,N-diisopropylethylamine (6.47 mL, 39.07 mmol), and N-methylpyrrolidone (15 mL) were reacted at 130°C for 18 hours. The reaction solution was then mixed with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 88-3 (1.0 g). MS m / z (ESI): 233.1 [M+1]. + .

[0916] 3) Preparation of the third step compound 88-4

[0917] Iodosuccinimide (1.94 g, 8.61 mmol) was added to a solution containing compound 88-3 (1.00 g, 4.30 mmol) and acetonitrile (15 mL). The reaction was allowed to react at 25°C for 18 hours. The reaction solution was then quenched with a saturated sodium sulfite solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 88-4 (600 mg). 1H NMR (400MHz, DMSO-d6): δ8.68(d,J=8.0Hz,1H),7.97(s,1H),6.79(d,J=8.0Hz,1H),3.81–3.78(m,2H),3.57–3.54(m,2H),3.41(s,2H),1.54(s,6H).

[0918] 4) Preparation of the fourth step compound 88-5

[0919] Under nitrogen, bis(triphenylphosphine)palladium dichloride (235 mg, 0.34 mmol) was added to a solution containing compound 88-4 (600 mg, 1.68 mmol), trimethylethynylsilane (2.40 mL, 16.8 mmol), triethylamine (0.70 mL, 5.03 mmol), and tetrahydrofuran (10 mL). The reaction was purged with nitrogen three times and allowed to react at 25°C for 18 hours. The reaction solution was then quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to yield compound 88-5 (400 mg). MS m / z (ESI): 329.2 [M+1] + .

[0920] 5) Step 5 Preparation of Compound 88-6

[0921] Potassium carbonate (337 mg, 2.45 mmol) was added to a solution containing compound 88-5 (400 mg, 1.22 mmol) and methanol (5 mL). The reaction was stirred at 25°C for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain compound 88-6 (260 mg). MS m / z (ESI): [M+23] + .

[0922] 6) Step 6: Preparation of Compound 88A

[0923] Sodium vitamin C (8.00 mg, 0.04 mmol) was added to a solution containing compound 88-2 (158.76 mg, 0.59 mmol), compound 88-6 (100 mg, 0.39 mmol), copper sulfate pentahydrate (9.80 mg, 0.04 mmol), ethanol (1 mL) and water (1 mL), replaced with nitrogen three times, and then stirred at 25 ° C for 18 hours. The reaction mixture was then quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% FA / H2O B: ACN, column: Wetch-Ultimate-XB-C18-10μm-21.2*150mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25%-45%, flow rate: 25 mL / min) to obtain compound 88A (150 mg). MS m / z (ESI): 528.4 [M+1]. + . 1 H NMR (400MHz, DMSO-d6): δ8.74(d,J=8.0Hz,1H),8.65(s,1H),8.45–8.37(m,2H),7.19( t,J=53.2Hz,1H),6.85(d,J=8.0Hz,1H),4.58–4.36(m,1H),4.34–4.23(m,1H),3.88–3 .77(m,2H),3.67–3.59(m,2H),3.43(s,2H),3.29–3.26(m,2H),2.19–2.10(m,2H),1.9 3–1.86(m,2H),1.84–1.74(m,2H),1.53(s,6H),1.49–1.39(m,1H),1.20–1.05(m,2H).

[0924] Example 31

[0925] Preparation of ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-(2,2-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methanol (89A)

[0926] 1) Preparation of Compound 89-1

[0927] Compound 1-7 (1.00 g, 6.51 mmol, Bid) was dissolved in acetonitrile (15 mL), and 2,2-methylmorpholine (900 mg, 7.81 mmol, Bid) and cesium carbonate (6.36 g, 19.5 mmol) were added. After stirring at 80°C for 12 hours, water (40 ml) was added to the reaction solution, and extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 89-1 (1.2 g). MS m / z (ESI): 233.5 [M+1] + .

[0928] 2) Preparation of the second step compound 89-2

[0929] Compound 89-1 (1.00 g, 4.30 mmol) was dissolved in acetonitrile (20 mL), and N-iodosuccinimide (970 mg, 4.30 mmol) was added at 0°C. After stirring at room temperature for 1 hour, the reaction solution was quenched by adding saturated sodium bicarbonate solution (100 ml). The mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain compound 89-2 (1.7 g). MS m / z (ESI): 359.1 [M+1]. + .

[0930] 3) Preparation of the third step compound 89-3

[0931] Compound 89-2 (1.70 g, 4.75 mmol) was dissolved in tetrahydrofuran (20 mL), and cuprous iodide (90 mg, 0.47 mmol), bis(triphenylphosphine)palladium dichloride (330 mg, 0.47 mmol), and triethylamine (1.97 mL, 14.2 mmol) were added sequentially. The nitrogen atmosphere was replaced three times, and trimethylethynylsilane (6.76 mL, 47.5 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was added with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain compound 89-3 (1 g). MS m / z (ESI): 329.2 [M+1] + .

[0932] 4) Preparation of the fourth step compound 89-4

[0933] Compound 89-3 (800 mg, 2.44 mmol) was dissolved in methanol (12 mL), potassium carbonate (673 mg, 4.87 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 89-4 (400 mg). MS m / z (ESI): 257.2 [M+1] + .

[0934] 5) Step 5: Preparation of Compound 89A

[0935] Compound 89-4 (100 mg, 0.39 mmol) and 88-2 (159 mg, 0.59 mmol) were dissolved in a mixed solution of water (2.5 mL) and ethanol (2.5 mL). Copper sulfate pentahydrate (9.74 mg, 0.04 mmol) and sodium ascorbate (7.73 mg, 0.04 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove ethanol. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 89A (96 mg). MS m / z(ESI):528.4[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.9Hz,1H),8.69(s,1H),8.53(s,1H),8.37(s,1H ),7.24(t,J=53.1Hz,1H),6.83(d,J=7.9Hz,1H),4.52(t,J=5.3Hz,1H),4.30–4.25(m ,1H),3.74(s,4H),3.63(s,2H),3.28(t,J=5.7Hz,2H),2.17–2.10(m,2H),1.89(d,J =13.4Hz,2H),1.84–1.74(m,2H),1.49–1.40(m,1H),1.19(s,6H),1.16–1.06(m,2H).

[0936] Example 32

[0937] Preparation of ((1r,4r)-4-(4-(4-(5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]cyclohexyl)methanol (90A)

[0938] 1) Preparation of Compound 90-1

[0939] Compound 1-7 (2.00 g, 13.0 mmol, Bid) and 6-aza-2-oxaspiro[3.3]heptane (1.68 g, 17.0 mmol, Bid) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (6.5 mL, 39.1 mmol) was added. The reaction solution was stirred at 80°C for 12 hours, and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 90-1 (2.8 g). MS m / z (ESI): 217.1. [M+1] +1 H NMR (400MHz, CDCl3): δ8.31(d,J=7.5Hz,1H),7.88(d,J=2.2Hz,1H),6.17(d,J=1.7Hz,1H),5.96(d,J=7.5Hz,1H),4.88(s,4H),4.33(s,4H).

[0940] 2) Preparation of the second step compound 90-2

[0941] Compound 90-1 (500 mg, 2.31 mmol) was dissolved in dichloromethane (10 mL), and N-iodosuccinimide (624 mg, 2.77 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, then poured into a saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous sodium sulfite solution (10 mL). The aqueous phase was separated and extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 90-2 (680 mg). MS m / z (ESI): 343.1 [M+1] +1 . H NMR (400MHz, DMSO-d6): δ8.62(d,J=7.6Hz,1H),7.89(s,1H),6.23(d,J=7.6Hz,1H),4.73(s,4H),4.29(s,4H).

[0942] 3) Preparation of the third step compound 90-3

[0943] Compound 90-2 (580 mg, 1.70 mmol), triethylamine (0.7 mL, 5.09 mmol), trimethylethynylsilane (2.4 mL, 17.0 mmol), bistriphenylphosphine palladium dichloride (119 mg, 0.17 mmol), and cuprous iodide (32.3 mg, 0.17 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction mixture was purged with nitrogen three times. After stirring at 25°C under nitrogen for 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 90-3 (464 mg). MS m / z (ESI): 313.2 [M+1] + . 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.6Hz,1H),7.97(s,1H),5.97(d,J=7.5Hz,1H),4.88(s,4H),4.39(s,4H),0.28(s,9H).

[0944] 4) Preparation of the fourth step compound 90-4

[0945] Compound 90-3 (110 mg, 0.35 mmol) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (0.5 mL, 0.46 mmol, 1.0 M tetrahydrofuran solution) was added. The reaction mixture was stirred at 25°C for 1 hour, then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (5 mL × 3) and dried over sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure to give compound 90-4 (84.6 mg). MS m / z (ESI): 241.1 [M+1] + .

[0946] 5) Step 5: Preparation of Compound 90A

[0947] Compound 90-4 (84.6 mg, 0.35 mmol), compound 88-2 (95.5 mg, 0.35 mmol), and copper sulfate pentahydrate (8.79 mg, 0.04 mmol) were dissolved in water (2 mL) and ethanol (2 mL), and sodium ascorbyl palmitate (6.97 mg, 0.04 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours, then concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 90A (70.3 mg). MS m / z (ESI): 512.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=7.6Hz,1H),8.68(s,1H),8.51(s,1H),8.35(s,1H),7.23(t,J=53.2Hz,1H),6.31(d,J=7.6Hz,1H),4.74( s,4H),4.52(t,J=5.3Hz,1H),4.33(s,4H),4.30–4.24(m,1H),3.29–3.26(m,2H),2.17–2.11(m,2H),1.93–1.77(m,5H),1.16–1.08(m,2H).

[0948] Example 33

[0949] Preparation of 4-(3-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)thiomorpholine 1,1-dioxide (91A)

[0950] 1) Preparation of Compound 91-1

[0951] Compound 1-7 (1.02 g, 6.51 mmol) was dissolved in N-methylpyrrolidone (10 mL). N,N-diisopropylethylamine (3.24 mL, 19.5 mmol) and thiomorpholine-1,1-dioxide (1.32 g, 9.77 mmol) were added sequentially. The reaction mixture was stirred at 130°C for 18 hours. The reaction mixture was filtered to obtain compound 91-1 (3.84 g). MS m / z (ESI): 253.1 [M+1] + .

[0952] 2) Preparation of the second step compound 92-2

[0953] Compound 91-1 (900 mg, 3.57 mmol) was dissolved in acetonitrile (10 mL) and dichloromethane (10 mL). N-iodosuccinimide (882 mg, 3.92 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered to obtain compound 92-2 (1.10 g). MS m / z (ESI): 379.0 [M+1] + .

[0954] 3) Preparation of the third step compound 91-3

[0955] Compound 91-2 (500 mg, 1.32 mmol), triethylamine (0.6 mL, 3.97 mmol), trimethylethynylsilane (1.9 mL, 13.2 mmol), bistriphenylphosphine palladium dichloride (92.8 mg, 0.13 mmol), and cuprous iodide (25.2 mg, 0.13 mmol) were dissolved in tetrahydrofuran (15 mL). The reaction mixture was purged with nitrogen three times. The reaction mixture was stirred at 25°C under nitrogen for 12 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 91-3 (420 mg). MS m / z (ESI): 349.0 [M+1] +

[0956] 4) Preparation of the fourth step compound 91-4

[0957] Compound 91-3 (390 mg, 1.12 mmol) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.3 mL, 1.34 mmol, 1.0 M tetrahydrofuran solution) was added. The reaction solution was stirred at 25°C for 1 hour, then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (5 mL × 2) and dried over sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure to obtain compound 91-4 (260 mg). MS m / z (ESI): 277.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ8.78(d,J=7.9Hz,1H),8.08(s,1H),6.95(d,J=7.9Hz,1H),4.18(s,4H),4.03(s,1H),3.24(s,4H).

[0958] 5) Step 5: Preparation of Compound 91A

[0959] Compound 91-4 (50.0 mg, 0.18 mmol) and compound 88-2 (51.2 mg, 0.19 mmol) were dissolved in water (1.5 mL) and ethanol (1.5 mL). Copper sulfate pentahydrate (4.52 mg, 0.02 mmol) and sodium ascorbyl palmitate (3.58 mg, 0.02 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours and then concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 91A (25.7 mg). MS m / z (ESI): 548.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=7.9Hz,1H),8.65(s,1H),8.55(s,1H),8.42(s,1H),7.20(t,J=53.2Hz,1H),6.97(d,J=7.9Hz,1H),4.47(t,J=5 .3Hz,1H),4.32–4.20(m,5H),3.29–3.21(m,6H),2.17–2.10(m,2H),1.9 3–1.86(m,2H),1.85–1.75(m,2H),1.50–1.41(m,1H),1.19–1.08(m,2H).

[0960] Example 34

[0961] Preparation of 4-((3-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-methylbutan-2-ol (92A)

[0962] 1) Preparation of compound 92-2

[0963] Compound 92-1 (2.30 g, 13.0 mmol, prepared using the synthesis method for the intermediate 5-chloro-3-ethynylpyrazolo[l,5-a]pyrimidine described on page 102 of the specification of patent application "WO2015108490 A2") and 88-2 (3.51 g, 13.0 mmol) were dissolved in a mixture of water (40 mL) and ethanol (40 mL). Copper sulfate pentahydrate (320 mg, 1.30 mmol) and sodium ascorbate (260 mg, 1.30 mmol) were added. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove the ethanol. Water (50 mL) was added to the reaction solution, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed twice with (petroleum ether / ethyl acetate = 1 / 1) and filtered. The filter cake was used directly as the starting material for the next step without purification to obtain compound 92-2 (2.30 g). MS m / z (ESI): 449.1 [M+1]. + .

[0964] 2) Preparation of Compound 92A in the Second Step

[0965] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and 4-amino-2-methyl-butan-2-ol (23.0 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 92A (12 mg). MS m / z (ESI): 516.3 [M+1]. + . 1 HNMR(400MHz,DMSO-d6)δ8.64(s,1H),8.52–8.48(m,2H),8.27(s,1H),7.68( s,1H),7.27(t,J=53.3Hz,1H),6.30(d,J=7.6Hz,1H),4.49–4.32(m,2H),4.3 0–4.22(m,1H),3.54–3.46(m,2H),3.32–3.27(m,2H),2.19–2.12(m,2H),1.9 0(d,J=13.1Hz,2H),1.85–1.70(m,4H),1.55–1.47(m,1H),1.20–1.11(m,8H).

[0966] Example 35

[0967] Preparation of 1-(3-(1-(3-difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-ylpyrazolo[1,5-a]pyrimidin-5-yl)-4-methylpiperidin-4-ol (93A)

[0968] 1) Preparation of Compound 93A

[0969] Compound 92-2 (50.0 mg, 0.110 mmol), 4-methyl-4-hydroxypiperidine (19.3 mg, 0.170 mmol, Leyan), and acetonitrile (1 mL) were added sequentially to a single-necked flask at room temperature. N,N-diisopropylethylamine (27.7 μL, 0.170 mmol) was added with stirring. The reaction system was purged with nitrogen three times and allowed to react at 80°C for 2 hours. The reaction solution was purified by HPLC (Gilson 306-1741, column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 24%-95%, flow rate: 25 mL / min) to obtain compound 93A (30.1 mg). MS m / z (ESI): 528.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.67–8.65(m,2H),8.52(s,1H),8.33(s,1H),7.21(t,J= 53.2Hz,1H),6.81(d,J=8.0Hz,1H),4.48(t,J=5.3Hz,1H),4.44(s,1H),4.30–4. 24(m,1H),4.20–3.95(m,2H),3.54–3.40(m,2H),3.28(t,J=5.7Hz,2H),2.16–2. 12(m,2H),1.94–1.73(m,4H),1.61–1.41(m,5H),1.16(s,3H),1.15–1.05(m,4H).

[0970] Example 36

[0971] Preparation of ((1r,4r)-4-(4-(4-(5-((cyclopropylmethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (94A)

[0972] 1) Preparation of Compound 94A

[0973] To a solution of 92-2 (50.0 mg, 0.110 mmol) in acetonitrile (3 mL) were added cyclopropylmethylamine (0.030 mL, 0.340 mmol) and N,N-diisopropylethylamine (58.0 mg, 0.450 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 30% to 95%, flow rate: 25 mL / min) to afford compound 94A (30.0 mg). MS m / z (ESI): 484.2 [M+1]. + . 1 HNMR(400MHz,DMSO-d6)δ8.66(s,1H),8.52–8.50(m,2H),8.27(s,1H),7.81( s,1H),7.20(t,J=53.2Hz,1H),6.35(d,J=7.6Hz,1H),4.47(t,J=5.2Hz,1H), 4.32–4.24(m,1H),3.29–3.25(m,4H),2.16–2.13(m,2H),2.02–1.70(m,4H), 1.53–1.37(m,1H),1.20–1.04(m,3H),0.56–0.44(m,2H),0.33–0.21(m,2H).

[0974] Example 37

[0975] Preparation of (1R,4R)-4-(3-difluoromethyl)-4-(4-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexylmethanol formate (95A)

[0976] 1) Preparation of Compound 95A

[0977] Compound 92-2 (50 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and N-methylpiperazine (20 mg, 0.20 mmol) and N,N-diisopropylethylamine (20 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to obtain compound 95A formate (35 mg). MS m / z (ESI): 513.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.72(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.36(s,1 H),8.17(s,1H),7.20(t,J=53.2Hz,1H),6.81(d,J=7.9Hz,1H),4.31–4.24(m,1H),3 .78–3.70(m,4H),3.28(d,J=6.2Hz,2H),2.47–2.39(m,4H),2.24(s,3H),2.19–2.11 (m,2H),1.94–1.86(m,2H),1.85–1.74(m,2H),1.50–1.40(m,1H),1.18–1.06(m,2H).

[0978] Example 38

[0979] 1-(3-(1-(3-difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-ylpyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol (96A)

[0980] 1) Preparation of Compound 96A

[0981] Compound 92-2 (50.0 mg, 0.110 mmol), 3-hydroxyazetidine hydrochloride (18.3 mg, 0.170 mmol, Leyan), and acetonitrile (1 mL) were added sequentially to a single-necked flask at room temperature. N,N-diisopropylethylamine (27.3 μL, 0.170 mmol) was added with stirring. The reaction system was purged with nitrogen three times and allowed to react at 80°C for 2 hours. The reaction solution was purified by HPLC (Gilson 306-1741, column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19% to 95%, flow rate: 25 mL / min) to obtain compound 96A (12.0 mg). MS m / z (ESI): 486.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.73–8.64(m,2H),8.52(s,1H),8.34(s,1H),7.22(t,J=53.2Hz,1H ),6.31(d,J=7.6Hz,1H),5.80(d,J=6.5Hz,1H),4.64–4.62(m,1H),4.47(t,J=5.3Hz,1H),4. 42–4.32(m,2H),4.32–4.19(m,1H),3.92–3.88(m,2H),3.27(d,J=5.7Hz,2H),2.14(d,J=11 .8Hz,2H),1.89(d,J=13.3Hz,2H),1.82–1.79(m,2H),1.53–1.39(m,1H),1.17–1.07(m,2H).

[0982] Example 39

[0983] Preparation of 1-(3-(1-(3-difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-4-ol (97A)

[0984] 1) Preparation of Compound 97A

[0985] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (1 mL) at 25°C, and 4-hydroxypiperidine (0.010 mL, 0.20 mmol) and N,N-diisopropylethylamine (43.1 mg, 0.33 mmol) were added. The reaction was stirred at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 97A (20.0 mg). MS m / z (ESI): 514.3 [M+1]. + . 1 H NMR (400MHz, DMSO-d6): δ8.65–8.62(m,2H),8.48(s,1H),8.29(s,1H),7.17(t,J=5 3.1Hz,1H),6.78(d,J=8.0Hz,1H),4.74(d,J=4.2Hz,1H),4.49–4.45(m,1H),4.27– 4.20(m,1H),4.15–4.07(m,2H),3.75–3.71(m,1H),3.25–3.20(m,3H),2.11–2.06( m,2H),1.86–1.74(m,6H),1.41–1.33(m,3H),1.22–1.16(m,1H),1.11–1.02(m,2H).

[0986] Example 40

[0987] Preparation of ((1r,4r)-4-(4-(4-(5-(1,4-oxolan-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]cyclohexyl)methanol (98A)

[0988] 1) Preparation of Compound 98A

[0989] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and 1,4-oxazepane (22.3 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 98A (22 mg). MS m / z (ESI): 514.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.71(d,J=7.9Hz,1H),8.66(s,1H),8.49(s,1H),8.35(s,1H),7 .21(t,J=53.1Hz,1H),6.74(d,J=7.9Hz,1H),4.48(t,J=5.3Hz,1H),4.30–4.21(m,1H), 4.05–3.80(m,4H),3.79–3.75(m,2H),3.64(t,J=5.5Hz,2H),3.30–3.25(m,2H),2.17–2 .10(m,2H),1.95–1.86(m,4H),2.00–1.75(m,2H),1.50–1.40(m,1H),1.20–1.05(m,2H).

[0990] Example 41

[0991] Preparation of ((1r,4r)-4-(4-(4-(5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (99A)

[0992] 1) Preparation of Compound 99A

[0993] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and 8-oxa-3-azabicyclo[3.2.1]octane (33.3 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 99A (17 mg). MS m / z (ESI): 526.3 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ8.73(d,J=7.9Hz,1H),8.66(s,1H),8.52(s,1H),8.37(s, 1H),7.26(t,J=53.2Hz,1H),6.72(d,J=7.9Hz,1H),4.49–4.44(m,3H),4.31–4.23( m,1H),4.15–4.05(m,2H),3.29–3.26(m,2H),3.16(d,J=12.8Hz,2H),2.17–2.11(m ,2H),1.91–1.78(m,6H),1.75–1.71(m,2H),1.52–1.40(m,1H),1.17–1.08(m,2H).

[0994] Example 42

[0995] Preparation of 1-(3-(1-(3-difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-3-ol (100A)

[0996] 1) Preparation of Compound 100A

[0997] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and 3-hydroxypiperidine (23.0 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 100A (27 mg). MS m / z (ESI): 514.3 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=5.0Hz,2H),8.49(s,1H),8.33(d,J=2.0Hz,1H),7.19(t, J=53.2Hz,1H),6.77(d,J=7.9Hz,1H),4.87(d,J=4.2Hz,1H),4.48(t,J=5.4Hz,1H),4.27(t ,J=12.1Hz,1H),4.11–3.97(m,2H),3.59(s,1H),3.49–3.35(m,1H),3.30–3.25(m,2H),3.2 5–3.20(m,1H),2.18–2.12(m,2H),2.00–1.75(m,6H),1.53–1.43(m,3H),1.18–1.08(m,2H).

[0998] Example 43

[0999] Preparation of 1-(3-(1-(3-difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-ol (101A)

[1000] 1) Preparation of Compound 101A

[1001] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and 3-hydroxypyrrolidine (19.2 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 101A (15 mg). MS m / z (ESI): 500.3 [M+1]. + .

[1002] 1 H NMR (400MHz, DMSO-d6): δ8.70–8.65(m,2H),8.52(s,1H),8.33(s,1H),7.20(t,J=53.2Hz,1H),6.47(s,1H),5.10–5.01(m,1H),4.50–4.41(m,2H), 4.31–4.24(m,1H),3.63(s,3H),3.30–3.25(m,2H),2.20–2.00(m,3H),2. 00–1.81(m,4H),1.80–1.74(m,2H),1.50–1.42(m,1H),1.20–1.10(m,2H).

[1003] Example 44

[1004] Preparation of ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-(4-(dimethylamino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methanol (102A)

[1005] 1) First step: Synthesis of compound 102A

[1006] Compound 92-2 (80 mg, 0.18 mmol) and 4-dimethylaminopiperidine (46 mg, 0.36 mmol, Bid) were dissolved in acetonitrile (2 mL). N,N-diisopropylethylamine (0.060 mL, 0.36 mmol) was added and stirred at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 102A (15.0 mg). MS m / z (ESI): 541.8 [M+1]. + . 1 HNMR (400MHz, DMSO-d6): δ8.71(d,J=7.9Hz,1H),8.69(s,1H),8.53(s,1H),8.36(s,1H),7. 22(t,J=53.2Hz,1H),6.84(d,J=8.0Hz,1H),4.63–4.48(m,2H),4.34–4.21(m,2H),3.28(d, J=6.2Hz,2H),3.02(t,J=12.3Hz,2H),2.64–2.54(m,1H),2.27(s,6H),2.18–2.09( m,2H),1.94–1.85(m,3H),1.86–1.73(m,3H),1.50–1.36(m,3H),1.18–1.05(m,2H).

[1007] Example 45

[1008] Preparation of ((1r,4r)-4-(4-(4-(5-((S)-3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]cyclohexyl)methanol (103A)

[1009] 1) First step: Synthesis of compound 103-1

[1010] Compound 92-2 (60 mg, 0.13 mmol) and compound (S)-3-Boc-aminopiperidine (27 mg, 0.13 mmol) were dissolved in acetonitrile (2 mL). N,N-diisopropylethylamine (0.07 mL, 0.40 mmol) was added and the mixture was stirred at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain the title compound 103-1 (30 mg). MS m / z (ESI): 611.5 [M-1]. - .

[1011] 2) Synthesis of Compound 103A

[1012] Trifluoroacetic acid (1.0 mL) was added to a solution containing compound 103-1 (25 mg, 0.040 mmol) and dichloromethane (2 mL). The reaction mixture was stirred at 25°C for one hour. The reaction mixture was concentrated, and the residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 103A (10 mg). MS m / z (ESI): 513.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.77–8.72(m,1H),8.71(s,1H),8.57(s,1H),8.37(s,1H),7.21(t,J =53.3Hz,1H),6.80(d,J=7.9Hz,1H),4.44–4.33(m,2H),4.32–4.23(m,2H),4.19–4.10(m,2H) ,3.32–3.26(m,3H),3.22–3.17(m,1H),3.05(s,1H),2.19–2.09(m,2H),2.02–1.93(m,1H),1. 93–1.85(m,2H),1.85–1.74(m,3H),1.59–1.50(m,2H),1.48–1.37(m,1H),1.18–1.05(m,2H).

[1013] Example 46

[1014] Preparation of ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl]cyclohexyl)methanol (104A)

[1015] 1) Preparation of Compound 104A

[1016] Compound 88-2 (2.20 g, 8.11 mmol) was dissolved in ethanol (30 mL) and water (10 mL). Vitamin C sodium (0.33 g, 1.67 mmol, Anaiji), copper sulfate pentahydrate (0.41 g, 1.64 mmol, Anaiji) and compound 4-5 (1.86 g, 8.15 mmol) were added to the reaction solution. The reaction solution was stirred at 25 ° C for 18 hours. The reaction solution was filtered, the solid was collected and slurried with a mixed solvent (petroleum ether / ethyl acetate=1 / 1, 30 mL) to obtain compound 104A (3.20 g). MS m / z(ESI):500.4[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ8.76(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),6.81(d,J=7.9Hz,1H),4.50(s ,1H),4.27(t,J=11.9Hz,1H),3.73(s,8H),3.28(d,J=5.7Hz,2H),2.19 –2.07(m,2H),1.93–1.76(m,4H),1.54–1.38(m,1H),1.20–1.07(m,2H).

[1017] Example 47

[1018] Preparation of ((1R,4r)-4-(4-(4-(5-((1R,4r)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (105A)

[1019] 1) Preparation of Compound 105A

[1020] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (29.8 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 105A (15 mg). MS m / z (ESI): 512.3 [M+1]. + . 1 HNMR(400MHz,DMSO-d6)δ:8.73(d,J=7.7Hz,1H),8.67(s,1H),8.61–8.50(m,1H),8.35(s,1H), 7.21(t,J=53.2Hz,1H),6.80–6.33(m,1H),5.30–4.98(m,1H),4.74(s,1H),4.55–4.48(m,1H),4 .32–4.24(m,1H),3.84–3.81(m,1H),3.79–3.68(m,1H),3.60–3.40(m,2H),3.30–3.26(m,2H), 2.17–2.11(m,2H),1.99–1.87(m,4H),1.84–1.75(m,2H),1.49–1.41(m,1H),1.17–1.07(m,2H).

[1021] Example 48

[1022] Preparation of ((1r,4r)-4-(4-(4-(5-(((R)-3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]cyclohexyl)methanol (106A)

[1023] 1) Preparation of Compound 106-1

[1024] To a solution of compound 92-2 (50.0 mg, 0.11 mmol) in acetonitrile (1 mL) were added N,N-diisopropylethylamine (43.1 mg, 0.33 mmol) and compound (R)-3-Boc-aminopiperidine (44.6 mg, 0.22 mmol) at room temperature. The reaction was stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain the title compound 106-1 (30.0 mg). MS m / z (ESI): 613.8 [M+1] + .

[1025] 2) Preparation of the second step compound 106A

[1026] Compound 106-1 (30.0 mg, 0.05 mmol) was dissolved in a 4M solution of hydrogen chloride in dioxane (1 mL). The mixture was stirred at 25°C for 1 hour, and the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 106A (21.3 mg). MS m / z (ESI): 514.0 [M+1] + .

[1027] Example 49

[1028] Preparation of (1R,2S)-2-((3-(1-(3-(difluoromethyl)-1-((1R,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexan-1-ol (107A)

[1029] 1) Preparation of Compound 107A

[1030] Compound 92-2 (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (3 mL), and (1R,2S)-2-aminocyclohexanol hydrochloride (33.4 mg, 0.22 mmol, Bidler) and N,N-diisopropylethylamine (43.2 mg, 0.33 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 107A (7 mg). MS m / z (ESI): 528.3 [M+1]. + . 1 H NMR(400MHz, DMSO-d6)δ:8.68(s,1H),8.49(d,J=7.6Hz,1H),8.43(s,1H),8.26(s,1H),7.48(d,J=7.6 Hz,1H),7.23(t,J=53.1Hz,1H),6.50(d,J=7.6Hz,1H),4.74–4.67(m,1H),4.51(t,J=5.4Hz,1H),4.32 –4.23(m,1H),4.13–4.05(m,1H),3.95(s,1H),3.27(t,J=5.6Hz,2H),2.17–2.11(m,2H),1.91–1.85(m ,2H),1.82–1.70(m,4H),1.63–1.52(m,4H),1.47–1.41(m,1H),1.37–1.29(m,2H),1.17–1.08(m,2H).

[1031] Example 50

[1032] Preparation of ((1r,4r)-4-(4-(4-(5-(5-amino-3,3-difluoropiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-ylcyclohexyl)methanol (108A)

[1033] 1) Preparation of Compound 108-1

[1034] Compound 92-2 (100 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL), and tert-butyl N-(5,5-difluoropiperidin-3-yl)carbamate (105 mg, 0.45 mmol, Jiangsu Aikang) and N,N-diisopropylethylamine (86.4 mg, 0.67 mmol) were added. After stirring at 80°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 108-1 (100 mg). MS m / z (ESI): 649.5 [M+1] + .

[1035] 2) Preparation of the second step compound 108A

[1036] Compound 108-1 (100 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and hydrogen chloride in dioxane (5 mL, 4 M) was added. After stirring at room temperature for 1 hour, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 108A (25 mg). MS m / z (ESI): 549.5 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ:8.82(d,J=7.8Hz,1H),8.70(s,1H),8.58(s,1H),8.41(s,1H) ,7.23(t,J=53.3Hz,1H),6.92(d,J=7.9Hz,1H),4.80–4.44(m,3H),4.34–4.21(m,3H),3 .68–3.55(m,1H),3.28(d,J=6.1Hz,2H),3.12–2.99(m,2H),2.45–2.35(m,1H),2.19–2. 11(m,2H),2.02–1.86(m,3H),1.85–1.74(m,2H),1.51–1.41(m,1H),1.20–1.06(m,2H).

[1037] Example 51

[1038] ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-((2S,6S)-2,6-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methanol (109A)

[1039] 1) Preparation of Compound 109A

[1040] To a solution of compound 92-2 (45.0 mg, 0.100 mmol) in acetonitrile (2 mL) were added (2S,6S)-2,6-dimethylmorpholine (23.0 mg, 0.200 mmol) and N,N-diisopropylethylamine (52.0 mg, 0.400 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson 306-1741, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-95%, flow rate: 25 mL / min) to obtain compound 109A (35.0 mg). MS m / z (ESI): 528.3 [M+1]. + . 1 HNMR(400MHz,DMSO-d6)δ8.74(d,J=8.0Hz,1H),8.68(s,1H),8.52(s,1H),8.36(s,1 H),7.23(t,J=53.2Hz,1H),6.82(d,J=8.0Hz,1H),4.50(t,J=5.2Hz,1H),4.33–4.21 (m,1H),4.09–3.99(m,2H),3.87(d,J=12.8Hz,2H),3.55–3.43(m,2H),3.27(t,J=5. 6Hz, 2H), 2.13 (d, J = 9.6Hz, 2H), 1.96–1.72 (m, 4H), 1.45 (s, 1H), 1.22–1.07 (m, 8H).

[1041] Example 52

[1042] Preparation of ((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methanol (110A)

[1043] 1) Preparation of Compound 110A

[1044] To a solution of 92-2 (50.0 mg, 0.110 mmol) in acetonitrile (2 mL) were added piperazine (48.0 mg, 0.56 mmol) and N,N-diisopropylethylamine (144 mg, 1.11 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson 306-1741, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20%-95%, flow rate: 25 mL / min) to afford compound 110A (35.0 mg). MS m / z (ESI): 499.2 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.73–8.64(m,2H),8.52(s,1H),8.35(s,1H),7.21(t,J=53.2Hz,1H),6.78(d,J=8.0Hz,1H),4.51(t,J=5.2Hz,1H),4.35–4 .18(m,1H),3.67(s,4H),3.27(t,J=5.4Hz,2H),2.86–2.74(m,4H),2.13( d,J=9.8Hz,2H),1.95–1.72(m,4H),1.53–1.38(m,1H),1.19–1.03(m,2H).

[1045] Example 53

[1046] Preparation of (1S,2R)-2-((3-(1-(3-(difluoromethyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexan-1-ol (111A)

[1047] 1) Preparation of Compound 111A

[1048] To a solution of 92-2 (100 mg, 0.220 mmol) in acetonitrile (2 mL) were added (1S,2R)-2-aminocyclohexanol hydrochloride (101 mg, 0.670 mmol) and N,N-diisopropylethylamine (173 mg, 1.34 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson 306-1741, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 42% to 95%, flow rate: 20 mL / min) to afford the title compound 111A (50.0 mg). MS m / z (ESI): 528.3 [M+1]. + . 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.49(d,J=7.6Hz,1H),8.43(s,1H),8.26(s,1H),7.46(d,J=7.4Hz ,1H),7.22(t,J=53.2Hz,1H),6.49(d,J=7.6Hz,1H),4.70(d,J=4.0Hz,1H),4.50(t,J=5.2Hz,1H),4.33–4 .21(m,1H),4.15–4.04(m,1H),3.95(s,1H),3.27(t,J=5.6Hz,2H),2.14(d,J=9.8Hz,2H),1.89(d,J=12. 2Hz,2H),1.84–1.67(m,4H),1.66–1.51(m,4H),1.49–1.40(m,1H),1.38–1.26(m,2H),1.19–1.05(m,2H).

[1049] Example 54

[1050] Preparation of (S)-1-(3-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-3-ol (112A)

[1051] 1) Preparation of Compound 112A

[1052] Compound 92-2 (50.0 mg, 0.110 mmol), (S)-3-hydroxypiperidine hydrochloride (18.3 mg, 0.170 mmol), and acetonitrile (1 mL) were added sequentially to a single-necked flask at room temperature. N,N-diisopropylethylamine (27.3 μL, 0.170 mmol) was added with stirring. The reaction system was purged with nitrogen three times and allowed to react at 80°C for 18 hours. The reaction solution was purified by HPLC (Gilson 306-1741, column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 21% to 95%, flow rate: 25 mL / min) to afford compound 112A (10.1 mg). MS m / z (ESI): 514.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.67–8.65 (m, 2H) 8.49 (s, 1H), 8.34 (s, 1H), 7.20 (t, J = 53.2Hz, 1H), 6. 77(d,J=7.9Hz,1H),4.89(d,J=4.2Hz,1H),4.51(t,J=5.3Hz,1H),4.32–4.22(m,1H),4.15–4.0 3(m,1H),4.00(d,J=13.3Hz,1H),3.63–3.53(m,1H),3.49–3.39(m,1H),3.27(t,J=5.8Hz,2H), 3.24–3.14(m,1H),2.19–2.08(m,2H),1.93–1.75(m,6H),1.52–1.40(m,3H),1.18–1.05(m,2H).

[1053] Example 55

[1054] Preparation of (R)-1-(3-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-3-ol (113A)

[1055] 1) Preparation of Compound 113A

[1056] Compound 92-2 (50.0 mg, 0.110 mmol), (R)-3-hydroxypiperidine hydrochloride (17.0 mg, 0.170 mmol), and acetonitrile (2 mL) were added sequentially to a single-necked flask at room temperature. N,N-diisopropylethylamine (60.0 μL, 0.39 mmol) was added with stirring. The reaction system was purged with nitrogen three times and allowed to react at 80°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by HPLC (A: 0.1% FA / H2O B: ACN, column: Wetch-Ultimate-XB-C18-10 μm-21.2*150 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 25% to 45%, flow rate: 25 mL / min) to afford compound 113A (30 mg). MS m / z (ESI): 514.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ8.71–8.63(m,2H),8.50(s,1H),8.34(s,1H),7.20(t,J=52.8 Hz,1H),6.78(d,J=8.0Hz,1H),4.96–4.85(m,1H),4.58–4.45(m,1H),4.34–4.22(m,1H) ,4.15–3.93(m,2H),3.66–3.54(m,1H),3.47–3.39(m,1H),3.30–3.25(m,2H),3.23–3. 16(m,1H),2.19–2.09(m,2H),1.94–1.74(m,6H),1.55–1.40(m,3H),1.19–1.05(m,2H).

[1057] Test Case

[1058] Test Example 1, IRAK4 kinase inhibition experimental method:

[1059] This experiment uses the Cisbio HTRF KinEASE-STK SI kit (62S1PEB). The assay / detection buffer, STK Substrate 1-biotin, Streptavidin-XL665, and STK Antibody-Crypatete are all included in the kit.

[1060] Compounds / DMSO were added to a 384-well plate (PerkinElmer 6008280) using an Echo 665. 5 μL of assay buffer [1 volume of 5X kinase buffer + 20 mM magnesium chloride (Sigma) solution + 1 mM DTT (Alfa Aesar) solution + 4 volumes of deionized water] was added to the plate at a 2-fold reaction concentration of IRAK4 kinase protein (final concentration: 10 nM). The plate was sealed, shaken, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 5 minutes. 5 μL of assay buffer was then added to the plate at a 2-fold reaction concentration of STK Substrate 1-biotin (final concentration: 1 μM) and ATP (Sigma) were added. A 1:1 mixture of Streptavidin-XL665 (final concentration: 62.5 nM) and STK-antibody-cryptate (final concentration: 200 μM) was added to the sealed shallow well plate and centrifuged at 1000 rpm for 1 minute after shaking. After incubation at 37°C for 2 hours, 10 μL of a 1:1 mixture of Streptavidin-XL665 (final concentration: 62.5 nM) and STK-antibody-cryptate dissolved in the detection buffer was added. The shallow well plate was sealed and centrifuged at 1000 rpm for 1 minute after shaking. After incubation at room temperature for 1 hour, the values ​​were read at 620 nm / 665 nm using a microplate reader. Data were analyzed using Prism 9.3 software, and the IC of IRAK4 kinase inhibition was fitted using a four-parameter logistic equation. 50 value.

[1061] The experimental results show that the compounds of the present invention have excellent inhibitory activity against IRAK4 kinase. The IC50 values ​​of representative compounds of the present invention are shown in the following table.

[1062] Table 1 IRAK4 kinase inhibitory activity of representative compounds of the present invention

[1063] In Table 1, A represents: >5000 nM; B represents 1000-5000 nM; C represents 100-1000 nM; and D represents <100 nM.

[1064] Test Example 2: HiBit fluorescence detection method for protein degradation:

[1065] Using HiBiT tag technology, a plasmid containing a HiBiT tag was attached to IRAK4. The plasmid was transfected into HEK293T cells, and the HiBiT fluorescence level was measured to characterize the degradation level of IRAK4 by the compound. 1 mL of fresh culture medium was used to seed 300,000 HEK293T cells into a 6-well plate (Corning 3516) and placed in a constant temperature incubator at 37°C and 5% CO2 overnight. 3 μL X-tremeGENE TM9 DNA Transfection Reagent (Roche #06365787001), 1 μg of pcDNA3.1-IRAK4-HiBiT was added to 200 μL of Opti-MEM (Gibico 31985062) and gently mixed. The 6-well plate was removed from the overnight incubation, allowed to stand at room temperature for 15 minutes, and then added dropwise to the 6-well plate. Six hours after transient transfection, cells were trypsinized and centrifuged at 1000 rpm for 3 minutes. 5,000 HEK293T cells were seeded into 384-well plates (Corning 3765) with 40 μL of fresh culture medium and incubated overnight at 37°C, 5% CO2. Then, 40 nL of compound was added to the 384-well plate using an Echo 655 Liquid Handler. The final concentration was 10 μM, and serial dilutions were made in 1:3, for a total of 10 concentrations. The plates were incubated at 37°C, 5% CO2 for 24 hours. Take out the 384-well plate and equilibrate to room temperature. Add 40 μL to each well. HiBiT Lytic Detection System (Promega N3030) was used for incubation at room temperature for 15 minutes, and fluorescence values ​​were recorded using EnVision Xcite Multilabel Reader (PerkinElmer 2105-0020). Data were analyzed using Prism 9.3 software, and a four-parameter logistic equation was fitted to the DC degradation of IRAK4. 50 value.

[1066] The experimental results show that the PROTAC molecule containing the compound of the present invention has an excellent degradation level of IRAK4.

Claims

1. A compound of formula A, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof, in: A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k replaced by; More preferably, A is selected from and Optionally substituted R k Replaced by, where #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 The attachment site; More preferably, A is selected from Among them #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 The attachment site; More preferably, A is selected from Among them #R 1 Indicates connection R 1 The connection site, $L 1 Indicates connection L 1 The attachment site; R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl; further preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl; B is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B is optionally substituted by R a 、R b Preferably, B is substituted by at least one of the substituents R a 、R b Preferably, B is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B is substituted by R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms; Preferably, B is selected from a 9-membered heteroaryl group, a pyridyl group, and a phenyl group, and B is substituted by R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms; More preferably, B is selected from Pyridyl, phenyl, pyrimidinyl, and B is substituted by R a 、R b replaced by at least one of; More preferably, B is selected from Pyridyl, phenyl, and B is substituted by R a 、R b replaced by at least one of; More preferably, B is selected from and B is substituted with R a 、R b replaced by; More preferably, B is selected from and B is substituted with R a 、R b replaced by; R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxy), wherein the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl are optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, Cy1 is optionally replaced by R cy1 and R cy2 More preferably, Cy1 is optionally substituted by R cy1 and R cy2 substituted 6-membered heterocyclic group, further preferably, Cy1 is optionally replaced by R cy1 and R cy2 substituted morpholine, piperazine, thiomorpholine; R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; Preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo; Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl substituents; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and the pyrrolidinyl, imidazolidinyl, piperidinyl is optionally substituted with 1-3 substituents selected from F, Cl, Br, methyl; further preferably, Cy2 is selected from pyrrolidinyl, and the pyrrolidinyl is optionally substituted with 1-3 (such as 1 or 2 or 3) F; Preferably, R a Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with C1-C6 alkyl (preferably methyl), F, Cl, Br; m is selected from 0, 1, 2, 3; preferably, m is selected from 0, 1; n is selected from 0, 1, 2, 3; preferably, n is selected from 0, 1; p is selected from 0, 1, 2, 3; preferably, p is selected from 0, 1; More preferably, m is 0 and n is 0; More preferably, R a Selected from hydrogen, cyano, carboxyl, (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 More preferably, R a Selected from hydrogen, cyano, carboxyl, (Preferred (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )； More preferably, R a Selected from hydrogen, cyano, More preferably, R a Selected from hydrogen, cyano, R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), Preferably, R b Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Or, R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl); preferably, R a 、R b Together with the carbon atoms to which they are attached, they form R c is selected from hydrogen, C1-C6 alkyl; preferably, R c Selected from C1-C6 alkyl; Most preferably, B as a whole is selected from: (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, B as a whole is selected from (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、、 (Preferred )、 Most preferably, B as a whole is selected from (Preferred )、 (Preferred (Preferred )、 (Preferred (Preferred )、 Most preferably, B as a whole is selected from L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Selected from direct bond, methylene, Preferably, L 1 Select from direct keys, Preferably, L 1 Select from direct keys; R 1 Selected from C is selected from 5-6 membered heteroaryl, and C is optionally substituted by R d 、R e 、R f Preferably, C is selected from 5-6 membered heteroaryl, the 5-6 membered heteroaryl contains 1-3 heteroatoms, and C is optionally substituted by R d 、R e 、R f More preferably, C is selected from pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, oxazolyl, furyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C is optionally substituted by R d 、R e 、R f More preferably, C is selected from pyrazolyl, thiazolyl, pyridyl, pyrrolyl, oxazolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C is optionally substituted by R d 、R e 、R f replaced by at least one of; R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclic group are each independently optionally substituted with C1-C6 alkyl, 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; Preferably, R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclic group are each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; Preferably, R d C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, morpholinyl, piperazinyl, piperidinyl, said C3-C6 cycloalkyl, phenyl, pyridyl, morpholinyl, piperazinyl, piperidinyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen, alkoxy substituted by a substituent such as a C1-C6 alkyl group (e.g., a C1-C6 alkoxy group), a hydroxyl group, an amino group, a hydroxy C1-C6 alkyl group (e.g., a hydroxymethyl group), an amino C1-C6 alkyl group, or a formyl group; Preferably, R d Selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperidinyl, wherein the C3-C6 cycloalkyl, phenyl, morpholinyl, piperidinyl are each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl; More preferably, R d Selected from C1-C6 alkyl, Phenyl, morpholinyl, piperazinyl, piperidinyl, the Phenyl, morpholinyl, piperazinyl, piperidinyl are optionally substituted by C1-C6 alkyl (preferably methyl); more preferably, R d Selected from Phenyl, morpholinyl, piperidinyl; p is selected from 0, 1, 2; R g is selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl; More preferably, R d Selected from methyl, ethyl, isopropyl, Piperazinyl, piperidinyl, More preferably, R d Selected from piperazinyl; More preferably, R d Selected from R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl; preferably, R e Selected from hydrogen, methyl, F3C-、 -NHCH3; Preferably, R e Selected from hydrogen, methyl, F3C-、 Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl; Preferably, R e 、R f Together with the carbon atoms to which they are attached, they form Each R j Independently selected from hydrogen, C1-C6 alkyl, alkoxy (e.g., C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy; More preferably, R e 、R f Together with the carbon atoms to which they are attached, they form R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms; Preferably, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl, Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form Most preferably, R 1 As a whole, selected from: Most preferably, R 1 As a whole, selected from: Most preferably, R 1 As a whole, selected from: Most preferably, R 1 As a whole, selected 2. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula I, in: A 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by R k Preferably, A 1 is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A 1 Selected from 1,2,3-triazole ring, 1,2,4- triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring; further preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 More preferably, A 1 Selected from Among them #R 11 Indicates connection R 11 The connection site, $L 1 Indicates connection L 1 The attachment site; R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl; further preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl; B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 Optionally substituted R a 、R b Preferably, B 1 Substituted group R a 、R b Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; Preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, and B 1 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; More preferably, B 1 Selected from Pyridyl, phenyl, pyrimidinyl, and B 1 Substituted group R a 、R b More preferably, B 1 Selected from Pyridyl, phenyl, and B 1 Substituted group R a 、R b replaced by at least one of; More preferably, B 1 Selected from And B 1 Substituted group R a 、R b replaced by; More preferably, B 1 Selected from And B 1 Substituted group R a 、R b Replaced by; R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkane C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, (where Cy1 is optionally replaced by R cy1 and R cy2 substituted 4-9 membered heterocyclic group), -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl, the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl is optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted with C1-C6 alkyl, halogen, hydroxy, or cyano; Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is a morpholinyl group, a piperazinyl group, or a thiomorpholinyl group; R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo; Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; further preferably, Cy2 is selected from pyrrolidinyl, and the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F groups; Preferably, R a Selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br); m is selected from 0, 1, 2, 3; preferably, m is selected from 0, 1; n is selected from 0, 1, 2, 3; preferably, n is selected from 0, 1; p is selected from 0, 1, 2, 3; preferably, p is selected from 0, 1; More preferably, R a Selected from hydrogen, cyano, carboxyl, (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 More preferably, R a Selected from hydrogen, cyano, (Preferred (Preferred )、 (Preferred )、 R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), Preferably, R b Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Or, R a 、R b Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as tert-butyl); Preferably, R a 、R b Together with the carbon atoms to which they are attached, they form R c is selected from hydrogen, C1-C6 alkyl; preferably, R c Selected from C1-C6 alkyl; Most preferably, B 1 As a whole, selected from: (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, B 1 As a whole, selected from: (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, B 1 As a whole, selected L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Selected from direct bond, methylene, Preferably, L 1 Select from direct keys, R 11 Selected from C 1 is selected from 5-6 membered heteroaryl, and C 1 Optionally substituted R d 、R e 、R f Preferably, C 1 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f More preferably, C 1 is selected from pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, and C 1 Optionally substituted R d 、R e 、R f replaced by at least one of; R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclic group, The C3-C7 cycloalkyl and 4-7 membered saturated heterocyclic group are optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; R d 、R e 、R f Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, The C3-C7 cycloalkyl group is optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; Preferably, R d is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; preferably, R d is selected from 4-7 membered saturated heterocyclic groups, wherein the 4-7 membered saturated heterocyclic groups are optionally substituted by 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, and formyl; Preferably, R d Selected from C1-C6 alkyl, Or more preferably, R d is selected from pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl, wherein the pyrrolyl, piperidinyl, imidazolidinyl, piperazinyl is optionally substituted by 1-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl); more preferably, R d Selected from p is selected from 0, 1, 2; Or more preferably, R d Selected from pyrrolyl and piperidinyl, wherein the pyrrolyl and piperidinyl are optionally substituted by 1-2 groups selected from halogen and C1-C6 alkyl (preferably methyl); R g is selected from hydrogen, amino, hydroxy, hydroxy C1-C6 alkyl, formyl; More preferably, R d Selected from methyl, ethyl, isopropyl, Piperidinyl, More preferably, R d Selected from More preferably, R d Selected from R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; Preferably, R h 、R i Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl; Preferably, R e Selected from hydrogen, methyl, -NHCH3; preferably, R e Selected from hydrogen, methyl, F3C-、 Or, R e 、R f Together with the carbon atoms to which they are respectively attached, they form a substituted or unsubstituted 5-9 membered heterocyclic ring, wherein the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl; Preferably, R e 、R f Together with the carbon atoms to which they are attached, they form Each R j Independently selected from hydrogen, C1-C6 alkyl, alkoxy (e.g., C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxy; More preferably, R e 、R f Together with the carbon atoms to which they are attached, they form R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are commonly connected, they form a 5-6 membered saturated heterocyclic group. Preferably, the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms. Preferably, R 2 、R 3 Each independently selected from hydrogen, methyl, ethyl, propyl, Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form Most preferably, R 11 As a whole, selected from: Most preferably, R 11 As a whole, selected from: Most preferably, R 11 As a whole, 3. The compound of claim 2, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is formula i-1, Among them: A 1 、B 1 、R 11 The definition is as defined in claim 2.

4. The compound according to any one of claims 2 to 3, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is formula i-1-1, Among them: A 1 、B 1 、C 1 The definition is as defined in claim 2.

5. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula II, Among them: A 2 is selected from a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is optionally substituted by R k Preferably, A 2 is selected from a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least one heteroatom is a nitrogen atom, and the 6-membered heteroaromatic ring is optionally substituted by R k More preferably, A 2 is selected from 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k Further preferably, A 2 Selected from and Optionally substituted R k Replaced by, where #R 12 Indicates connection R 12 The connection site, $B 2 Indicates connection B 2 The attachment site; More preferably, A 2 Selected from Among them #R 12 Indicates connection R 12 The connection site, $B 2 Indicates connection B 2 The attachment site; R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl; R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl, B 2 is selected from 6-10 membered heteroaryl, and B 2 Optionally substituted R a 、R b Preferably, B 2 Substituted group R a 、R b Preferably, B 2 is selected from 9-membered heteroaryl groups, and B 2 Substituted group R a 、R b Preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms selected from N, O, and S atoms; More preferably, B 2 Selected from And B 2 Substituted group R a 、R b replaced by at least one of; R a Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g., trifluoromethyl); preferably, R a Selected from hydrogen, cyano, C1-C6 haloalkyl (e.g. trifluoromethyl); more preferably, R a Selected from hydrogen, cyano, R b Selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl), Preferably, R b Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Most preferably, B 2 As a whole, selected R 12 Selected from C 2 is selected from 5-6 membered heteroaryl, and C 2 Optionally substituted R d 、R e 、R f replaced by at least one of; Preferably, C 2 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups contain 1-3 heteroatoms, and C 2 Optionally substituted R d 、R e 、R f More preferably, C 2 is selected from pyrrolyl, oxazolyl, furyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C 2 Optionally substituted R d 、R e 、R f replaced by at least one of; R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group, and the C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclic group is each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxyC1-C6 alkyl (e.g., hydroxymethyl), aminoC1-C6 alkyl, and formyl; Preferably, R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl, wherein the C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl are each independently optionally substituted with 1-2 substituents selected from halogen, alkoxy (e.g., C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g., hydroxymethyl), amino C1-C6 alkyl, formyl; more preferably, R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl; further preferably, R d Selected from piperazinyl; Preferably, R e Selected from hydrogen, methyl, F3C-、 Most preferably, R 12 As a whole, selected from:

6. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The structural formula of the compound is Formula I, Wherein: A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by R k Further preferably, A is selected from and Optionally substituted R k Replaced by, where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site; More preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site; More preferably, A is selected from Where #C represents the connection site of C, $L 1 Indicates connection L 1 The attachment site; R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl; R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl, B is selected from any one of the groups (1) to (7): (1) Where: R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclic group, 4-9 membered saturated heterocyclic group-C1-C6 alkyl, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclic group), the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclic group may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl) alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3; m1 is preferably 0; n1 is selected from 0, 1, 2, 3; n1 is preferably 0, 1; More preferably, R 4 Selected from hydrogen, (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )； R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 5 is selected from hydrogen, cyano; Most preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred ) (Preferred )、 (Preferred )、 (2) Where: R 6 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 6 Selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 for R 7 Selected from hydrogen, C1-C6 alkyl; Most preferably, As a whole, (3) Where: R 8 、R 9 、R 10 、R 11 wherein any one is selected from cyano, C1-C6 haloalkyl (e.g., trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and the rest are hydrogen; preferably, R 8 、R 9 、R 10 、R 11 In, R 8 、R 9 or R 11 Selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), The rest are hydrogen; m3 is selected from 0, 1, 2, 3; n3 is selected from 0, 1, 2, 3; most preferably, As a whole, selected (4) Where: R 12 is selected from hydrogen, C1-C6 alkyl; preferably, R 12 Selected from C1-C6 alkyl; (5) Where: R 22 Selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; Preferably, R 22 Selected from hydrogen, m4 is selected from 0, 1, 2, 3; n4 is selected from 0, 1, 2, 3; more preferably, R 22 Selected from hydrogen, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 Selected from hydrogen, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected (6) Where: R 24 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 24 Selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3; more preferably, R 24 for (7) Where: R 25 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; n6 is selected from 0, 1, 2, 3; more preferably, R 25 Selected from hydrogen, Preferably, R 25 is hydrogen; R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, Most preferably, As a whole, selected Most preferably, As a whole, selected L 1 Selected from direct bond, C1-C6 alkyl, Preferably, L 1 Select from direct keys, Preferably, L 1 Select from direct keys; C is selected from any one of the groups (1) to (10): (1) Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl; Preferably, R 13 Selected from trifluoromethyl, Preferably, R 13 Selected from More preferably, R 13 Selected from R 14 is selected from C3-C6 cycloalkyl, piperidinyl, wherein the C3-C6 cycloalkyl and piperidinyl are optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl; preferably, R 14 is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl) and formyl; Preferably, R 14 Selected from p is selected from 0, 1, 2; R g Selected from hydrogen, hydroxy C1-C6 alkyl, formyl; Or, preferably, R 14 is selected from piperidinyl, said piperidinyl being optionally substituted by 1-2 C1-C6 alkyl groups (preferably methyl); More preferably, R 14 Selected from Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected (2) Where: R 15 Selected from C1-C6 haloalkyl; R 16 Selected from C3-C6 cycloalkyl; Most preferably, As a whole, (3) Where: R 17 Selected from hydrogen, C1-C6 alkyl; preferably, As a whole, (4) Where: R 18 is selected from hydrogen, C1-C6 alkyl; preferably, R 18 Selected from C1-C6 alkyl; most preferably, As a whole, (5) Where: R 19 is selected from hydrogen, C1-C6 alkyl; preferably, R 19 Selected from C1-C6 alkyl; most preferably, As a whole, (6) Where: R 20 Selected from C3-C6 cycloalkyl; most preferably, As a whole, (7) Where: R 27 Selected from phenyl, C3-C6 cycloalkyl; most preferably, As a whole, selected (8) Where: R 28 is selected from 6-membered saturated heterocyclic groups; preferably, R 28 is morpholinyl; most preferably, As a whole, (9) Where: R 29 Selected from C3-C6 alkyl; most preferably, As a whole, (10) Where: R 30 Selected from C3-C6 cycloalkyl; R 31 Selected from C1-C6 alkyl; most preferably, As a whole, 7. The compound of claim 6, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula I-1, Wherein, the definitions of A, B, and C are as defined in claim 6.

8. The compound according to any one of claims 6 to 7, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The structural formula of the compound is Formula I-1-1, Wherein: A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by R k Preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is a N atom, and the 5-membered heteroaromatic ring and the 6-membered heteroaromatic ring are optionally substituted with R k More preferably, A is selected from 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone ring, pyridazine ring, and the 2-pyridone ring is optionally substituted by R k replaced by; More preferably, A is selected from and Optionally substituted R k substituted, wherein #C represents the attachment site for C, and $B represents the attachment site for B; More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; R k Selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (e.g., C1-C6 alkoxy), 4-9 membered heterocyclic group (e.g., 5-6 membered saturated heterocyclic group), 6-10 membered aryl, 5-10 membered heteroaryl; preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclic group (e.g. 5-6 membered saturated heterocyclic group); more preferably, R k Selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl; R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p 、R q Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl, B is selected from any one of the groups (1) to (7): (1) Where: R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclic group, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); n1 is selected from 0, 1, 2, 3; More preferably, R 4 Selected from hydrogen, (Preferred (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )； R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 Selected from hydrogen, cyano, Preferably, R 5 Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Most preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Most preferably, As a whole, selected (2) Where: R 6 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 6 Selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 for R 7 Selected from hydrogen, C1-C6 alkyl; most preferably, As a whole, (3) Where: R 8 、R 9 、R 10 、R 11 Among them, any one is selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and the rest are hydrogen; Preferably, R 8 、R 9 、R 10 、R 11 In, R 8 、R 9 or R 11 Selected from cyano, C1-C6 haloalkyl (such as trifluoromethyl), The rest are hydrogen; m3 is selected from 0, 1, 2, 3; n3 is selected from 0, 1, 2, 3; Most preferably, As a whole, selected (4) Where: R 12 is selected from hydrogen, C1-C6 alkyl; preferably, R 12 Selected from C1-C6 alkyl; (5) Where: R 22 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 22 Selected from hydrogen, m4 is selected from 0, 1, 2, 3; m4 is preferably 0; n4 is selected from 0, 1, 2, 3; n4 is preferably 0, 1; more preferably, R 22 Selected from hydrogen, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, (where Cy1 is optionally replaced by R cy1 and R cy2 taken substituted 4-9 membered heterocyclic group), (where R z is H or C1-C6 alkyl, Cy2 is a 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, and the 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl is optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl); Preferably, Cy1 is a 5-7 membered heterocyclic group, more preferably, Cy1 is a 6 membered heterocyclic group, further preferably, Cy1 is morpholine, piperazine, or thiomorpholine; R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 Each is independently selected from C1-C6 alkyl, halogen, hydroxy, amino, oxo, and more preferably R cy1 and R cy2 are each independently selected from oxo; Preferably, Cy2 is a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy; further preferably, Cy2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl, and the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy2 is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and the pyrrolidinyl, imidazolidinyl, piperidinyl are optionally substituted by 1-3 F, Cl, Br, and methyl groups; preferably, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 Selected from hydrogen, cyano, Preferably, R 23 Selected from hydrogen, cyano, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected (6) Where: R 24 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; Preferably, R 24 Selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3; more preferably, R 24 for (7) Where: R 25 is selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; m6 is preferably 0; n6 is selected from 0, 1, 2, 3; n6 is preferably 0, 1; More preferably, R 25 Selected from hydrogen, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 Selected from hydrogen, cyano, Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected C is selected from any one of the groups (1) to (11): (1) Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl; Preferably, R 13 Selected from More preferably, R 13 Selected from R 14 is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (eg hydroxymethyl), formyl; or R 14 is selected from phenyl, morpholinyl, piperazinyl, piperidinyl, wherein the phenyl, morpholinyl, piperazinyl, piperidinyl is optionally substituted with 1-2 substituents selected from C1-C6 alkyl, halogen, alkoxy (e.g. C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (e.g. hydroxymethyl), amino C1-C6 alkyl, formyl. Preferably, R 14 Selected from p is selected from 0, 1, 2; Or preferably, R 14 Selected from piperidinyl, the piperidinyl is optionally substituted by 1-2 substituents selected from C1-C6 alkyl (preferably methyl), halogen, hydroxyl, amino R g Selected from hydrogen, hydroxy C1-C6 alkyl, formyl; More preferably, R 14 Selected from More preferably, R 14 Selected from Most preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, selected (2) Where: R 15 Selected from C1-C6 haloalkyl; R 16 Selected from C3-C6 cycloalkyl; most preferably, As a whole, (3) Where: R 17 Selected from hydrogen, C1-C6 alkyl; preferably, As a whole, (4) Where: R 18 is selected from hydrogen, C1-C6 alkyl; preferably, R 18 Selected from C1-C6 alkyl; most preferably, As a whole, (5) Where: R 19 is selected from hydrogen, C1-C6 alkyl; preferably, R 19 Selected from C1-C6 alkyl; most preferably, As a whole, (6) Where: R 20 Selected from C3-C6 cycloalkyl; most preferably, As a whole, (7) Where: R 27 Selected from phenyl, C3-C6 cycloalkyl; most preferably, As a whole, selected (8) Where: R 28 is selected from 6-membered saturated heterocyclic groups; preferably, R 28 is morpholinyl; Most preferably, As a whole, (9) Where: R 29 Selected from C3-C6 alkyl; most preferably, As a whole, (10) Where: R 30 Selected from C3-C6 cycloalkyl; R 31 Selected from C1-C6 alkyl; Most preferably, As a whole, (11) Where: R 32 is selected from phenyl, C3-C6 cycloalkyl; R 33 is selected from C1-C6 alkyl, C1-C6 haloalkyl (e.g. trifluoromethyl, difluoromethyl); most preferably, As a whole, selected 9. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula II, in: A is selected from a 5-membered heteroaromatic ring; preferably, A is selected from a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably, A is selected from a 1,2,3-triazole ring, an imidazole ring; most preferably, A is selected from Among them #R 31 Indicates the attachment site of the carbonyl group, $B 11 represents the attachment site for joining the fused-ring bicyclic ring; R 2 、R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 、R 3 Together with the nitrogen atom to which they are connected, they form a 6-membered saturated heterocyclic group. Preferably, the 6-membered saturated heterocyclic group contains 2 heteroatoms, and the heteroatoms are nitrogen atoms. Preferably, R 2 、R 3 are each independently selected from hydrogen, methyl, ethyl, isopropyl, Or preferably, R 2 、R 3 Together with the N atoms they are connected to, they form Most preferably, Overall selection R 21 Selected from C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; Preferably, R 21 Selected from m7 is selected from 0, 1, 2, 3; n7 is selected from 0, 1, 2, 3; Preferably, R 21 Selected from 10. The compound of any one of claims 1 to 9, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula III, in: A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; Most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; B is Where: R 4 Selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclic group, -NR Na R Nb (where R Na and R Nb Each is independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl may be optionally substituted with 1-3 substituents selected from halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclyl may be optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, R 4 Selected from hydrogen, described Optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halogen, hydroxy, cyano, -NH2, -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); n1 is selected from 0, 1, 2, 3; preferably n1 is 0; More preferably, R 4 Selected from hydrogen, (Preferred )、 (Preferred )、 (Preferred )、 ； More preferably, R 4 Selected from hydrogen, R 5 Selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 is selected from hydrogen, cyano; Preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 More preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 More preferably, As a whole, selected C is Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl; Preferably, R 13 is selected from C1-C6 haloalkyl (eg difluoromethyl); preferably, R 13 Selected from More preferably, R 13 Selected from R 14 is selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxy C1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl); preferably, R 14 Selected from Piperidinyl, which is optionally substituted with 1-2 C1-C6 alkyl (preferably methyl) substituents; p is selected from 0, 1, 2; preferably, p is 2; R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen; More preferably, R 14 Selected from More preferably, R 14 Selected from Most preferably, As a whole, selected Most preferably, As a whole, selected 11. The compound of any one of claims 1 to 9, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula IV, in: A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; Most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; B is Where: R 22 Selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; Preferably, R 22 Selected from hydrogen, m4 is selected from 0, 1, 2, 3; preferably, m4 is selected from 0; n4 is selected from 0, 1, 2, 3; preferably, n4 is selected from 0, 1; more preferably, R 22 Selected from hydrogen, R 23 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 Selected from hydrogen, carboxyl, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl; Most preferably, As a whole, selected C is Where: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i Each is independently selected from hydrogen, methyl, isopropyl; Preferably, R 13 is selected from C1-C6 haloalkyl (eg difluoromethyl); preferably, R 13 Selected from More preferably, R 13 Selected from R 14 is selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxy C1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl); preferably, R 14 Selected from Piperidinyl, which is optionally substituted with 1-2 C1-C6 alkyl (preferably methyl) substituents; p is selected from 0, 1, 2; preferably, p is 2; R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen; More preferably, R 14 Selected from More preferably, R 14 Selected from Most preferably, As a whole, selected Most preferably, As a whole, selected 12. The compound of any one of claims 1 to 9, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound (deuterated compound), metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The structural formula of the compound is Formula V, in: A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; More preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; Most preferably, A is selected from Where #C represents the linking site for C, and $B represents the linking site for B; B is Where: R 25 Selected from hydrogen, C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl; Preferably, R 25 Selected from hydrogen, m6 is selected from 0, 1, 2, 3; preferably, m6 is 0; n6 is selected from 0, 1, 2, 3; preferably, n6 is 0, 1; More preferably, R 25 Selected from hydrogen, R 26 Selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 Selected from hydrogen, cyano, carboxyl, Most preferably, As a whole, selected Most preferably, As a whole, selected C is in: R 13 Selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl), R h 、R i Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R h 、R i are each independently selected from hydrogen, methyl, isopropyl; preferably, R 13 is selected from C1-C6 haloalkyl (eg difluoromethyl); preferably, R 13 Selected from More preferably, R 13 Selected from R 14 Selected from C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl, wherein the C3-C6 cycloalkyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted with 1-2 substituents selected from hydroxyC1-C6 alkyl (e.g., hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl); Preferably, R 14 Selected from Piperidinyl, the piperidinyl is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl) substituents; p is selected from 0, 1, 2; preferably, p is 2; R g is selected from hydrogen, hydroxy C1-C6 alkyl, formyl; preferably, R g is hydrogen; More preferably, R 14 Selected from More preferably, R 14 Selected from Most preferably, As a whole, selected Most preferably, As a whole, selected 13. The compound of any one of claims 1 to 12, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula VI-1 or Formula VI-2 or Formula VII-1 or Formula VII-1-1 or Formula VII-1-2, A, B, C, R in Formula VI-1, Formula VI-2 and Formula VI-3 d 、R e 、R f The definition as defined in any one of claims 1 to 12; In formula VII-1-1, A, B, and R e 、R f 、R g , p is defined as defined in any one of claims 1 to 12; In formula VII-1-2, each R x independently selected from halogen, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkyl, cyano, s is selected from 0, 1, 2, 3, or two R x The C atom to which it can be connected forms a C1-C6 cycloalkyl group, R y Selected from H, C1-C6 alkyl; A, B, R e 、R f The definition is as defined in any one of claims 1 to 12.

14. The compound of any one of claims 1 to 13, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof, wherein: The structural formula of the compound is Formula VII-2-1 or Formula VII-2-2 or Formula VII-3-1 or Formula VII-3-2 or Formula VII-3-3, In formula VII-2-1, B, R e 、R f 、R g , p is defined as defined in any one of claims 1 to 13; In formula VII-2-2, B, R e 、R f 、R x 、R y s is as defined in any one of claims 1 to 13; In formula VII-3-1, A, R d 、R e 、R f 、R a 、R b As defined in any one of claims 1 to 13; In formula VII-3-2, A, R d 、R e 、R f 、R a 、R b As defined in any one of claims 1 to 13; In formula VII-3-3, A, R d 、R e 、R f 、R a 、R b The definition is as defined in any one of claims 1 to 13.

15. The compound of any one of claims 1 to 14, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The structural formula of the compound is Formula VIII-1, Formula VIII-2 or Formula VIII-3, In Formula VIII-1, R d 、R e 、R f 、R a 、R b As defined in any one of claims 1 to 14; In Formula VIII-2, R d 、R e 、R f 、R a 、R b As defined in any one of claims 1 to 14; In Formula VIII-3, R d 、R e 、R f 、R a 、R b The definition is as defined in any one of claims 1 to 14.

16. The compound of any one of claims 1 to 15, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: The compound is selected from: ; Preferably, the compound is selected from:

17. A method for preparing the compound of formula A according to any one of claims 1 to 16, characterized in that: In formula A, A is The method comprises: Compound A-1-B1 undergoes a halogenation reaction to obtain compound A-1-B2, compound A-1-B2 undergoes a substitution reaction to obtain compound A-1-B3, and compound A-1-B3 and compound A-1-C1 undergo a cyclization reaction to obtain compound A-1; Where X1 is a halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, C ranges as described in any one of claims 1-27; Preferably, the preparation method of compound AC-1 comprises: Compound A-1-C1 is subjected to nitration reaction to obtain compound A-1-C2, compound A-1-C2 is subjected to reduction reaction to obtain compound A-1-C3, and compound A-1-C3 is subjected to azidation reaction to obtain compound AC-1, R d 、R e 、R f and C are as described in any one of claims 1-27.

18. A method for preparing the compound of formula A according to any one of claims 1 to 16, wherein: In formula A, A is The method comprises: Compound A-2-B1 is subjected to coupling reaction to obtain compound A-2-B2, and compound A-2-B2 and compound A-2-C2 are subjected to coupling reaction to obtain compound A-2, wherein X2 and X3 are each independently halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, C as described in any one of claims 1-16; Preferably, the preparation method of the compound A-2-C2 comprises: Compound A-2-C1 is subjected to halogenation reaction to obtain compound A-2-C2, wherein X3 is halogen (such as Cl, Br, I), R d 、R e 、R f , C as described in any one of claims 1-16; Or in formula A, A is The method comprises: Compound A-3-C1 is subjected to cyanation reaction to obtain compound A-3-C2, which undergoes cyclization reaction with A-3-B2 to obtain A-3; Wherein X4 is halogen (such as Cl, Br, I), R a 、R b 、R d 、R e 、R f , B, C as described in any one of claims 1-16; Preferably, the preparation method of A-3-B2 comprises: Compound A-3-B1 is acylated to obtain compound A-3-B2, wherein R a 、R b , B as described in any one of claims 1-16.

19. A pharmaceutical composition comprising the compound of any one of claims 1 to 16, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, and optionally a pharmaceutically acceptable excipient.

20. A PROTAC molecule comprising: a warhead portion, a ligase binding portion, and a linker, wherein the warhead portion is a compound according to any one of claims 1 to 16, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof, and the linker is covalently linked to the warhead portion and the ligase binding portion, respectively; Preferably, the ligase binding moiety is an E3 ubiquitin ligase binding moiety.

21. A compound according to any one of claims 1 to 16, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, or the pharmaceutical composition according to claim 19, or the PROTAC molecule according to claim 20 for the preparation of a medicament for treating and / or preventing a disease associated with IRAK4 kinase; Preferably, the disease associated with IRAK4 kinase is cancer or autoimmune disease; Preferably, the autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, ulcerative colitis, irritable bowel syndrome, or any combination thereof; Preferably, the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.

22. A method for treating and / or preventing a disease associated with IRAK4 kinase, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 16, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof, or the pharmaceutical composition according to claim 19, or the PROTAC molecule according to claim 20; Preferably, the disease associated with IRAK4 kinase is cancer or autoimmune disease; Preferably, the autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, ulcerative colitis, irritable bowel syndrome, or any combination thereof; Preferably, the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.

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