WO2024017381A1 - 一种抑制irak4活性的化合物及其应用 - Google Patents

一种抑制irak4活性的化合物及其应用 Download PDF

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WO2024017381A1
WO2024017381A1 PCT/CN2023/108727 CN2023108727W WO2024017381A1 WO 2024017381 A1 WO2024017381 A1 WO 2024017381A1 CN 2023108727 W CN2023108727 W CN 2023108727W WO 2024017381 A1 WO2024017381 A1 WO 2024017381A1
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alkyl
hydrogen
cycloalkyl
membered
compound
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French (fr)
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杜鑫明
徐贺
杜立飞
陈照强
李远鹏
米玉涛
屈孟杨
贾继龙
马君君
邹俊杰
邹荣峰
温晓明
王绍晖
陈斌
张佩宇
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深圳众格生物科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles
    • A61K31/41621,2-Diazoles condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41921,2,3-Triazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to the field of medicine, and in particular to a compound that inhibits IRAK4 activity and its application.
  • IRAK4 is a serine/threonine protein kinase that belongs to the interleukin-1 receptor-associated kinase family, which includes four subtypes IRAK1, IRAK2, IRAK3 (or IRAKM) and IRAK4. Among them, IRAK1, IRAK2 and IRAK4 promote the release of inflammatory factors, while IRAK3 is involved in the anti-inflammatory process. Among the four isoforms, the biological function of IRAK4 has been clearly elucidated. When TLR or IL-1R senses external signal stimulation, the Myddosome complex formed by IRAK4 activates the MAPK and NF- ⁇ B pathways, thereby releasing a variety of inflammatory factors.
  • IRAK4 is highly expressed in a variety of tumor cells and inflammation models.
  • the development of inhibitors targeting IRAK4 has increasingly become an important direction in the treatment of autoimmune diseases and tumors.
  • IRAK4 has two functions: kinase activity and skeleton activity, and plays an important role in both functions in downstream signal regulation.
  • PROTAC Proteolysis Targeting Chimeria
  • This bifunctional molecule is in vivo Recognizes and brings the target protein and E3 ubiquitin ligase together to form a ternary complex, and then ubiquitin marks the target protein, thereby initiating the ubiquitin-proteasome-dependent degradation pathway.
  • PROTAC technology achieves simultaneous inhibition of both functions of IRAK4 by degrading IRAK4 protein, which can effectively solve the problem of insufficient small molecule activity or mutation.
  • PROTAC molecules targeting IRAK4 can be obtained based on new small molecule IRAK4 kinase inhibitors.
  • the inventor of the present application has obtained a new small molecule IRAK4 kinase inhibitor, which can be used for the treatment of various diseases, and the new small molecule IRAK4 kinase inhibitor can provide a basis for further development of targeted IRAK4.
  • the PROTAC molecules lay the foundation.
  • the invention provides a compound represented by formula A, or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers , geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated) or prodrugs,
  • A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by a substituent Rk ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl;
  • B is selected from a 6-10-membered heteroaryl group and a 6-10-membered aryl group, and B is optionally substituted by at least one of the substituents R a and R b ; preferably, B is substituted by the substituents R a and R b replaced by at least one of;
  • R a is selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, 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, (where Cy 1 is a 4-9 membered heterocyclyl optionally substituted by R cy1 and R cy2 ), -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl,
  • the C1-C6 cycloalkyl group can be optionally replaced by 1-3 members selected from halogen, hydroxyl, C3-C6 cycloalkyl, C3-C6 halogenated cycloalkyl, 4-7 membered hetero substituted by the substituent of
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxyl, nitro, cyano, amino, -NH (C1-C6 alkyl) , -N(C1-C6 alkyl)(C1-C6 alkyl), oxo;
  • R b is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), R l and R m are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-membered heterocyclic ring, and the substituent is selected from C1-C6 alkyl (such as tert-butyl);
  • L 1 is selected from direct bond, C1-C6 alkyl,
  • R 1 is selected from
  • C is selected from 5-6 membered heteroaryl, and C is optionally substituted by at least one of the substituents R d , R e , and R f ;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5- 6-membered heteroaryl, 4-7-membered saturated heterocyclyl,
  • the C3-C7 cycloalkyl group, 6-10 membered aryl group, 5-6 membered heteroaryl group, and 4-7 membered saturated heterocyclic group are each independently optionally selected from C1-C6 alkyl group, 1-2 Substituted by halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R h , R i is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycl
  • R e , R f and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-9 membered heterocycle, and the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1 -C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • R 2 and R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 , R 3 and the N atoms to which they are commonly connected 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.
  • A is selected from a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is optionally substituted with a substituent Rk .
  • A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 6 The 5-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is an N atom, and the 5-membered heteroaromatic ring and 6-membered heteroaromatic ring are optionally substituted by the substituent Rk .
  • 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 the substituent R k .
  • A is selected from and Optionally substituted by the substituent R k , where #R 1 represents the attachment site for R 1 and $L 1 represents the attachment site for L 1 .
  • A is selected from Among them, #R 1 represents the connection site connecting R 1 , and $L 1 represents the connection site connecting L 1 .
  • A is selected from Among them, #R 1 represents the connection site connecting R 1 , and $L 1 represents the connection site connecting L 1 .
  • Rk is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (e.g., 5-6 membered saturated heterocyclyl).
  • Rk is selected from C1-C6 alkyl, 5-6 membered saturated heterocyclyl.
  • Rk is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl.
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl.
  • R p , R q are each independently selected from hydrogen, C1-C6 alkyl.
  • B is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B is substituted by substituents Ra, Rb .
  • B is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl
  • the radical contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms.
  • B is selected from 9-membered heteroaryl, pyridyl, phenyl, and B is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl contains 1 - 4 heteroatoms selected from N, O, S atoms.
  • B is selected from Pyridyl, phenyl, pyrimidinyl, and B is substituted by at least one of the substituents R a and R b .
  • B is selected from Pyridyl, phenyl, and B is substituted by at least one of the substituents R a and R b .
  • B is selected from And B is substituted by substituents R a and R b .
  • B is selected from And B is substituted by substituents R a and R b .
  • R is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can optionally be Substituted with 1-3 substituents selected from hydroxyl, C3-C6 cycloalkyl, and 4-7-membered heterocyclyl), the C4-C9 cycloalkyl and 4-9-membered saturated heterocyclyl are optionally substituted by 1-3 selected from C1-C6 alkyl, halogen,
  • R is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -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.
  • R is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -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. .
  • R is selected from hydrogen, cyano, C1-C6 haloalkyl (such as 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.
  • R is selected from hydrogen, cyano, carboxyl,
  • R is selected from hydrogen, cyano, carboxyl,
  • R is selected from hydrogen, cyano,
  • R is selected from hydrogen, cyano,
  • 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.
  • Cy 1 is a 5-7 membered heterocyclyl optionally substituted by R cy1 and R cy2 . More preferably, Cy 1 is a 6-membered heterocyclyl optionally substituted by R cy1 and R cy2 group, further preferably, Cy 1 is morpholine, piperazine, or thiomorpholine optionally substituted by R cy1 and R cy2 .
  • Cy 2 is a 5-7 membered heterocyclyl group, and the 5-7 membered heterocyclyl group is optionally substituted by 1-3 members selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, Substituted with CN and hydroxyl substituents.
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, said azetidinyl, pyrrolidinyl, Imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1 to 3 substituents selected from halogen and C1-C6 alkyl.
  • Cy 2 is selected from pyrrolidinyl, imidazolidinyl, and piperidinyl, and the pyrrolidinyl, imidazolidinyl, and piperidinyl groups are optionally replaced by 1-3 selected from F, Cl, Br, Substituted with methyl substituents.
  • Cy 2 is selected from pyrrolidinyl, which is optionally substituted with 1-3 (eg, 1 or 2 or 3) F.
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, amino, oxo, further preferably R cy1 and R cy2 are each independently selected from oxo.
  • R b is selected from hydrogen, cyano,
  • R1 , Rm are each independently selected from hydrogen, C1-C6 alkyl.
  • Ra , Rb and the carbon atoms to which they are respectively attached together form Wherein R c is selected from hydrogen and C1-C6 alkyl.
  • Rc is selected from C1-C6 alkyl.
  • B as a whole, is selected from:
  • B as a whole, is selected from
  • B as a whole, is selected from
  • B as a whole, is selected from
  • L is selected from direct bonds, In some embodiments, L is selected from direct bond, methylene, In some embodiments, L is selected from direct bonds, In some embodiments, L1 is selected from direct bonds.
  • C is selected from 5-6 membered heteroaryl containing 1-3 heteroatoms, and C is optionally substituted with R d , Re , R f replaced by at least one of them.
  • C is selected from pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, oxazolyl, furyl, 1,2,3-triazole group, 1,2,4-triazolyl, and C is optionally substituted by at least one of the substituents R d , Re , and R f .
  • C is selected from pyrazolyl, thiazolyl, pyridyl, pyrrolyl, oxazolyl, furyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C is optionally substituted by at least one of the substituents Rd , Re , Rf .
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (e.g., difluoromethyl), C3-C7 cycloalkyl, 6-10 Yuanaryl group, 5-6 membered heteroaryl group, 4-7 membered saturated heterocyclic group,
  • the C3-C7 cycloalkyl group, 6-10 membered aryl group, 5-6 membered heteroaryl group, and 4-7 membered saturated heterocyclic group are each independently optionally selected from halogen and alkoxy groups. Substituted with substituents (such as C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, and formyl.
  • R d is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, morpholinyl, piperazinyl, piperidyl, said C3-C6 cycloalkyl, Phenyl, pyridyl, morpholinyl, piperazinyl, and piperidinyl are each independently optionally substituted by 1-2 selected from C1-C6 alkyl, halogen, alkoxy (such as C1-C6 alkoxy), Substituted with substituents of hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, and formyl.
  • R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, and piperidinyl, and each of the C3-C6 cycloalkyl, phenyl, morpholinyl, and piperidinyl groups is independently any Optionally 1-2 selected from halogen, alkoxy (for example C1-C6 alkoxy), hydroxyl, amino, hydroxy C1-C6 alkyl (for example hydroxymethyl), amino C1-C6 alkyl, formyl substituted by substituents.
  • alkoxy for example C1-C6 alkoxy
  • hydroxyl amino
  • amino C1-C6 alkyl for example hydroxymethyl
  • amino C1-C6 alkyl formyl substituted by substituents.
  • R d is selected from C1-C6 alkyl, Phenyl, morpholinyl, piperazinyl, piperidinyl, the Phenyl, morpholinyl, piperazinyl, and piperidinyl are optionally substituted by C1-C6 alkyl (preferably methyl), where p is selected from 0, 1, 2, and Rg is selected from hydrogen, amino, hydroxyl, Hydroxy C1-C6 alkyl, formyl.
  • Rd is selected from Phenyl, morpholinyl, piperidinyl, where p is selected from 0, 1, and 2, and Rg is selected from hydrogen, amino, hydroxyl, hydroxyl C1-C6 alkyl, and formyl.
  • Rd is selected from methyl, ethyl, isopropyl, piperazinyl, piperidinyl,
  • Rd is selected from Piperazinyl.
  • Rd is selected from
  • each of R h and R i is independently selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.
  • Re is selected from hydrogen, methyl, F 3 C-, -NHCH 3 .
  • Re is selected from hydrogen, methyl, F 3 C-,
  • Re, Rf and the carbon atoms to which they are respectively connected form a substituted or unsubstituted 5-9 membered heterocyclic ring, and the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy group (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl.
  • Re , Rf and the carbon atoms to which they are respectively attached together form Each R j is independently selected from hydrogen, C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxyl.
  • Re , Rf and the carbon atoms to which they are respectively attached together form
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, propyl,
  • R 2 , R 3 and the N atom to which they are commonly attached together form
  • R 1 as a whole is selected from:
  • R 1 as a whole is selected from:
  • R 1 as a whole is selected from:
  • R 1 as a whole is selected from
  • the invention provides the compound represented by formula i, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers. Conforms, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs thereof,
  • a 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by a substituent R k ; preferably, A 1 is selected from a 5-membered heteroaromatic ring, and 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;
  • a 1 is selected from Among them, #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ;
  • a 1 is selected from Among them, #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl; preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl); more preferably, R k is selected from C1-C6 alkyl, C3-C6 Cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 is optionally substituted by at least one of the substituents R a and R b ; preferably, B 1 is substituted by the substituent R a , substituted by at least one of R b ; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 is substituted by at least one of the substituents R a and R b ;
  • the 9-membered heteroaryl contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, and phenyl, And B 1 is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms
  • B 1 is selected from Pyridyl, phenyl, pyrimidinyl, and B 1 Substituted by at least one of the substituents R a and R b ; more preferably, B 1 is selected from Pyridyl, phenyl, and B 1 is substituted by at least one of the substituents R a and R b ; further preferably, B 1 is selected from And B 1 is substituted by substituents R a and R b ;
  • B 1 is selected from And B 1 is substituted by substituents R a and R b ;
  • R a is selected from hydrogen, halogen, cyano group, carboxyl group, C1-C6 alkyl, 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, (where Cy 1 is a 4-9 membered heterocyclyl optionally substituted by R cy1 and R cy2 ), -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl,
  • the C1-C6 cycloalkyl group may be optionally substituted by 1-3 substituents selected from halogen, hydroxyl, C3-C6 cycloalky
  • R z is H or C1-C6 alkyl
  • Cy 2 is 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 by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl
  • the base, 4-9 membered saturated heterocyclic group is optionally substituted by 1-3 members selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, Substituted by hydroxyl-C1-C6 alkyl-, cyano, oxo, -NH 2 , -N(C1-C
  • Cy 1 is a 5-7 membered heterocyclyl group, more preferably, Cy 1 is a 6-membered heterocyclyl group, and further preferably, Cy 1 is morpholine, piperazine, or thiomorpholine;
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxyl, nitro, cyano, amino, -NH (C1-C6 alkyl) , -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, amino, oxo, further Preferably R cy1 and R cy2 are each independently selected from oxo;
  • Cy 2 is a 5-7-membered heterocyclyl group, and the 5-7-membered heterocyclyl group is optionally substituted by 1-3 members selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl.
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, the azetidinyl, Pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy 2 is selected from Pyrrolidinyl, imidazolidinyl, piperidinyl, the pyrrolidinyl, imidazolidinyl, piperidinyl are optionally substituted by 1-3 F, Cl, Br, methyl; further preferably, Cy 2 is selected From pyrrolidinyl, the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F;
  • R a is selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can optionally be Substituted with 1-3 substituents selected from hydroxyl, C3-C6 cycloalkyl, and 4-7-membered heterocyclyl), the C4-C9 cycloalkyl and 4-9-membered saturated heterocyclyl are optionally substituted by 1-3 selected from C1-C6 alkyl, halogen,
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;;
  • R a is selected from hydrogen, cyano, C1-C6 haloalkyl (such as trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);
  • R a is selected from hydrogen, cyano, carboxyl,
  • R a is selected from hydrogen, cyano,
  • R b is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl),
  • R b is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-membered heterocyclic ring, and the substituent is selected from C1-C6 alkyl (such as tert-butyl); preferably, R a , R b and the carbon atoms connected to them respectively form
  • R c is selected from hydrogen and C1-C6 alkyl; preferably, R c is selected from C1-C6 alkyl;
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from
  • L 1 is selected from direct bond, C1-C6 alkyl, Preferably, L 1 is selected from direct bonds, Preferably, L 1 is selected from direct bond, methylene, Preferably, L 1 is selected from direct bonds,
  • R 11 selected from
  • C 1 is selected from 5-6 membered heteroaryl, and C 1 is optionally substituted by at least one of the substituents R d , Re , and R f ; preferably, C 1 is selected from 5-6 membered heteroaryl , the 5-6 membered heteroaryl group contains 1-3 heteroatoms, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ; more preferably, C 1 is selected from Pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , Re , and R f ; more preferably, C 1 is selected from pyrazole base, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclyl,
  • the C3-C7 cycloalkyl and 4-7 membered saturated heterocyclyl are optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxyl C1-C6 Substituted by alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl,
  • the C3-C7 cycloalkyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (such as C1-C6 alkoxy group), hydroxyl group, amino group, hydroxy C1-C6 alkyl group (such as hydroxymethyl group), Substituted with amino C1-C6 alkyl and formyl substituents;
  • R d is selected from C3-C6 cycloalkyl, and the C3-C6 cycloalkyl is optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino , substituted by substituents of hydroxyl C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, and formyl;
  • R d is selected from a 4-7-membered saturated heterocyclyl group, and the 4-7-membered saturated heterocyclyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (for example, C1-C6 alkoxy group) Substituted with hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d is selected from C1-C6 alkyl, Or more preferably, R d is selected from pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl, and the pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl groups are optionally selected from 1 to 2 Halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl) substitution; more preferably, R d is selected from
  • p is selected from 0, 1, 2;
  • R d is selected from pyrrolyl and piperidinyl, and the pyrrolyl and piperidinyl are optionally substituted by 1-2 selected from halogen, C1-C6 alkyl (preferably methyl);
  • Rg is selected from hydrogen, amino, hydroxyl, hydroxyl C1-C6 alkyl, formyl;
  • R d is selected from methyl, ethyl, isopropyl, Piperidinyl,
  • R d is selected from
  • R d is selected from
  • R h and R i are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h and R i are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;
  • R e is selected from hydrogen, methyl, F 3 C-, -NHCH 3 ;
  • Re is selected from hydrogen, methyl, F 3 C-,
  • R e , R f and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-9 membered heterocycle, and the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1 -C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form
  • Each Rj is independently selected from hydrogen, C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form
  • R 2 and R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 , R 3 and the N atoms to which they are commonly connected form a 5-6 membered saturated heterocyclic group.
  • the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms;
  • R 2 and R 3 are each independently selected from hydrogen , methyl, ethyl, propyl,
  • R 2 , R 3 and the N atoms to which they are commonly linked form together
  • R 11 as a whole is selected from:
  • R 11 as a whole is selected from:
  • the invention provides the compound represented by formula i-1, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated) or prodrugs,
  • a 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by a substituent R k ; preferably, A 1 is selected from a 5-membered heteroaromatic ring, and 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 is selected from Where #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ; further preferably, A 1 is selected from Among them, #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl; preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl); more preferably, R k is selected from C1-C6 alkyl, C3-C6 Cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 is optionally substituted by at least one of the substituents R a and R b ; preferably, B 1 is substituted by the substituent R a , substituted by at least one of R b ; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 is substituted by at least one of the substituents R a and R b ;
  • the 9-membered heteroaryl contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, and phenyl, And B 1 is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms
  • B 1 is selected from Pyridyl, phenyl, pyrimidinyl, and B 1 is substituted by at least one of the substituents R a and R b ; more preferably, B 1 is selected from Pyridyl, phenyl, and B 1 is substituted by at least one of the substituents R a and R b ;
  • B 1 is selected from And B 1 Substituted by substituents R a and R b ; further preferably, B 1 is selected from And B 1 is substituted by substituents R a and R b ;
  • R a is selected from hydrogen, halogen, cyano group, carboxyl group, C1-C6 alkyl, 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, (where Cy 1 is a 4-9 membered heterocyclyl optionally substituted by R cy1 and R cy2 ), -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl,
  • the C1-C6 cycloalkyl group may be
  • R z is H or C1-C6 alkyl
  • Cy 2 is 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 by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl
  • the base, 4-9 membered saturated heterocyclic group is optionally substituted by 1-3 members selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, Substituted by hydroxyl-C1-C6 alkyl-, cyano, oxo, -NH 2 , -N(C1-C
  • Cy 1 is a 5-7 membered heterocyclyl group, more preferably, Cy 1 is a 6-membered heterocyclyl group, and further preferably, Cy 1 is morpholine, piperazine, or thiomorpholine;
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxyl, nitro, cyano, amino, -NH (C1-C6 alkyl) , -N(C1-C6 alkyl)(C1-C6 alkyl), oxo;
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, amino, oxo, further preferably R cy1 and R cy2 are each independently selected from oxo;
  • Cy 2 is a 5-7-membered heterocyclyl group, and the 5-7-membered heterocyclyl group is optionally substituted by 1-3 members selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl.
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, the azetidinyl, Pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy 2 is selected from Pyrrolidinyl, imidazolidinyl, piperidinyl, the pyrrolidinyl, imidazolidinyl, piperidinyl are optionally substituted by 1-3 F, Cl, Br, methyl; further preferably, Cy 2 is selected From pyrrolidinyl, the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F;
  • R a is selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can optionally be Substituted with 1-3 substituents selected from hydroxyl, C3-C6 cycloalkyl, and 4-7-membered heterocyclyl), the C4-C9 cycloalkyl and 4-9-membered saturated heterocyclyl are optionally substituted by 1-3 selected from C1-C6 alkyl, halogen,
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;;
  • R a is selected from hydrogen, cyano, C1-C6 haloalkyl (such as trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);
  • R a is selected from hydrogen, cyano, carboxyl,
  • R a is selected from hydrogen, cyano,
  • R b is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl),
  • R b is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-membered heterocyclic ring, and the substituent is selected from C1-C6 alkyl (such as tert-butyl);
  • R a , R b and the carbon atoms to which they are respectively connected together form
  • R c is selected from hydrogen and C1-C6 alkyl; preferably, R c is selected from C1-C6 alkyl;
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from
  • L 1 is selected from direct bond, C1-C6 alkyl, Preferably, L 1 is selected from direct bonds, Preferably, L 1 is selected from direct bond, methylene, Preferably, L 1 is selected from direct bonds,
  • R 11 selected from
  • C 1 is selected from 5-6 membered heteroaryl, and C 1 is optionally substituted by at least one of the substituents R d , Re , and R f ; preferably, C 1 is selected from 5-6 membered heteroaryl , the 5-6 membered heteroaryl group contains 1-3 heteroatoms, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ; more preferably, C 1 is selected from Pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , Re , and R f ; more preferably, C 1 is selected from pyrazole base, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclyl,
  • the C3-C7 cycloalkyl and 4-7 membered saturated heterocyclyl are optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxyl C1-C6 Substituted by alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl,
  • the C3-C7 cycloalkyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (such as C1-C6 alkoxy group), hydroxyl group, amino group, hydroxy C1-C6 alkyl group (such as hydroxymethyl group), Substituted with amino C1-C6 alkyl and formyl substituents;
  • R d is selected from C3-C6 cycloalkyl, and the C3-C6 cycloalkyl is optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino , substituted by substituents of hydroxyl C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, and formyl;
  • R d is selected from a 4-7-membered saturated heterocyclyl group, and the 4-7-membered saturated heterocyclyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (for example, C1-C6 alkoxy group) Substituted with hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d is selected from C1-C6 alkyl
  • R d is selected from pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl, and the pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl groups are optionally selected from 1 to 2 Halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl) substitution;
  • Rd is selected from p is selected from 0, 1, 2;
  • R d is selected from pyrrolyl and piperidinyl, and the pyrrolyl and piperidinyl are optionally substituted by 1-2 selected from halogen, C1-C6 alkyl (preferably methyl);
  • Rg is selected from hydrogen, amino, hydroxyl, hydroxyl C1-C6 alkyl, formyl;
  • R d is selected from methyl, ethyl, isopropyl, Piperidinyl, Further preferably, R d is selected from Further preferably, R d is selected from
  • R h and R i are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h and R i are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;
  • R e is selected from hydrogen, methyl, F 3 C-, -NHCH 3 ;
  • Re is selected from hydrogen, methyl, F 3 C-,
  • R e , R f and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-9 membered heterocycle, and the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1 -C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form Each Rj is independently selected from hydrogen, C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form
  • R 2 and R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 , R 3 and the N atoms to which they are commonly connected form a 5-6 membered saturated heterocyclic group.
  • the 5-6 membered saturated heterocyclic group contains 2-3 heteroatoms, and the heteroatoms are selected from N, S, and O atoms;
  • R 2 and R 3 are each independently selected from hydrogen , methyl, ethyl, propyl,
  • R 2 , R 3 and the N atoms to which they are commonly linked form together
  • R 11 as a whole is selected from:
  • R 11 as a whole is selected from:
  • the invention provides the compound represented by formula i-1-1, or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers. isomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs thereof,
  • a 1 is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring is optionally substituted by a substituent R k ; preferably, A 1 is selected from a 5-membered heteroaromatic ring, and 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;
  • a 1 is selected from Where #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ; further preferably, A 1 is selected from Among them, #R 11 represents the connection site connecting R 11 , $L 1 represents the connection site connecting L 1 ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl; preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl);
  • R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected Ground is selected from hydrogen, C1-C6 alkyl;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • B 1 is selected from 6-10 membered heteroaryl, 6-10 membered aryl, and B 1 is optionally substituted by at least one of the substituents R a and R b ; preferably, B 1 is substituted by the substituent R a , substituted by at least one of R b ; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, phenyl, pyrimidinyl, and B 1 is substituted by at least one of the substituents R a and R b ;
  • the 9-membered heteroaryl contains 1-4 heteroatoms, and the heteroatoms are selected from N, O, and S atoms; preferably, B 1 is selected from 9-membered heteroaryl, pyridyl, and phenyl, And B 1 is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl group contains 1-4 heteroatoms, and the heteroatoms
  • B 1 is selected from And B 1 is substituted by substituents R a and R b ;
  • B 1 is selected from And B 1 is substituted by substituents R a and R b ;
  • R a is selected from hydrogen, halogen, cyano group, carboxyl group, C1-C6 alkyl, 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, (where Cy 1 is a 4-9 membered heterocyclyl optionally substituted by R cy1 and R cy2 ), -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl,
  • the C1-C6 cycloalkyl group may be optionally substituted by 1-3 substituents selected from halogen, hydroxyl, C3-C6 cycloalky
  • R z is H or C1-C6 alkyl
  • Cy 2 is 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 by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl
  • the base, 4-9 membered saturated heterocyclic group is optionally substituted by 1-3 members selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, Substituted by hydroxyl-C1-C6 alkyl-, cyano, oxo, -NH 2 , -N(C1-C
  • Cy 1 is a 5-7 membered heterocyclyl group, more preferably, Cy 1 is a 6-membered heterocyclyl group, and further preferably, Cy 1 is morpholine, piperazine, or thiomorpholine;
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxyl, nitro, cyano, amino, -NH (C1-C6 alkyl) , -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 are each independently selected from C1-C6 Alkyl, halogen, hydroxyl, amino, oxo, further preferably R cy1 and R cy2 are each independently selected from oxo;
  • Cy 2 is a 5-7-membered heterocyclyl group, and the 5-7-membered heterocyclyl group is optionally substituted by 1-3 members selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl.
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, the azetidinyl, Pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy 2 is selected from Pyrrolidinyl, imidazolidinyl, piperidinyl, the pyrrolidinyl, imidazolidinyl, piperidinyl are optionally substituted by 1-3 F, Cl, Br, methyl; further preferably, Cy 2 is selected From pyrrolidinyl, the pyrrolidinyl is optionally substituted by 1-3 (such as 1 or 2 or 3) F;
  • R a is selected from hydrogen, halogen, cyano, carboxyl, C1-C6 alkyl, 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can optionally be Substituted with 1-3 substituents selected from hydroxyl, C3-C6 cycloalkyl, and 4-7-membered heterocyclyl), the C4-C9 cycloalkyl and 4-9-membered saturated heterocyclyl are optionally substituted by 1-3 selected from C1-C6 alkyl, halogen,
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituent substituted;
  • R a is selected from hydrogen, cyano, carboxyl, C1-C6 haloalkyl (such as trifluoromethyl), described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;
  • R a is selected from hydrogen, cyano, C1-C6 haloalkyl (such as trifluoromethyl), described Optionally substituted by C1-C6 alkyl (preferably methyl), halogen (such as F, Cl, Br);
  • R a is selected from hydrogen, cyano, carboxyl,
  • R a is selected from hydrogen, cyano,
  • R b is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), Preferably, R b is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-membered heterocyclic ring, and the substituent is selected from C1-C6 alkyl (such as tert-butyl);
  • R a , R b and the carbon atoms to which they are respectively connected together form R c is selected from hydrogen and C1-C6 alkyl; preferably, R c is selected from C1-C6 alkyl;
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from:
  • B 1 as a whole is selected from
  • L 1 is selected from direct bond, C1-C6 alkyl, Preferably, L 1 is selected from direct bonds, Preferably, L 1 is selected from direct bond, methylene, Preferably, L 1 is selected from direct bonds,
  • R 11 selected from
  • C 1 is selected from 5-6 membered heteroaryl, and C 1 is optionally substituted by at least one of the substituents R d , Re , and R f ; preferably, C 1 is selected from 5-6 membered heteroaryl , the 5-6 membered heteroaryl group contains 1-3 heteroatoms, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ; more preferably, C 1 is selected from Pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , R e , R f ; more preferably, C 1 is selected from pyrazole base, thiazolyl, pyridyl, pyrrolyl, and C 1 is optionally substituted by at least one of the substituents R d , R e , and R f ;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 4-7 membered saturated heterocyclyl,
  • the C3-C7 cycloalkyl and 4-7 membered saturated heterocyclyl are optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxyl C1-C6 Substituted by alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl,
  • the C3-C7 cycloalkyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (such as C1-C6 alkoxy group), hydroxyl group, amino group, hydroxy C1-C6 alkyl group (such as hydroxymethyl group), Substituted with amino C1-C6 alkyl and formyl substituents;
  • R d is selected from C3-C6 cycloalkyl, and the C3-C6 cycloalkyl is optionally replaced by 1-2 selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino , substituted by substituents of hydroxyl C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, and formyl;
  • R d is selected from a 4-7-membered saturated heterocyclyl group, and the 4-7-membered saturated heterocyclyl group is optionally replaced by 1-2 members selected from halogen, alkoxy group (for example, C1-C6 alkoxy group) Substituted with hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl substituents;
  • R d is selected from C1-C6 alkyl
  • R d is selected from pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl, and the pyrrolyl, piperidinyl, imidazolidinyl, and piperazinyl groups are optionally selected from 1 to 2 Halogen, C1-C6 alkoxy, C1-C6 alkyl (preferably methyl) substitution;
  • Rd is selected from p is selected from 0, 1, 2;
  • R d is selected from pyrrolyl and piperidinyl, and the pyrrolyl and piperidinyl are optionally substituted by 1-2 selected from halogen, C1-C6 alkyl (preferably methyl);
  • Rg is selected from hydrogen, amino, hydroxyl, hydroxyl C1-C6 alkyl, formyl;
  • R d is selected from methyl, ethyl, isopropyl, Piperidinyl,
  • R d is selected from
  • R d is selected from
  • R h and R i are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R h and R i are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl;
  • R e is selected from hydrogen, methyl, F 3 C-, -NHCH 3 ;
  • R e is selected from hydrogen, methyl, F 3 C-,
  • R e , R f and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-9 membered heterocycle, and the substituents are selected from C1-C6 alkyl (such as ethyl), alkoxy (such as C1 -C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form
  • Each Rj is independently selected from hydrogen, C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, hydroxyl;
  • Re , Rf and the carbon atoms to which they are respectively connected together form
  • R 2 and R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 2 , R 3 and the N atoms to which they are commonly connected 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;
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, propyl,
  • R 2 , R 3 and the N atoms to which they are commonly linked form together
  • R 11 as a whole is selected from:
  • R 11 as a whole is selected from:
  • the present invention provides compounds represented by formula ii, or stereoisomers, tautomers, prodrugs, crystal forms, hydrates, isotopically labeled compounds, metabolites, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate,
  • a 2 is selected from a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is optionally substituted by a substituent R k ; preferably, A 2 is selected from a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring contains 1-2 heteroatoms, and at least 1 heteroatom is an N atom, and the 6-membered heteroaromatic ring is optionally substituted by a substituent Rk ; more preferably, A2 is selected from 2-pyridone, pyridazine ring, and the 2-pyridone is optionally substituted by the substituent Rk ; further preferably, A 2 is selected from and Optionally substituted by substituent R k , wherein #R 12 represents the connection site connecting R 12 , $B 2 represents the connection site connecting B 2 ; further preferably, A 2 is selected from Among them, #R 12 represents the connection site connecting R 12 , $B 2 represents the connection site connecting B 2 ; further
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl;
  • R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclic base); more preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • B 2 is selected from 6-10 membered heteroaryl, and B 2 is optionally substituted by at least one of the substituents Ra and R b ; preferably, B 2 is substituted by at least one of the substituents Ra and R b Substituted; preferably, B 2 is selected from a 9-membered heteroaryl group, and B 2 is substituted by at least one of the substituents R a and R b ; preferably, the 9-membered heteroaryl group contains 1 to 4 heteroaryl groups.
  • Atoms, the heteroatoms are selected from N, O, S atoms; more preferably, B 2 is selected from And B 2 is substituted by at least one of the substituents R a and R b ;
  • R a is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl); preferably, R a is selected from hydrogen, cyano, C1-C6 haloalkyl (such as trifluoromethyl); more preferably, R a is selected from hydrogen, cyano,
  • R b is selected from hydrogen, halogen, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), Preferably, R b is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • B 2 as a whole is selected from
  • R 12 selected from
  • C 2 is selected from 5-6 membered heteroaryl, and C 2 is optionally substituted by at least one of the substituents R d , Re , and R f ; preferably, C 2 is selected from 5-6 membered heteroaryl , the 5-6 membered heteroaryl group contains 1-3 heteroatoms, and C 2 is optionally substituted by at least one of the substituents R d , R e , and R f ; more preferably, C 2 is selected from Pyrrolyl, oxazolyl, furyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and C 2 is optionally substituted by at least one of the substituents R d , R e , and R f replaced by one;
  • R d , Re , and R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5- 6-membered heteroaryl, 4-7-membered saturated heterocyclyl, the C3-C7 cycloalkyl, 6-10-membered aryl, 5-6-membered heteroaryl, 4-7-membered saturated heterocyclyl are each independently optional Optionally 1-2 selected from halogen, alkoxy (for example C1-C6 alkoxy), hydroxyl, amino, hydroxy C1-C6 alkyl (for example hydroxymethyl), amino C1-C6 alkyl, formyl Substituted by substituents;
  • R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, and piperazinyl, and each of the C3-C6 cycloalkyl, phenyl, morpholinyl, and piperazinyl groups is independently optionally replaced by 1-2 substituents selected from halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl Substituted; more preferably, R d is selected from C3-C6 cycloalkyl, phenyl, morpholinyl, piperazinyl; further preferably, R d is selected from piperazinyl;
  • R e is selected from hydrogen, methyl, F 3 C-,
  • R 12 as a whole is selected from:
  • the present invention provides a compound represented by Formula I, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, or metabolite of the compound , ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate,
  • A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by a substituent Rk ; preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, 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 N atoms, and the 5-membered heteroaromatic ring and 6-membered heteroaromatic ring are optionally substituted by the substituent 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
  • A is selected from Where #C represents the connection site to C, $L 1 represents the connection site to L 1 ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl; preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl); more preferably, R k is selected from C1-C6 alkyl, C3-C6 Cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • R 4 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can be optionally replaced by 1-3 selected from halogen , hydroxyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl substituents), the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl optionally 1-3 selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hal
  • R 4 is selected from hydrogen, described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent;
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R5 is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R 5 is selected from hydrogen and cyano
  • 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;
  • R6 is selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3;
  • R 6 is
  • R 7 is selected from hydrogen, C1-C6 alkyl
  • R 8 , R 9 , R 10 , and R 11 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, the rest are hydrogen;
  • R 8 , R 9 or R 11 is 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;
  • R 12 is selected from hydrogen, C1-C6 alkyl
  • R 12 is selected from C1-C6 alkyl
  • 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;
  • R 22 is selected from hydrogen, m4 is selected from 0, 1, 2, 3; n4 is selected from 0, 1, 2, 3;
  • R 22 is selected from hydrogen
  • R 23 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl,
  • R 23 is selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 is selected from hydrogen, cyano, carboxyl, Preferably, R 23 is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • 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;
  • R 24 is selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3;
  • R 24 is
  • 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;
  • R 25 is selected from hydrogen, m6 is selected from 0, 1, 2, 3; n6 is selected from 0, 1, 2, 3;
  • R 25 is selected from hydrogen, Preferably, R 25 is hydrogen;
  • R 26 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 is selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 is selected from hydrogen, C1-C6 alkyl,
  • L 1 is selected from direct bond, C1-C6 alkyl,
  • L 1 is selected from direct bonds, Preferably, L 1 is selected from direct bonds;
  • C is selected from any one of the groups (1)-(10):
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl),
  • R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl;
  • R 13 is selected from trifluoromethyl, Preferably, R 13 is selected from More preferably, R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl and piperidinyl, and the C3-C6 cycloalkyl and piperidinyl are optionally replaced by 1-2 hydroxyl C1-C6 alkyl (such as hydroxymethyl), Substituted with formyl, C1-C6 alkyl substituents;
  • R 14 is selected from C3-C6 cycloalkyl, which is optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (such as hydroxymethyl), formyl substituted; preferably, R 14 is selected from p is selected from 0, 1, 2; Rg is selected from hydrogen, hydroxyl C1-C6 alkyl, and formyl;
  • R 14 is selected from piperidinyl, which is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl);
  • R 14 is selected from
  • R 15 is selected from C1-C6 haloalkyl
  • R 16 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 17 is selected from hydrogen and C1-C6 alkyl; preferably, as a whole, for
  • R 18 is selected from hydrogen and C1-C6 alkyl; preferably, R 18 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 19 is selected from hydrogen and C1-C6 alkyl; preferably, R 19 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 20 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 27 is selected from phenyl, C3-C6 cycloalkyl; most preferably, as a whole, selected from
  • R 28 is selected from 6-membered saturated heterocyclyl; preferably, R 28 is morpholinyl; most preferably, as a whole, for
  • R 29 is selected from C3-C6 alkyl; most preferably, as a whole, for
  • R 30 is selected from C3-C6 cycloalkyl
  • R 31 is selected from C1-C6 alkyl; most preferably, do for the whole, for
  • the present invention provides compounds represented by formula I-1, or stereoisomers, tautomers, prodrugs, crystal forms, hydrates, isotopically labeled compounds of the compound, Metabolites, esters, pharmaceutically acceptable salts or pharmaceutically acceptable solvates,
  • A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by a substituent Rk ; preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, 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 N atoms, and the 5-membered heteroaromatic ring and 6-membered heteroaromatic ring are optionally substituted by the substituent 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
  • A is selected from and Optionally substituted by the substituent R k , where #C represents the connection site for C, $L 1 represents the connection site for L 1 ;
  • A is selected from Where #C represents the connection site to C, $L 1 represents the connection site to L 1 ;
  • A is selected from Where #C represents the connection site to C, $L 1 represents the connection site to L 1 ;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl; preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl); more preferably, R k is selected from C1-C6 alkyl, C3-C6 Cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • R 4 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, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1-C6 alkyl, the C1-C6 cycloalkyl can be optionally replaced by 1-3 selected from halogen , hydroxyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 4-7 membered heterocyclyl substituents), the C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl optionally 1-3 selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hal
  • R 4 is selected from hydrogen, described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted; 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;
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R5 is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R 5 is selected from hydrogen and cyano
  • 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 heterocycle Base-C1-C6 alkyl; preferably, R 6 is selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 is
  • R 7 is selected from hydrogen, C1-C6 alkyl
  • any one of R 8 , R 9 , R 10 and R 11 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, the rest are hydrogen; preferably, among R 8 , R 9 , R 10 , and R 11 , R 8 , R 9 or R 11 is 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;
  • R 12 is selected from hydrogen and C1-C6 alkyl; preferably, R 12 is selected from C1-C6 alkyl; (5) Among them: 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 group; preferably, R 22 is selected from hydrogen, m4 is selected from 0, 1, 2, 3; n4 is selected from 0, 1, 2, 3;
  • R 22 is selected from hydrogen
  • R 23 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 is selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 23 is selected from hydrogen, cyano, carboxyl, Preferably, R 23 is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • 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 heterocycle Base-C1-C6 alkyl; preferably, R 24 is selected from m5 is selected from 0, 1, 2, 3;
  • n5 is selected from 0, 1, 2, 3; more preferably, R 24 is
  • 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 group; preferably, R 25 is selected from hydrogen, m6 is selected from 0, 1, 2, 3; n6 is selected from 0, 1, 2, 3;
  • R 25 is selected from hydrogen, Preferably, R 25 is hydrogen;
  • R 26 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 is selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 is selected from hydrogen, C1-C6 alkyl,
  • L 1 is selected from direct bond, C1-C6 alkyl, Preferably, L 1 is selected from direct bonds, Preferably, L 1 is selected from direct bonds;
  • C is selected from any one of the groups (1)-(10):
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl),
  • R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl;
  • R 13 is selected from trifluoromethyl, Preferably, R 13 is selected from More preferably, R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl and piperidinyl, and the C3-C6 cycloalkyl and piperidinyl are optionally replaced by 1-2 hydroxyl C1-C6 alkyl (such as hydroxymethyl), Substituted with formyl, C1-C6 alkyl substituents;
  • R 14 is selected from C3-C6 cycloalkyl, which is optionally substituted by 1-2 substituents selected from hydroxy C1-C6 alkyl (such as hydroxymethyl), formyl replaced;
  • R 14 is selected from p is selected from 0, 1, 2;
  • Rg is selected from hydrogen, hydroxyl C1-C6 alkyl, and formyl;
  • R 14 is selected from piperidinyl, which is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl);
  • R 14 is selected from
  • R 15 is selected from C1-C6 haloalkyl
  • R 16 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 17 is selected from hydrogen and C1-C6 alkyl; preferably, as a whole, for
  • R 18 is selected from hydrogen and C1-C6 alkyl; preferably, R 18 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 19 is selected from hydrogen and C1-C6 alkyl; preferably, R 19 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 20 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 27 is selected from phenyl, C3-C6 cycloalkyl; most preferably, as a whole, selected from
  • R 28 is selected from 6-membered saturated heterocyclyl; preferably, R 28 is morpholinyl; most preferably, as a whole, for
  • R 29 is selected from C3-C6 alkyl; most preferably, as a whole, for
  • R 30 is selected from C3-C6 cycloalkyl
  • R 31 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • the present invention provides a compound represented by formula I-1-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, or isotope labeling of the compound compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate,
  • A is selected from a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring is optionally substituted by a substituent Rk ; preferably, A is selected from a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring, 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 N atoms, and the 5-membered heteroaromatic ring and 6-membered heteroaromatic ring are optionally substituted by the substituent 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,
  • A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • R k is selected from C1-C6 alkyl, C3-C7 cycloalkyl, R p R q N-, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 yuan Heterocyclyl (such as 5-6-membered saturated heterocyclyl), 6-10-membered aryl, 5-10-membered heteroaryl;
  • R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclic base); more preferably, R k is selected from C1-C6 alkyl, C3-C6 cycloalkyl, R p R q N-, C1-C6 haloalkyl, morpholinyl;
  • R p and R q are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, R p and R q are each independently selected from hydrogen, C1-C6 alkyl base;
  • Rk is selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,
  • R 4 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1 -C6 alkyl, the C1-C6 cycloalkyl can be optionally replaced by 1-3 members selected from halogen, hydroxyl, C3-C6 cycloalkyl, C3-C6 halogenated cycloalkyl, 4-7 membered heterocyclyl substituted by substituents), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted by 1-3 selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 Haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, hydroxy-C1-C6 alkyl-, cyano, oxo, -
  • R 4 is selected from hydrogen, described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 Alkyl) substituted by a substituent; n1 is selected from 0, 1, 2, 3;
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R 5 is selected from hydrogen, cyano, C1-C6 alkyl, Preferably, R5 is selected from hydrogen, cyano, Preferably, R5 is selected from hydrogen, cyano, Preferably, R5 is selected from hydrogen, cyano, R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • 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 heterocycle Base-C1-C6 alkyl; preferably, R 6 is selected from m2 is selected from 0, 1, 2, 3; n2 is selected from 0, 1, 2, 3; more preferably, R 6 is
  • R 7 is selected from hydrogen, C1-C6 alkyl; most preferably, as a whole, for
  • any one of R 8 , R 9 , R 10 and R 11 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, the rest are hydrogen; preferably, among R 8 , R 9 , R 10 , and R 11 , R 8 , R 9 or R 11 is 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;
  • R 12 is selected from hydrogen and C1-C6 alkyl; preferably, R 12 is selected from C1-C6 alkyl;
  • 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 group; preferably, R 22 is 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 is selected from hydrogen,
  • R 23 is selected from hydrogen, C1-C6 alkyl, cyano, (where Cy 1 is a 4-9 membered heterocyclyl optionally substituted by R cy1 and R cy2 ), (where Rz is H or C1-C6 alkyl, Cy 2 is 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 by 1-3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, hydroxyl);
  • Cy 1 is a 5-7 membered heterocyclyl group, more preferably, Cy 1 is a 6-membered heterocyclyl group, and further preferably, Cy 1 is morpholine, piperazine, or thiomorpholine;
  • R cy1 and R cy2 are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxyl, nitro, cyano, amino, -NH (C1-C6 alkyl) , -N(C1-C6 alkyl)(C1-C6 alkyl), oxo; preferably, R cy1 and R cy2 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, amino, oxo, further Preferably R cy1 and R cy2 are each independently selected from oxo;
  • Cy 2 is a 5-7-membered heterocyclyl group, and the 5-7-membered heterocyclyl group is optionally substituted by 1-3 members selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxyl.
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, the azetidinyl, Pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted by 1-3 substituents selected from halogen and C1-C6 alkyl; further preferably, Cy 2 is selected from Pyrrolidinyl, imidazolidinyl, piperidinyl, the pyrrolidinyl, imidazolidinyl, piperidinyl is optionally substituted by 1-3 F, Cl, Br, methyl; preferably, R 23 is selected from Hydrogen, C1-C6 alkyl, cyano group,
  • R 23 is selected from hydrogen, cyano, Preferably, R 23 is selected from hydrogen, cyano,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • 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 is selected from m5 is selected from 0, 1, 2, 3; n5 is selected from 0, 1, 2, 3; more preferably, R 24 is
  • 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 group; preferably, R 25 is 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 is selected from hydrogen,
  • R 26 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 is selected from hydrogen, C1-C6 alkyl, cyano, Preferably, R 26 is selected from hydrogen, cyano,
  • C is selected from any one of the groups (1)-(11)::
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl), R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl;
  • R 13 is selected from Further preferably, R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl, and the C3-C6 cycloalkyl is optionally substituted by 1-2 substituents selected from hydroxyl C1-C6 alkyl (such as hydroxymethyl) and formyl; Or R 14 is selected from phenyl, morpholinyl, piperazinyl, piperidinyl, and the phenyl, morpholinyl, piperazinyl, piperidinyl is optionally replaced by 1-2 selected from C1-C6 alkane Preferably substituted by substituents of base, halogen, alkoxy (such as C1-C6 alkoxy), hydroxyl, amino, hydroxy C1-C6 alkyl (such as hydroxymethyl), amino C1-C6 alkyl, formyl , R 14 is selected from p is selected from 0, 1, 2; or preferably, R 14 is selected from piperidinyl, which is optionally replaced by 1-2 selected from C1-C6 alkyl (preferably
  • Rg is selected from hydrogen, hydroxyl C1-C6 alkyl, formyl
  • R 14 is selected from
  • R 14 is selected from
  • R 15 is selected from C1-C6 haloalkyl
  • R 16 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 17 is selected from hydrogen and C1-C6 alkyl; preferably, as a whole, for
  • R 18 is selected from hydrogen and C1-C6 alkyl; preferably, R 18 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 19 is selected from hydrogen and C1-C6 alkyl; preferably, R 19 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 20 is selected from C3-C6 cycloalkyl; most preferably, as a whole, for
  • R 27 is selected from phenyl, C3-C6 cycloalkyl; most preferably, as a whole, selected from
  • R 28 is selected from 6-membered saturated heterocyclyl; preferably, R 28 is morpholinyl; most preferably, as a whole, for
  • R 29 is selected from C3-C6 alkyl; most preferably, as a whole, for
  • R 30 is selected from C3-C6 cycloalkyl
  • R 31 is selected from C1-C6 alkyl; most preferably, as a whole, for
  • R 32 is selected from phenyl, C3-C6 cycloalkyl
  • R 33 is selected from C1-C6 alkyl, C1-C6 haloalkyl (example Such as trifluoromethyl, difluoromethyl); most preferably, as a whole, selected from
  • the present invention provides compounds represented by formula II, or stereoisomers, tautomers, prodrugs, crystal forms, hydrates, isotopically labeled compounds, and metabolites of the compound , ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate,
  • A is selected from a 5-membered heteroaromatic ring; preferably, A is selected from a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; more preferably , A is selected from 1,2,3-triazole ring and imidazole ring; most preferably, A is selected from Among them, #R 31 represents the connection site for connecting the carbonyl group, and $B 11 represents the connection site for connecting the fused ring bicyclic ring;
  • R 2 and R 3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R 2 , R 3 and the N atom connected to them together form a 6-membered saturated heterocyclic group.
  • the 6-membered saturated heterocyclic group contains 2 heteroatoms, and the heteroatoms are N atoms;
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, isopropyl,
  • R 2 , R 3 and the N atoms to which they are commonly linked form together
  • R 21 is selected from C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl;
  • R 21 is selected from m7 is selected from 0, 1, 2, 3; n7 is selected from 0, 1, 2, 3;
  • R 21 is selected from
  • the present invention provides a compound represented by formula III, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is Formula III ,
  • A is selected from Where #C represents the connection site connecting C, $B represents the connection site connecting B; further preferably, A is selected from Where #C represents the connection site connecting C, $B represents the connection site connecting B; most preferably, A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • R 4 is selected from hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered saturated heterocyclyl, -NR Na R Nb (where R Na and R Nb are each independently selected from H, C1 -C6 alkyl, the C1-C6 cycloalkyl can be optionally replaced by 1-3 members selected from halogen, hydroxyl, C3-C6 cycloalkyl, C3-C6 halogenated cycloalkyl, 4-7 membered heterocyclyl substituted by substituents), the C4-C9 cycloalkyl and 4-9 membered saturated heterocyclic groups are optionally substituted by 1-3 selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 Haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, hydroxy-C1-C6 alkyl-, cyano, oxo,
  • R 4 is selected from hydrogen, described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) substituted; m1 is selected from 0, 1, 2, 3; n1 is selected from 0, 1, 2, 3; preferably n1 is 0; more preferably, R 4 is selected from hydrogen, described optionally 1-3 selected from C1-C6 alkyl, halogen, hydroxyl, cyano, -NH 2 , -N(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) substituted; m1 is selected from 0, 1, 2, 3; n1 is selected from 0, 1, 2, 3; preferably n1 is 0; more preferably, R 4 is selected from hydrogen,
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, cyano, C1-C6 alkyl, R m and R I are each independently selected from hydrogen, C1-C6 alkyl; preferably, R m and R I are each independently selected from hydrogen, methyl, isopropyl; preferably, R 5 is selected from hydrogen, cyanide base;
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl),
  • R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl; preferably, R 13 is selected from C1-C6 Haloalkyl (e.g. difluoromethyl);
  • R 13 is selected from Further preferably, R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl, piperidyl, piperazinyl, and morpholinyl, which are optionally replaced by 1-2 Substituted with a substituent selected from hydroxyl C1-C6 alkyl (such as hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);
  • R 14 is 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;
  • Rg is selected from hydrogen, hydroxyl C1-C6 alkyl, formyl group; preferably, Rg is hydrogen;
  • R 14 is selected from
  • R 14 is selected from
  • the present invention provides the compound described in Formula IV, or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers. , geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula IV,
  • A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • A is selected from Where #C represents the connection site connecting C, $B represents the connection site connecting B; most preferably, A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • 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 group; preferably, R 22 is selected from hydrogen,
  • n4 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;
  • R 22 is selected from hydrogen
  • R 23 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 23 is selected from hydrogen, carboxyl,
  • R l and R m are each independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; preferably, R l and R m are each independently selected from hydrogen and C1-C6 alkyl;
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl),
  • R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl;
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl); preferably, R 13 is selected from Enter Preferably, R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl, piperidyl, piperazinyl, and morpholinyl, which are optionally replaced by 1-2 Substituted with a substituent selected from hydroxyl C1-C6 alkyl (such as hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);
  • R 14 is 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, hydroxyl C1-C6 alkyl, and formyl; preferably, R g is hydrogen;
  • R 14 is selected from
  • R 14 is selected from
  • the present invention provides a compound represented by Formula V, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, or isotope-labeled compound of the compound ( Deuterated products), metabolites, esters, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, wherein the structural formula of the compound is formula V,
  • A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • A is selected from Where #C represents the connection site to C, $B represents the connection site to B;
  • 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 group; preferably, R 25 is selected from hydrogen,
  • n6 is selected from 0, 1, 2, 3; preferably, m6 is 0; n6 is selected from 0, 1, 2, 3; preferably, n6 is 0, 1;
  • R 25 is selected from hydrogen
  • R 26 is selected from hydrogen, C1-C6 alkyl, cyano, carboxyl, Preferably, R 26 is selected from hydrogen, cyano, carboxyl,
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl or trifluoromethyl), R h and R i are each independently selected from hydrogen and C1-C6 alkyl; preferably, R h and R i are each independently selected from hydrogen, methyl and isopropyl;
  • R 13 is selected from C1-C6 haloalkyl (such as difluoromethyl); preferably, R 13 is selected from
  • R 13 is selected from
  • R 14 is selected from C3-C6 cycloalkyl, piperidyl, piperazinyl, and morpholinyl, which are optionally replaced by 1-2 Substituted with a substituent selected from hydroxyl C1-C6 alkyl (such as hydroxymethyl), formyl, C1-C6 alkyl (preferably methyl);
  • R 14 is selected from Piperidinyl, the piperidinyl is optionally substituted by 1-2 C1-C6 alkyl (preferably methyl) substituents;
  • p is selected from 0, 1, and 2; preferably, p is 2;
  • Rg is selected from hydrogen, hydroxyl C1-C6 alkyl, formyl group; preferably, Rg is hydrogen;
  • R 14 is selected from
  • R 14 is selected from
  • the invention provides the compound represented by formula VI-1, or its enantiomers, diastereomers, elimination Spin bodies, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) Or a prodrug, wherein the structural formula of the compound is formula VI-1,
  • B and C are as defined in any one of the first to twelfth aspects of the present invention.
  • the invention provides the compound represented by Formula VI-2 or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers. body, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug, wherein the structural formula of the compound is Formula VI-2,
  • B and C are as defined in any one of the first to twelfth aspects of the present invention.
  • the invention provides a compound of formula VII-1 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is Formula VII -1,
  • A, B, R d , Re and R f are as defined in any one of the first to twelfth aspects of the present invention.
  • the present invention provides the compound of formula VII-1-1 or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers , geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VII-1-1,
  • A, B, Re , R f , R g and p are as defined in the fifteenth aspect of the present invention.
  • the present invention provides compounds of formula VII-1-2 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is Formula VII -1-2,
  • Each R x is independently selected from halogen, C1-C6 alkoxy, hydroxyl, amino, C1-C6 alkyl, cyano, s is selected from 0, 1, 2, 3, or two R The C atoms form a C1-C6 cycloalkyl group, R y is selected from H, C1-C6 alkyl group, and the definitions of A, B, R e and R f are as defined in the fifteenth aspect of the present invention.
  • the present invention provides a compound of formula VII-2-1 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is Formula VII -2-1,
  • the present invention provides a compound of formula VII-2-2 or its enantiomers, diastereomers, racemates, tautomers, and stereoisomers. , geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VII-2-2,
  • B, Re , Rf , Rx , Ry and s are as defined in the seventeenth aspect of the present invention.
  • the present invention provides compounds of formula VII-3-1 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, Geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is Formula VII -3-1,
  • A, Rd , Re , Rf , Ra and Rb are as defined in the fifteenth aspect of the present invention.
  • the present invention provides compounds of formula VII-3-2 or their enantiomers, diastereomers, racemates, tautomers, and stereoisomers. , geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VII-3-2,
  • A, R d , Re , R f , Ra and R b are defined in the fifteenth aspect of the present invention.
  • the present invention provides compounds of formula VII-3-3 or their enantiomers, diastereomers, racemates, tautomers, and stereoisomers. , geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VII-3-3,
  • A, Rd , Re , Rf , Ra and Rb are as defined in the fifteenth 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, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VIII- 1 compound,
  • R d , Re , R f , Ra and R b are as defined in any one of the first to twelfth aspects of the present invention.
  • the present invention provides a compound of formula VIII-2 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric Isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VIII- 2 compounds,
  • R d , Re , R f , Ra and R b are as defined in any one of the first to twelfth aspects of the present invention.
  • the present invention provides a compound of formula VIII-3 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric Isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds) or prodrugs, wherein the structural formula of the compound is formula VIII- 3 compounds,
  • R d , Re , R f , Ra and R b are as defined in any one of the first to twelfth aspects of the present invention.
  • the compound is selected from:
  • the compound is selected from:
  • the invention provides a method for preparing the compound of formula A according to any one of the above aspects of the invention, wherein A in formula A is The methods include:
  • Compound A-1-B 1 undergoes halogenation reaction to obtain compound A-1-B 2
  • compound A-1-B 2 undergoes substitution reaction to obtain compound A-1-B 3
  • compound A-1-B 3 and compound A- Compound A-1 is obtained through cyclization reaction of 1-C 1 ;
  • the present invention provides a method for preparing compound AC-1, which includes:
  • Compound A-1-C 1 is obtained through nitration reaction to obtain compound A-1-C 2
  • compound A-1-C 2 is obtained through reduction reaction to obtain compound A-1-C 3
  • compound A-1-C 3 is obtained through azidation.
  • the ranges of compound AC-1, Rd , Re , Rf and C are as described in any one of the first to twenty-fifth aspects 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 methods include:
  • Compound A-2-B 1 undergoes a coupling reaction to obtain compound A-2-B 2
  • compound A-2-B 2 and compound A-2-C 2 undergo a coupling reaction to obtain compound A-2
  • X 2 and X 3 is each independently a halogen (such as Cl, Br, I)
  • R a , R b , R d , Re , R f , B and C are as described in any one of the first to twenty-fifth aspects of the present invention.
  • the present invention provides a preparation method of compound A-2-C 2 , which includes:
  • Compound A-2 - C 1 is subjected to halogenation reaction to obtain compound A-2- C 2 , wherein Any of the twenty-fifth aspects.
  • the present invention provides a method for preparing the compound of formula A described in any one of the first to twenty-fifth aspects of the present invention, characterized in that: A in formula A is The methods include:
  • the present invention provides a preparation method of compound A-3-B 2 , which includes:
  • Compound A-3-B 1 is subjected to an acylation reaction to obtain compound A-3-B 2 , wherein R a , R b , and B are as described in claims 1-27.
  • the present invention provides a pharmaceutical composition, which contains the aforementioned compound, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, Isotopically labeled compounds, metabolites, esters, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, and optional pharmaceutically acceptable excipients.
  • the invention provides a PROTAC molecule, which includes: a warhead part, a ligase binding part and a connecting chain, the warhead part is the aforementioned compound, or a stereoisomer of the compound , tautomers, prodrugs, crystal forms, hydrates, isotope labeled compounds, metabolites, esters, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, the connecting chain is respectively with the warhead moiety and the ligase binding moiety are covalently linked.
  • the ligase binding moiety is an E3 ubiquitin ligase binding moiety.
  • the invention provides the aforementioned compounds, or stereoisomers, tautomers, prodrugs, crystal forms, hydrates, isotope-labeled compounds, and metabolites of the compounds , ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition, or the use of the aforementioned PROTAC molecule in the preparation of medicines for the treatment and/or prevention of IRAK4 kinase related diseases.
  • the disease associated with IRAK4 kinase is cancer or an autoimmune disease.
  • 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.
  • the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma , multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.
  • the present invention provides the aforementioned compounds, or stereoisomers, tautomers, prodrugs, crystal forms, hydrates, isotope labeled compounds, and metabolites of the compounds , ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition, or the aforementioned PROTAC molecule, which is used to treat and/or prevent diseases related to IRAK4 kinase.
  • the disease associated with IRAK4 kinase is cancer or an autoimmune disease.
  • 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.
  • the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma , multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.
  • the present invention provides a method for treating and/or preventing diseases related to IRAK4 kinase, which includes: administering to a subject an effective amount of the aforementioned compound, or a stereoisomer of the compound isomers, tautomers, prodrugs, crystal forms, hydrates, isotopically labeled compounds, metabolites, esters, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, or the aforementioned pharmaceutical compositions, or or the aforementioned PROTAC molecule.
  • the disease associated with IRAK4 kinase is cancer or an autoimmune disease.
  • 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.
  • the cancer is selected from B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma , multiple myeloma, Waldenstrom's macroglobulinemia, or any combination thereof.
  • C1-C6 alkyl refers specifically to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.
  • alkyl is meant to include branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms.
  • C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, preferably “C1-C4 alkyl”, and more preferably “C1-C3 alkyl”.
  • C1-C6 alkyl examples include, but are not limited to, methyl, ethyl, propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl group (such as n-pentyl, isopentyl, neopentyl), etc.
  • cycloalkyl refers to a saturated hydrocarbon monovalent ring containing 3-15 ring carbon atoms or 3-10 ring carbon atoms, such as “C3-C7 cycloalkyl” or “C4-C9 cycloalkyl” , “C3-C6 cycloalkyl”, cycloalkyl can be in the form of a single ring, fused ring, bridged ring or spiro ring.
  • Exemplary cycloalkyl examples include, but are not limited to, the following:
  • C3-C6 cycloalkyl examples include
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • heteroalkyl refers to any alkyl group as described above (such as C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) in which one or more backbone carbon atoms are replaced by heteroatoms ( N, O or S) substituted group.
  • alkoxy refers to any alkyl group as described above (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) connected to the rest of the molecule through an O atom, for example C1-C6 alkoxy group, C1-C4 alkoxy group, C1-C3 alkoxy group, specifically such as methoxy group, ethoxy group, etc.
  • C1-C6 haloalkyl refers to one or more hydrogen atoms in any of the above alkyl groups (such as C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) replaced by halogen (preferably fluorine, The group obtained by replacing chlorine), for example, monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, etc.
  • halogen preferably fluorine, The group obtained by replacing chlorine
  • 6-10 membered aryl and “6-10 membered aromatic ring” are used interchangeably and refer to aromatic 6-10 membered monocyclic or bicyclic groups. Specific examples include phenyl and naphthyl, with phenyl being preferred.
  • Heteroatom refers to N, O or S.
  • heteroaryl and “heteroaryl ring” are used interchangeably and refer to substituted and unsubstituted aromatic 5-membered aromatic groups having at least one heteroatom (N, O, or S) in at least one ring Or a 6-membered monocyclic group, an 8-membered, a 9-membered or a 10-membered bicyclic group and an 11- to 14-membered tricyclic group.
  • the heteroatom-containing ring optionally also has 1, 2 One or three heteroatoms selected from N, O or S.
  • the 14-membered tricyclic group is a "condensed heteroaryl” or "condensed heteroaromatic ring". It is a bicyclic or tricyclic heteroaryl or heteroaromatic ring, and requires a bicyclic or tricyclic overall structure to form an aromatic system.
  • a heteroaryl or heteroaromatic ring can be attached at any available nitrogen or carbon atom of either ring. And those skilled in the art can understand that two adjacent atoms (preferably carbon atoms) are shared between each two rings in the fused ring.
  • Exemplary monocyclic heteroaryl or monocyclic heteroaryl rings include, but are not limited to: pyrrolyl/ring, pyrazolyl/ring, imidazolyl/ring, oxazolyl/ring, isoxazolyl/ring, thiazolyl/ Ring, thiadiazolyl/ring, isothiazolyl/ring, furyl/ring, thienyl/ring, oxadiazolyl/ring, pyridyl/ring, pyrazinyl/ring, pyrimidinyl/ring, pyridazine Base/ring, triazinyl/ring, triazolyl/ring, pyridazinyl/ring, 2-pyridone, etc.
  • bicyclic heteroaryl groups include, but are not limited to: indolyl, 5-azaindolyl, pyrro[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl Heteroindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridyl, pyrro[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl , Thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolyl , isoquinolyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridyl, iso
  • Exemplary "9-membered heteroaryl groups” include, but are not limited to wait.
  • heterocycle refers to substituted and unsubstituted 3- to 7-membered (preferably 4-7-membered, more preferably 5-membered) 6-membered) 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 an aromatic ring; wherein at least A ring has at least one heteroatom (N, O or S).
  • the fused, bridged or spiro rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated or partially saturated, but do not constitute an aromatic ring.
  • Heterocyclic groups can be attached at any available nitrogen or carbon atom.
  • Exemplary heterocyclic examples include, but are not limited to, the following:
  • Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinetrienyl, 1-pyridonyl, 4-piperidine Keto group, tetrahydropyranyl group, morpholinyl group, 1,3-dioxolyl group, etc., preferably such as
  • saturated heterocyclyl refers to the heterocyclic ring defined above that does not contain unsaturated bonds, such as double bonds.
  • saturated heterocyclic rings include but are not limited to hexahydropyrimidine, Hexahydropyrazine,
  • examples of "6-membered saturated heterocyclyl” include but are not limited to morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, hexahydropyrimidinyl, and hexahydropyrazinyl, specifically such as
  • any group whose name is a compound name, such as "hydroxy C1-C6 alkyl”, shall refer to the moiety from which it is derived conventionally from left to right e.g. Constructed from "C1-C6 alkyl” substituted with hydroxyl, wherein “C1-C6 alkyl” is as defined above.
  • the "hydroxy C1-C6 alkyl group” may be, for example, hydroxymethyl.
  • Other similar composite groups can be understood with reference to the foregoing content.
  • direct bond means that the groups on both sides of it are directly connected, for example, the structural formula shown in formula A , if L 1 is a direct bond, the structural formula shown in formula A is
  • substituted or “substituted by a substituent" means that any one or more hydrogens on a specified atom or group are replaced by a selected selection of the specified group, provided that the normal valence of the specified atom is not exceeded.
  • B is selected from a 6-10-membered heteroaryl group, a 6-10-membered aryl group, and B is substituted by the substituents R a and R b " means that B can be a 6-10-membered heteroaryl group, and the 6 -The 10-membered heteroaryl group is substituted by 2 substituents, that is, the substituents R a and R b.
  • B can also be a 6-10-membered aryl group, and the 6-10-membered aryl group is substituted by 2 substituents, that is, the substituent group R a and R b are substituted, and the substituents of the 6-10-membered heteroaryl group and the 6-10-membered aryl group are independent of each other and are not affected by each other, that is, the substituents of the 6-10-membered heteroaryl group are
  • the substituents and the substituents of the 6- to 10-membered aryl group may be the same or different.
  • R a and R b are both hydrogen, those skilled in the art can understand that in fact the 6-10-membered heteroaryl group or the 6-10-membered aryl group is not substituted. Other similar definitions can be understood with reference to the foregoing content.
  • R d is selected from C3-C6 cycloalkyl, and the C3-C6 cycloalkyl is optionally substituted by a substituent selected from hydroxy C1-C6 alkyl (such as hydroxymethyl), formyl
  • hydroxy C1-C6 alkyl such as hydroxymethyl
  • formyl means What is important is that the C3-C6 cycloalkyl group may not be substituted by a substituent, or may be substituted by a substituent selected from the group consisting of hydroxyl C1-C6 alkyl group (such as hydroxymethyl) and formyl group.
  • Other similar definitions can be understood with reference to the foregoing content.
  • B is phenyl, and B is substituted by substituents R a and R b ", and "R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted 5-membered heterocyclic ring, and the substituents are selected from
  • C1-C6 alkyl such as tert-butyl
  • R a , R b and the two adjacent carbon atoms on the benzene ring connected to R a and R b respectively form 5
  • the 5-membered heterocyclic ring may be unsubstituted or substituted by a substituent at any position, and the substituent may be selected from C1-C6 alkyl (such as tert-butyl).
  • B is a phenyl group
  • B is substituted by the substituents R a and R b , and R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted
  • R a and R b substituents connected to them respectively form a substituted or unsubstituted
  • R a , R b and the carbon atoms connected to them respectively form a substituted or unsubstituted
  • the substituent is tert-butyl
  • the dotted double bond in represents the fusion site of the 5-membered heterocyclic ring and the benzene ring.
  • Other similar definitions can be understood with reference to the foregoing content.
  • C is selected from 5-6 membered heteroaryl groups, and C is optionally substituted by at least one of the substituents R d , R e , and R f " means that C may be unsubstituted, substituted, or substituted.
  • the substituent can be only R d , Re or R f , the substituent can also be a combination of any two of R d , Re , and R f , and the substituent can also be R d , Re and R f .
  • Other similar definitions can be understood with reference to the foregoing content.
  • R 1 is And "R 2 , R 3 and the N atoms connected to them together form a 6-membered saturated heterocyclic group” means that R 2 , R 3 and the N atoms connected to R 2 and R 3 together form a 6-membered saturated heterocyclic group.
  • 6-membered saturated heterocyclyl for example, if the 6-membered saturated heterocyclyl is Then N atom No. 1 is the N atom jointly connected with R 2 and R 3 .
  • treatment generally refers to obtaining the desired pharmacological and/or physiological effects.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptoms in a patient who is susceptible to the disease or symptoms but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., arresting its progression; or (c) alleviating the symptoms of a disease, i.e., causing regression of the disease or symptoms.
  • 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.
  • the mammal is a human.
  • an effective amount refers to an amount that is effective in achieving the desired therapeutic or preventive effect at the necessary dose and time.
  • the "therapeutically effective amount” of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit the desired response in the individual.
  • a therapeutically effective amount also encompasses an amount of the substance/molecule in which the therapeutically beneficial effects outweigh any toxic or harmful consequences.
  • “Prophylactically effective amount” refers to an amount effective in the dosage and time necessary to achieve the desired preventive effect.
  • the prophylactically effective amount will be less than the therapeutically effective amount because the prophylactic dose is administered to the subject prior to the onset of disease or in the early stages of the disease.
  • a therapeutically effective amount of the drug reduces the number of cancer cells; reduces the size of the tumor; inhibits (i.e., somewhat slows, preferably halts) the infiltration of cancer cells into surrounding organs; inhibits (ie, somewhat slows, preferably halts) the infiltration of cancer cells into surrounding organs; ) Tumor metastasis; inhibiting tumor growth to a certain extent; and/or alleviating one or more symptoms related to cancer to a certain extent.
  • the pharmaceutical composition involved in the present invention may contain pharmaceutically acceptable excipients.
  • the excipients include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human albumin, and buffer substances such as phosphates.
  • glycerin 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 oxidation Silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and more.
  • the pharmaceutical composition of the present invention can be prepared in various forms according to different administration routes.
  • the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, peritoneal administration.
  • Medications are administered intravenously, intrathecally, intraventricularly, intrasternally, and intracranially by injection or infusion, or by means of an explanted reservoir. Among them, oral or intravenous administration is preferred.
  • the compounds described in the present invention can optionally be used in combination with one or more other active ingredients, and their respective dosages and proportions can be adjusted by those skilled in the art according to specific diseases and patient conditions, as well as clinical needs.
  • prodrug refers to derivatives that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they have no or only less activity in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th edition).
  • Stereoisomers in the compounds described herein when specifically designated by chemical name as the (R)- or (S)-isomer, shall be understood to mean that the predominant configuration is the (R)-isomer or (S)-isomer, respectively. S)-isomer. Any asymmetric carbon atom may be present in the (R)-, (S)- or (R, S)-configuration, preferably in the (R)- or (S)-configuration.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions, such as the very typical enol-keto tautomer.
  • isotopically labeled compound refers to a compound in which any atom in the compound is replaced by an atom of its isotope.
  • solvent or “solvate” are used interchangeably and refer to a compound that exists in combination with a certain solvent molecule. This combination can Including a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate” is formed, such as a monohydrate or dihydrate, or any amount of water can be included; for example, when the solvent is an alcohol, such as Methanol or ethanol, can form “alcoholates”, which can also be stoichiometric or non-stoichiometric.
  • solvate refers to a solid form, ie, a compound in solution in a solvent. Although it may be solvated, it is not a solvate as the term is used herein.
  • the term “metabolite” refers to a derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of processes by which specific substances are changed by organisms (including, but not limited to, hydrolysis reactions and enzymatic reactions).
  • esters refers to the ester of -COOH present in the compounds provided herein with a suitable alcohol, or -OH present in the compounds provided herein with a suitable acid (e.g. , carboxylic acid or oxygen-containing inorganic acid) ester formed.
  • suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate, or palmitate. Esters can undergo hydrolysis reactions in the presence of acids or bases to generate corresponding acids or alcohols.
  • the term "pharmaceutically acceptable salt” refers to (i) the acidic functional group (such as -COOH) present in the compound provided by the invention and the appropriate inorganic or organic cation (base) formed Salts, and include, but are 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, etc.
  • 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, etc.
  • inorganic alkali salts such as ammonium salt
  • organic alkali salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroplutide Caine salt, procaine salt, diethanolamine salt, N-benzyl-phenylethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt.
  • the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of substances, due to the influence of various factors, the bonding methods within or between molecules change, resulting in different arrangements of molecules or atoms in the crystal lattice space, forming different crystal structures.
  • the compound of the present invention can exist in one crystal structure or in multiple crystal structures, that is, it has "polymorphic form".
  • the compounds of the invention may exist in different crystalline forms.
  • the present invention also provides methods for preparing corresponding compounds.
  • Various synthetic methods can be used to prepare the compounds described herein, including the following methods.
  • the compounds of the present invention or their pharmaceutically acceptable salts, isomers or hydrates can be The following methods are used together with synthetic methods known in the field of organic chemical synthesis, or are synthesized by variations of these methods understood by those skilled in the art. Preferred methods include but are not limited to the following methods.
  • compound 1-10 100 mg, 0.41 mmol was added to a single-neck bottle, and compound 1-6 (100.41 mg, 0.41 mmol) was added to ethanol (5 mL) and water (2 ml) and stirred until dissolved.
  • Sodium vitamin C 8.21 mg, 0.04 mmol
  • 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.
  • 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
  • copper iodide 10.12 mg, 0.05 mmol
  • potassium phosphate 225.56 mg, 1.06 mmol
  • reaction solution was concentrated under reduced pressure, and the residue was passed through high-performance liquid phase (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile, gradient configuration Ratio: acetonitrile 19%-95% (flow rate: 25mL/min) prepared compound 2A (29.5mg).
  • reaction solution was concentrated under reduced pressure, and the residue was passed through high-performance liquid phase (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: Acetonitrile 19%-95% (flow rate: 25 mL/min) prepared compound 4A (82 mg).
  • compound 11-2 (430 mg, 1.77 mmol), 1-(1-cyclohexyl-3-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1 to the one-neck bottle.
  • a mixed solvent system of 2,3-triazole (554mg, 2.30mmol), potassium carbonate (489mg, 3.53mmol), copper sulfate pentahydrate and sodium ascorbate (140mg, 0.710mmol) dissolved in water (4mL) and methanol (4mL) medium, stir until dissolved, and stir the reaction solution at 30°C for 4 hours.
  • reaction solution was concentrated under reduced pressure, and the residue was prepared by high-performance liquid phase (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%-95% (flow rate: 25mL/min) to obtain compound 11A (640mg).
  • compound 2-1 (1.30 g, 4.66 mmol) and N,N-dimethylformamide (20 mL) were added to a single-neck bottle and stirred until dissolved. Then add zinc powder (0.30g, 4.66mmol), zinc cyanide (0.34g, 4.66mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (0.34g, 0.46) to the reaction solution. mmol). The reaction solution was stirred at 120°C for 18 hours. The reaction solution was diluted with water (30 mL) and extracted three times with ethyl acetate (50 mL).
  • reaction solution was passed through high performance liquid phase (Waters-2545, chromatographic column: SharpSil-TC18, 30*150mm, 5 ⁇ m; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate :30mL/min) to obtain compound 65A (20.0mg, 0.050mmol).
  • compound 29-1 300 mg, 2.10 mmol was added to acetonitrile (10 mL), using the intermediate pyrrolo[1,2-b]pyndazine-3-carbonitrile disclosed on page 75 of the specification in the patent application "WO2015117563 A1". Prepared by method), N-iodosuccinimide (707 mg, 3.14 mmol). The reaction solution was stirred at 60°C for 1 hour. TLC monitored that the reaction was complete, and saturated sodium sulfite solution (10 mL) was carefully added to the reaction solution.
  • compound 29-3 (175 mg, 1.05 mmol) and compound 1-6 (252.55 mg, 1.05 mmol) were added to a mixed solution of ethanol (8 mL) and water (4 mL), and then copper sulfate pentahydrate was added. (0.01mL, 0.10mmol) and sodium vitamin C (20.74mg, 0.10mmol), stir at room temperature overnight.
  • the crude product was processed by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10.0 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 19%- 95% flow rate: 25 mL/min) was purified to obtain compound 79A (53.1 mg). MS m/z(ESI):485.2[M+1] + .
  • Step 1 Preparation of compounds 72-1 and 73-1
  • compound 83-3 (770 mg, 2.45 mmol) and methanol (10 mL) were sequentially added to the one-neck bottle, stirred until dissolved, and then potassium carbonate (677 mg, 4.90 mmol) was added to the reaction bottle.
  • 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).
  • Step 1 Preparation of compounds 86-1 and 87-1
  • bistriphenylphosphine 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), triethyl A solution of amine (0.70 mL, 5.03 mmol) and tetrahydrofuran (10 mL). The reaction was replaced with nitrogen three times, and then reacted at 25°C for 18 hours.
  • reaction solution was quenched with water (5 mL), extracted with ethyl acetate (5 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure, and the residue was analyzed by high-performance liquid chromatography ( A: 0.1% FA/H2O B: ACN, column: Wetch-Ultimate-XB-C18-10 ⁇ m-21.2*150mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25%-45 %, flow rate: 25 mL/min) and purified to obtain compound 88A (150 mg).

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Abstract

涉及一种抑制IRAK4活性的化合物及其应用,具体提供了式A所示化合物,或所述化合物的对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药。

Description

一种抑制IRAK4活性的化合物及其应用 技术领域
本发明涉及医药领域,具体涉及一种抑制IRAK4活性的化合物及其应用。
背景技术
IRAK4是一种丝氨酸/苏氨酸蛋白激酶,属于白细胞介素-1受体相关激酶(Interleukin-1 receptor-associated kinase)家族,该家族包括四个亚型IRAK1,IRAK2,IRAK3(or IRAKM)和IRAK4。其中,IRAK1、IRAK2和IRAK4促进炎症因子的释放,而IRAK3参与抑炎进程。在四种亚型中,IRAK4的生物学功能已经被清楚的阐释。当TLR或IL-1R感知外界信号刺激后,通过IRAK4形成的Myddosome复合物激活MAPK和NF-κB通路,进而释放多种炎症因子。
研究证实,IRAK4在多种肿瘤细胞及炎症模型中高表达,靶向IRAK4的抑制剂研发日益成为自身免疫性疾病与肿瘤治疗的重要方向。IRAK4具有激酶活性和骨架活性两种功能,对下游的信号调节中这两种功能均发挥重要作用。
另外,蛋白降解靶向嵌合体(Proteolysis Targeting Chimeria,PROTAC)技术是近年来兴起的一项新技术,该技术自2001年问世以来备受瞩目,目前已有多个基于该技术的药物研发进入临床研究阶段,部分进入临床2期。PROTAC作为一种异质双功能分子,其由一端可识别靶蛋白的小分子抑制剂、连接链及另一端为可识别E3泛素连接酶的配体三部分组成,这种双功能分子在体内识别并将靶蛋白和E3泛素连接酶拉近形成三元复合物,然后对靶蛋白进行泛素化标记,进而启动依赖于泛素-蛋白酶体的降解途径。相较于常规的小分子抑制剂,PROTAC技术通过对IRAK4蛋白的降解,实现对IRAK4两种功能的同时抑制,能够有效解决小分子活性不足或突变问题。
因此,研发新的小分子IRAK4激酶抑制剂具有十分重要的意义,并且可基于新的小分子IRAK4激酶抑制剂获得靶向IRAK4的PROTAC分子。
发明内容
本申请发明人通过深入的研究和创造性的发现,获得了新的小分子IRAK4激酶抑制剂,可以用于多种疾病的治疗,并且新的小分子IRAK4激酶抑制剂可以为后续进一步研发靶向IRAK4的PROTAC分子奠定基础。
为此,在本发明的第一方面,本发明提供了式A所示化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,
其中:
A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;
B选自6-10元杂芳基、6-10元芳基,且B任选地被取代基Ra、Rb中的至少一个所取代;优选地,B被取代基Ra、Rb中的至少一个所取代;
Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基)、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂 环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),其中,所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;
Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;
或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);
L1选自直接键、C1-C6烷基、
R1选自
C选自5-6元杂芳基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基、所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被C1-C6烷基、1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;
或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子。
在一些实施方案中,A选自5元杂芳环、6元杂芳环,且所述6元杂芳环任选地被取代基Rk所取代。
在一些实施方案中,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代。
在一些实施方案中,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代。
在一些实施方案中,A选自 任选地被取代基Rk所取代,其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点。
在一些实施方案中,A选自 其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点。
在一些实施方案中,A选自其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点。
在一些实施方案中,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基)。
在一些实施方案中,Rk选自C1-C6烷基、5-6元饱和杂环基。
在一些实施方案中,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基。
在一些实施方案中,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
在一些实施方案中,Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基。
在一些实施方案中,Rp、Rq各自独立地选自氢、C1-C6烷基。
在一些实施方案中,B选自6-10元杂芳基、6-10元芳基,且B被取代基Ra、Rb所取代。
在一些实施方案中,B选自9元杂芳基、吡啶基、苯基、嘧啶基,且B被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子。
在一些实施方案中,B选自9元杂芳基、吡啶基、苯基,且B被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子。
在一些实施方案中,B选自吡啶基、苯基、嘧啶基,且B被取代基Ra、Rb中的至少一个所取代。
在一些实施方案中,B选自吡啶基、苯基,且B被取代基Ra、Rb中的至少一个所取代。
在一些实施方案中,B选自且B被取代基Ra、Rb所取代。
在一些实施方案中,B选自且B被取代基Ra、Rb所取代。
在一些实施方案中,Ra选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代。
在一些实施方案中,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,其中m选自0、1、2、3,n选自0、1、2、3,p选自0、1、2、3。
在一些实施方案中,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,其中m选自0、1、2、3,n选自0、1、2、3,p选自0、1、2、3。。
在一些实施方案中,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、F、Cl、Br所取代,其中,其中m选自0、1、2、3,n选自0、1、2、3。
在一些实施方案中,Ra选自氢、氰基、羧基、
在一些实施方案中,Ra选自氢、氰基、羧基、
在一些实施方案中,Ra选自氢、氰基、
在一些实施方案中,Ra选自氢、氰基、
在一些实施方案中,m选自0、1。在一些实施方案中,n选自0、1、2、3。在一些实施方案中,n选自0、1。在一些实施方案中,p选自0、1。在一些实施方案中,m为0且n为0。
在一些实施方案中,Cy1为任选被Rcy1和Rcy2所取代的5-7元杂环基,更优选地,Cy1为任选被Rcy1和Rcy2所取代的6元杂环基,进一步优选地,Cy1为任选被Rcy1和Rcy2所取代的吗啉、哌嗪、硫代吗啉。
在一些实施方案中,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代。
在一些实施方案中,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基。
在一些实施方案中,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个选自F、Cl、Br、甲基的取代基所取代。
在一些实施方案中,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代。
在一些实施方案中,Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代。
在一些实施方案中,Rb选自氢、氰基、
在一些实施方案中,Rl、Rm各自独立地选自氢、C1-C6烷基。
在一些实施方案中,Ra、Rb和与它们分别相连的碳原子一起形成其中Rc选自氢、C1-C6烷基。
在一些实施方案中,Rc选自C1-C6烷基。
在一些实施方案中,B作为整体,选自:

在一些实施方案中,B作为整体,选自
在一些实施方案中,B作为整体,选自
在一些实施方案中,B作为整体,选自
在一些实施方案中,L1选自直接键、在一些实施方案中,L1选自直接键、亚甲基、在一些实施方案中,L1选自直接键、在一些实施方案中,L1选自直接键。
在一些实施方案中,C选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C任选地被取代基Rd、Re、Rf中的至少一个所取代。
在一些实施方案中,C选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基、噁唑基、呋喃基、1,2,3-三唑 基、1,2,4-三唑基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代。
在一些实施方案中,C选自吡唑基、噻唑基、吡啶基、吡咯基、噁唑基、呋喃基、1,2,3-三唑基、1,2,4-三唑基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代。
在一些实施方案中,Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基、所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被、1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代。
在一些实施方案中,Rd选自C1-C6烷基、C3-C6环烷基、苯基、吡啶基、吗啉基、哌嗪基、哌啶基,所述C3-C6环烷基、苯基、吡啶基、吗啉基、哌嗪基、哌啶基各自独立任选地被1-2个选自C1-C6烷基、卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代。
在一些实施方案中,Rd选自C3-C6环烷基、苯基、吗啉基、哌啶基,所述C3-C6环烷基、苯基、吗啉基、哌啶基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代。
在一些实施方案中,Rd选自C1-C6烷基、苯基、吗啉基、哌嗪基、哌啶基,所述苯基、吗啉基、哌嗪基、哌啶基任选地被C1-C6烷基(优选甲基)取代,其中p选自0、1、2,Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基。
在一些实施方案中,Rd选自苯基、吗啉基、哌啶基,其中p选自0、1、2,Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基。
在一些实施方案中,Rd选自甲基、乙基、异丙基、 哌嗪基、哌啶基、
在一些实施方案中,Rd选自 哌嗪基。
在一些实施方案中,Rd选自
在一些实施方案中,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基。
在一些实施方案中,Re选自氢、甲基、F3C-、-NHCH3
在一些实施方案中,Re选自氢、甲基、F3C-、
在一些实施方案中,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基。
在一些实施方案中,Re、Rf和与它们分别相连的碳原子一起形成其中各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基。
在一些实施方案中,Re、Rf和与它们分别相连的碳原子一起形成
在一些实施方案中,R2、R3各自独立地选自氢、甲基、乙基、丙基、
在一些实施方案中R2、R3和与它们共同相连的N原子一起形成
在一些实施方案中,R1作为整体,选自:

在一些实施方案中,R1作为整体,选自:
在一些实施方案中,R1作为整体,选自:
在一些实施方案中,R1作为整体,选自
在本发明的第二方面,本发明提供了式i所示化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,
其中:
A1选自5元杂芳环,且所述5元杂芳环任选地被取代基Rk所取代;优选地,A1选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A1选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环;
进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;
更进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
B1选自6-10元杂芳基、6-10元芳基,且B1任选地被取代基Ra、Rb中的至少一个所取代;优选地,B1被取代基Ra、Rb中的至少一个所取代;优选地,B1选自9元杂芳基、吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;优选地,B1选自9元杂芳基、吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;
更优选地,B1选自吡啶基、苯基、嘧啶基,且B1 被取代基Ra、Rb中的至少一个所取代;更优选地,B1选自吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;进一步优选地,B1选自 且B1被取代基Ra、Rb所取代;
进一步优选地,B1选自且B1被取代基Ra、Rb所取代;Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基),-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,所述C4-C9环烷基、4-9元饱和杂环基任选地被C1-C6烷基、卤素、羟基、氰基所取代;
优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉、哌嗪、硫代吗啉;
Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;进一步优选地,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代;
优选地,Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;;
优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、卤素(如F、Cl、Br)所取代;
m选自0、1、2、3;优选地,m选自0、1;n选自0、1、2、3;优选地,n选自0、1;p选自0、1、2、3;优选地,p选自0、1;
更优选地,Ra选自氢、氰基、羧基、
更优选地,Ra选自氢、氰基、
Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、
优选地,Rb选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);优选地,Ra、Rb和与它们分别相连的碳原子一起形成
Rc选自氢、C1-C6烷基;优选地,Rc选自C1-C6烷基;
最优选地,B1作为整体,选自:

最优选地,B1作为整体,选自:

最更进一步优选地,B1作为整体,选自
L1选自直接键、C1-C6烷基、优选地,L1选自直接键、 优选地,L1选自直接键、亚甲基、优选地,L1选自直接键、
R11选自
C1选自5-6元杂芳基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C1选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、4-7元饱和杂环基、所述C3-C7环烷基和4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、所述C3-C7环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自4-7元饱和杂环基,所述4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
更优选地,Rd选自C1-C6烷基、或者更优选地,Rd选自吡咯基、哌啶基、咪唑烷基、哌嗪基,所述吡咯基、哌啶基、咪唑烷基、哌嗪基任选地被1-2个选自卤素、C1-C6烷氧基、C1-C6烷基(优选甲基)取代;更优选地,Rd选自
p选自0、1、2;
或者更优选地,Rd选自吡咯基、哌啶基,所述吡咯基、哌啶基任选地被1-2个选自卤素、C1-C6烷基(优选甲基)取代;
Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基;
进一步优选地,Rd选自甲基、乙基、异丙基、哌啶基、
进一步优选地,Rd选自
进一步优选地,Rd选自
Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基;
优选地,Re选自氢、甲基、F3C-、-NHCH3;优选地,Re选自氢、甲基、F3C-、
或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
优选地,Re、Rf和与它们分别相连的碳原子一起形成
各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
更优选地,Re、Rf和与它们分别相连的碳原子一起形成
R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子;优选地,R2、R3各自独立地选自氢、甲基、乙基、丙基、
或者优选地,R2、R3和与它们共同相连的N原子一起形成
最优选地,R11作为整体,选自:
最优选地,R11作为整体,选自:
最优选地,R11作为整体,
在本发明的第三方面,本发明提供了式i-1所示化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,

其中:
A1选自5元杂芳环,且所述5元杂芳环任选地被取代基Rk所取代;优选地,A1选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A1选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环;进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;更进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B1选自6-10元杂芳基、6-10元芳基,且B1任选地被取代基Ra、Rb中的至少一个所取代;优选地,B1被取代基Ra、Rb中的至少一个所取代;优选地,B1选自9元杂芳基、吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;优选地,B1选自9元杂芳基、吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;
更优选地,B1选自吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;更优选地,B1选自吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;
进一步优选地,B1选自且B1 被取代基Ra、Rb所取代;进一步优选地,B1选自且B1被取代基Ra、Rb所取代;Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基),-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,所述C4-C9环烷基、4-9元饱和杂环基任选地被C1-C6烷基、卤素、羟基、氰基所取代;
优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉、哌嗪、硫代吗啉;
Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;
优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;进一步优选地,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代;
优选地,Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;;
优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、卤素(如F、Cl、Br)所取代;
m选自0、1、2、3;优选地,m选自0、1;n选自0、1、2、3;优选地,n选自0、1;p选自0、1、2、3;优选地,p选自0、1;
更优选地,Ra选自氢、氰基、羧基、
更优选地,Ra选自氢、氰基、
Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、
优选地,Rb选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);
优选地,Ra、Rb和与它们分别相连的碳原子一起形成
Rc选自氢、C1-C6烷基;优选地,Rc选自C1-C6烷基;
最优选地,B1作为整体,选自:

最优选地,B1作为整体,选自:

最更进一步优选地,B1作为整体,选自
L1选自直接键、C1-C6烷基、优选地,L1选自直接键、优选地,L1选自直接键、亚甲基、优选地,L1选自直接键、
R11选自
C1选自5-6元杂芳基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C1选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、4-7元饱和杂环基、所述C3-C7环烷基和4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、所述C3-C7环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自4-7元饱和杂环基,所述4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
更优选地,Rd选自C1-C6烷基、
或者更优选地,Rd选自吡咯基、哌啶基、咪唑烷基、哌嗪基,所述吡咯基、哌啶基、咪唑烷基、哌嗪基任选地被1-2个选自卤素、C1-C6烷氧基、C1-C6烷基(优选甲基)取代;
更优选地,Rd选自p选自0、1、2;
或者更优选地,Rd选自吡咯基、哌啶基,所述吡咯基、哌啶基任选地被1-2个选自卤素、C1-C6烷基(优选甲基)取代;
Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基;
进一步优选地,Rd选自甲基、乙基、异丙基、哌啶基、进一步优选地,Rd选自进一步优选地,Rd选自
Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基;
优选地,Re选自氢、甲基、F3C-、-NHCH3;优选地,Re选自氢、甲基、F3C-、
或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
优选地,Re、Rf和与它们分别相连的碳原子一起形成各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
更优选地,Re、Rf和与它们分别相连的碳原子一起形成
R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子;优选地,R2、R3各自独立地选自氢、甲基、乙基、丙基、
或者优选地,R2、R3和与它们共同相连的N原子一起形成
最优选地,R11作为整体,选自:
最优选地,R11作为整体,选自:
最优选地,R11作为整体,
在本发明的第四方面,本发明提供了式i-1-1所示化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,
其中:
A1选自5元杂芳环,且所述5元杂芳环任选地被取代基Rk所取代;优选地,A1选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A1选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环;
进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;更进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);
更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立 地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B1选自6-10元杂芳基、6-10元芳基,且B1任选地被取代基Ra、Rb中的至少一个所取代;优选地,B1被取代基Ra、Rb中的至少一个所取代;优选地,B1选自9元杂芳基、吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;优选地,B1选自9元杂芳基、吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;更优选地,B1选自 吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;更优选地,B1选自吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;
进一步优选地,B1选自且B1被取代基Ra、Rb所取代;
进一步优选地,B1选自且B1被取代基Ra、Rb所取代;Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基),-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,所述C4-C9环烷基、4-9元饱和杂环基任选地被C1-C6烷基、卤素、羟基、氰基所取代;
优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉、哌嗪、硫代吗啉;
Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;优选地、Rcy1和Rcy2各自独立地选自C1-C6 烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;进一步优选地,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代;
优选地,Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代所取代;
优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、卤素(如F、Cl、Br)所取代;
m选自0、1、2、3;优选地,m选自0、1;n选自0、1、2、3;优选地,n选自0、1;p选自0、1、2、3;优选地,p选自0、1;
更优选地,Ra选自氢、氰基、羧基、
更优选地,Ra选自氢、氰基、
Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、优选地,Rb选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);
优选地,Ra、Rb和与它们分别相连的碳原子一起形成Rc选自氢、C1-C6烷基;优选地,Rc选自C1-C6烷基;
最优选地,B1作为整体,选自:

最优选地,B1作为整体,选自:

最更进一步优选地,B1作为整体,选自
L1选自直接键、C1-C6烷基、优选地,L1选自直接键、 优选地,L1选自直接键、亚甲基、优选地,L1选自直接键、
R11选自
C1选自5-6元杂芳基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C1选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、4-7元饱和杂环基、所述C3-C7环烷基和4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、所述C3-C7环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自4-7元饱和杂环基,所述4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
更优选地,Rd选自C1-C6烷基、
或者更优选地,Rd选自吡咯基、哌啶基、咪唑烷基、哌嗪基,所述吡咯基、哌啶基、咪唑烷基、哌嗪基任选地被1-2个选自卤素、C1-C6烷氧基、C1-C6烷基(优选甲基)取代;
更优选地,Rd选自p选自0、1、2;
或者更优选地,Rd选自吡咯基、哌啶基,所述吡咯基、哌啶基任选地被1-2个选自卤素、C1-C6烷基(优选甲基)取代;
Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基;
进一步优选地,Rd选自甲基、乙基、异丙基、哌啶基、
进一步优选地,Rd选自
进一步优选地,Rd选自
Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基;
优选地,Re选自氢、甲基、F3C-、-NHCH3
优选地,Re选自氢、甲基、F3C-、
或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
优选地,Re、Rf和与它们分别相连的碳原子一起形成
各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
更优选地,Re、Rf和与它们分别相连的碳原子一起形成
R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子;
优选地,R2、R3各自独立地选自氢、甲基、乙基、丙基、
或者优选地,R2、R3和与它们共同相连的N原子一起形成
最优选地,R11作为整体,选自:
最优选地,R11作为整体,选自:
最优选地,R11作为整体,
在本发明的第五方面,本发明提供了式ii所示化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,
其中:
A2选自6元杂芳环,且所述6元杂芳环任选地被取代基Rk所取代;优选地,A2选自6元杂芳环,所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述6元杂芳环任选地被取代基Rk所取代;更优选地,A2选自2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;进一步优选地,A2选自任选地被取代基Rk所取代,其中#R12表示连接R12的连接位点,$B2表示连接B2的连接位点;更进一步优选地,A2选自 其中#R12表示连接R12的连接位点,$B2表示连接B2的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;
优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B2选自6-10元杂芳基,且B2任选地被取代基Ra、Rb中的至少一个所取代;优选地,B2被取代基Ra、Rb中的至少一个所取代;优选地,B2选自9元杂芳基,且B2被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;更优选地,B2选自 且B2被取代基Ra、Rb中的至少一个所取代;
Ra选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基);优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基);更优选地,Ra选自氢、氰基、
Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、优选地,Rb选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,B2作为整体,选自
R12选自
C2选自5-6元杂芳基,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C2选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C2选自吡咯基、噁唑基、呋喃基、1,2,3-三唑基、1,2,4-三唑基,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;
Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基,所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
优选地,Rd选自C3-C6环烷基、苯基、吗啉基、哌嗪基,所述C3-C6环烷基、苯基、吗啉基、哌嗪基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;更优选地,Rd选自C3-C6环烷基、苯基、吗啉基、哌嗪基;进一步优选地,Rd选自哌嗪基;
优选地,Re选自氢、甲基、F3C-、
最优选地,R12作为整体,选自:
在本发明的第六方面,本发明提供了式I所示的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,
其中:
A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;进一步优选地,A选自 任选地被取代基Rk所取代,其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;更进一步优选地,A选自 其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
更进一步优选地,A选自其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B选自(1)-(7)组中的任一个:
(1)其中:
R4选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
m1选自0、1、2、3;m1优选为0;n1选自0、1、2、3;n1优选为0、1;
更优选地,R4选自氢、
R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;
优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
优选地,R5选自氢、氰基;
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
(2)其中:
R6选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
优选地,R6选自m2选自0、1、2、3;n2选自0、1、2、3;
更优选地,R6
R7选自氢、C1-C6烷基;
最优选地,作为整体,为
(3)其中:
R8、R9、R10、R11中,任意一个选自氰基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基,其余为氢;
优选地,R8、R9、R10、R11中,R8、R9或R11选自氰基、C1-C6卤代烷基(例如三氟甲基)、其余为氢;m3选自0、1、2、3;n3选自0、1、2、3;
最优选地,作为整体,选自
(4)其中:
R12选自氢、C1-C6烷基;
优选地,R12选自C1-C6烷基;
(5)其中:
R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R22选自氢、m4选自0、1、2、3;n4选自0、1、2、3;
更优选地,R22选自氢、
R23选自氢、C1-C6烷基、氰基、羧基、
优选地,R23选自氢、C1-C6烷基、氰基、优选地,R23选自氢、氰基、羧基、 优选地,R23选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,作为整体,选自
最进一步优选地,作为整体,选自最更进一步优选地,作为整体,选自
(6)其中:
R24选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
优选地,R24选自m5选自0、1、2、3;n5选自0、1、2、3;
更优选地,R24
(7)其中:
R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
优选地,R25选自氢、m6选自0、1、2、3;n6选自0、1、2、3;
更优选地,R25选自氢、优选地,R25为氢;
R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、C1-C6烷基、氰基、优选地,R26选自氢、C1-C6烷基、
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
L1选自直接键、C1-C6烷基、
优选地,L1选自直接键、优选地,L1选自直接键;
C选自(1)-(10)组中的任一个:
(1)其中:
R13选自C1-C6卤代烷基(例如二氟甲基)、
Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
优选地,R13选自三氟甲基、优选地,R13选自更优选地,R13选自
R14选自C3-C6环烷基、哌啶基,所述C3-C6环烷基和哌啶基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基的取代基所取代;
优选地,R14选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代;优选地,R14选自p选自0、1、2;Rg选自氢、羟基C1-C6烷基、甲酰基;
或者,优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)取代;
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
最优选地,作为整体,选自
(2)其中:R15选自C1-C6卤代烷基;R16选自C3-C6环烷基;最优选地,作为整体,为
(3)其中:R17选自氢、C1-C6烷基;优选地,作为整体,为
(4)其中:R18选自氢、C1-C6烷基;优选地,R18选自C1-C6烷基;最优选地,作为整体,为
(5)其中:R19选自氢、C1-C6烷基;优选地,R19选自C1-C6烷基;最优选地,作为整体,为
(6)其中:R20选自C3-C6环烷基;最优选地,作为整体,为
(7)其中:R27选自苯基、C3-C6环烷基;最优选地,作为整体,选自
(8)其中:R28选自6元饱和杂环基;优选地,R28为吗啉基;最优选地,作为整体,为
(9)其中:R29选自C3-C6烷基;最优选地,作为整体,为
(10)其中:R30选自C3-C6环烷基;R31选自C1-C6烷基;最优选地,作 为整体,为
在本发明的第七方面,本发明提供了式I-1所示的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,
其中:
A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;
进一步优选地,A选自 任选地被取代基Rk所取代,其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
更进一步优选地,A选自 其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
更进一步优选地,A选自其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B选自(1)-(7)组中的任一个:
(1)其中:
R4选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;m1选自0、1、2、3;m1优选为0;n1选自0、1、2、3;n1优选为0、1;
更优选地,R4选自氢、
R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
优选地,R5选自氢、氰基;
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
(2)其中:R6选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R6选自m2选自0、1、2、3;n2选自0、1、2、3;更优选地,R6
R7选自氢、C1-C6烷基;
最优选地,作为整体,为
(3)其中:R8、R9、R10、R11中,任意一个选自氰基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基,其余为氢;优选地,R8、R9、R10、R11中,R8、R9或R11选自氰基、C1-C6卤代烷基(例如三氟甲基)、其余为氢;m3选自0、1、2、3;n3选自0、1、2、3;
最优选地,作为整体,选自
(4)其中:R12选自氢、C1-C6烷基;优选地,R12选自C1-C6烷基;(5)其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R22选自氢、m4选自0、1、2、3;n4选自0、1、2、3;
更优选地,R22选自氢、
R23选自氢、C1-C6烷基、氰基、羧基、 优选地,R23选自氢、C1-C6烷基、氰基、优选地,R23选自氢、氰基、羧基、优选地,R23选自氢、氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,作为整体,选自 最进一步优选地,作为整体,选自最更进一步优选地,作为整体,选自
(6)其中:R24选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R24选自m5选自0、1、2、3;
n5选自0、1、2、3;更优选地,R24
(7)其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R25选自氢、m6选自0、1、2、3;n6选自0、1、2、3;
更优选地,R25选自氢、优选地,R25为氢;
R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、C1-C6烷基、氰基、 优选地,R26选自氢、C1-C6烷基、
最优选地,作为整体,选自最进一步优选地,作为整体,选自
L1选自直接键、C1-C6烷基、优选地,L1选自直接键、优选地,L1选自直接键;
C选自(1)-(10)组中的任一个:
(1)其中:R13选自C1-C6卤代烷基(例如二氟甲基)、
Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
优选地,R13选自三氟甲基、优选地,R13选自更优选地,R13选自
R14选自C3-C6环烷基、哌啶基,所述C3-C6环烷基和哌啶基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基的取代基所取代;
优选地,R14选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代;
优选地,R14选自p选自0、1、2;Rg选自氢、羟基C1-C6烷基、甲酰基;
或者,优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)取代;
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
最优选地,作为整体,选自
(2)其中:R15选自C1-C6卤代烷基;R16选自C3-C6环烷基;最优选地,作为整体,为
(3)其中:R17选自氢、C1-C6烷基;优选地,作为整体,为
(4)其中:R18选自氢、C1-C6烷基;优选地,R18选自C1-C6烷基;最优选地,作为整体,为
(5)其中:R19选自氢、C1-C6烷基;优选地,R19选自C1-C6烷基;最优选地,作为整体,为
(6)其中:R20选自C3-C6环烷基;最优选地,作为整体,为
(7)其中:R27选自苯基、C3-C6环烷基;最优选地,作为整体,选自
(8)其中:R28选自6元饱和杂环基;优选地,R28为吗啉基;最优选地,作为整体,为
(9)其中:R29选自C3-C6烷基;最优选地,作为整体,为
(10)其中:R30选自C3-C6环烷基;R31选自C1-C6烷基;最优选地,作为整体,为
在本发明的第八方面,本发明提供了式I-1-1所示的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,
其中:
A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪,且所述2-吡啶酮任选地被取代基Rk所取代;进一步优选地,A选自 任选地被取代基Rk所取代,其中#C表示连接C的连接位点,$B表示连接B的连接位点;更进一步优选地,A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;
优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
B选自(1)-(7)组中的任一个:
(1)其中:R4选自氢、C1-C6烷基、C4-C9环烷基、4-9元饱和杂环基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;;
优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;n1选自0、1、2、3;
更优选地,R4选自氢、
R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、优选地,R5选自氢、氰基、Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,作为整体,选自
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
最更进一步优选地,作为整体,选自
(2)其中:R6选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R6选自m2选自0、1、2、3;n2选自0、1、2、3;更优选地,R6
R7选自氢、C1-C6烷基;最优选地,作为整体,为
(3)其中:R8、R9、R10、R11中,任意一个选自氰基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基,其余为氢;优选地,R8、R9、R10、R11中,R8、R9或R11选自氰基、C1-C6卤代烷基(例如三氟甲基)、其余为氢;m3选自0、1、2、3;n3选自0、1、2、3;
最优选地,作为整体,选自
(4)其中:R12选自氢、C1-C6烷基;优选地,R12选自C1-C6烷基;
(5)其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R22选自氢、m4选自0、1、2、3;m4优选0;n4选自0、1、2、3;n4优选0、1;更优选地,R22选自氢、
R23选自氢、C1-C6烷基、氰基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代);
优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉、哌嗪、硫代吗啉;
Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;优选地,R23选自氢、C1-C6烷基、氰基、
优选地,R23选自氢、氰基、优选地,R23选自氢、 氰基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,作为整体,选自
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
(6)其中:
R24选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R24选自m5选自0、1、2、3;n5选自0、1、2、3;更优选地,R24
(7)其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R25选自氢、m6选自0、1、2、3;m6优选0;n6选自0、1、2、3;n6优选0、1;更优选地,R25选自氢、
R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、C1-C6烷基、氰基、优选地,R26选自氢、氰基、
最优选地,作为整体,选自最优选地,作为整体,选自最进一步优选地,作为整体,选自
C选自(1)-(11)组中的任一个::
(1)其中:R13选自C1-C6卤代烷基(例如二氟甲基)、Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
优选地,R13选自进一步优选地,R13选自
R14选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代;或者R14选自苯基、吗啉基、哌嗪基、哌啶基,所述苯基、吗啉基、哌嗪基、哌啶基任选地被1-2个选自C1-C6烷基、卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代优选地,R14选自p选自0、1、2;或者优选地,R14选自哌啶基,所述哌啶基任选地被1-2个选自C1-C6烷基(优选甲基)、卤素、羟基、氨基的取代基所取代
Rg选自氢、羟基C1-C6烷基、甲酰基;
更优选地,R14选自
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
最优选地,作为整体,选自
(2)其中:R15选自C1-C6卤代烷基;R16选自C3-C6环烷基;最优选地,作为整体,为
(3)其中:R17选自氢、C1-C6烷基;优选地,作为整体,为
(4)其中:R18选自氢、C1-C6烷基;优选地,R18选自C1-C6烷基;最优选地,作为整体,为
(5)其中:R19选自氢、C1-C6烷基;优选地,R19选自C1-C6烷基;最优选地,作为整体,为
(6)其中:R20选自C3-C6环烷基;最优选地,作为整体,为
(7)其中:R27选自苯基、C3-C6环烷基;最优选地,作为整体,选自
(8)其中:R28选自6元饱和杂环基;优选地,R28为吗啉基;最优选地,作为整体,为
(9)其中:R29选自C3-C6烷基;最优选地,作为整体,为
(10)其中:R30选自C3-C6环烷基;R31选自C1-C6烷基;最优选地,作为整体,为
(11)其中:R32选自苯基、C3-C6环烷基;R33选自C1-C6烷基、C1-C6卤代烷基(例 如三氟甲基、二氟甲基);最优选地,作为整体,选自
在本发明的第九方面,本发明提供了式II所示的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,
其中:
A选自5元杂芳环;优选地,A选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A选自1,2,3-三唑环、咪唑环;最优选地,A选自 其中#R31表示连接羰基的连接位点,$B11表示连接稠环双环的连接位点;
R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;
或者,R2、R3和与它们共同相连的N原子一起形成6元饱和杂环基,优选地,所述6元饱和杂环基含有2个杂原子,且所述杂原子为N原子;优选地,R2、R3各自独立地选自氢、甲基、乙基、异丙基、
或者优选地,R2、R3和与它们共同相连的N原子一起形成
最优选地,整体选自
R21选自C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
优选地,R21选自m7选自0、1、2、3;n7选自0、1、2、3;
更优选地,R21选自
在本发明的第十个方面,本发明提供了式III所示的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式III,
其中:
A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
B为其中:R4选自氢、C1-C6烷基、C4-C9环烷基、4-9元饱和杂环基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;m1选自0、1、2、3;n1选自0、1、2、3;优选地n1为0;更优选地,R4选自氢、
更进一步优选地,R4选自氢、
R5选自氢、氰基、C1-C6烷基、Rm、RI各自独立地选自氢、C1-C6烷基;优选地,Rm、RI各自独立地选自氢、甲基、异丙基;优选地,R5选自氢、氰基;
优选地,作为整体,选自
进一步优选地,作为整体,选自
进一步优选地,作为整体,选自
C为其中:R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、
Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;优选地,R13选自C1-C6卤代烷基(例如二氟甲基);
优选地,R13选自进一步优选地,R13选自
R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;
优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;p选自0、1、2;优选地,p为2;
Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
更优选地,R14选自
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
在本发明的第十一个方面,本发明提供了式IV所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式IV,

其中:
A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
B为其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R22选自氢、
m4选自0、1、2、3;优选地,m4选自0;n4选自0、1、2、3;优选地,n4选自0、1;
更优选地,R22选自氢、
R23选自氢、C1-C6烷基、氰基、羧基、优选地,R23选自氢、羧基、
Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
最优选地,作为整体,选自
C为其中:R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、
Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
优选地,R13选自C1-C6卤代烷基(例如二氟甲基);优选地,R13选自进 一步优选地,R13选自
R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;
优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;p选自0、1、2;优选地,p为2;Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
更优选地,R14选自
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
在本发明的第十二个方面,本发明提供了式V所示的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物(氘代物)、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,其中,所述化合物的结构式为式V,
其中:
A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
B为其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R25选自氢、
m6选自0、1、2、3;优选地,m6为0;n6选自0、1、2、3;优选地,n6为0、1;
更优选地,R25选自氢、
R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、氰基、羧基、
最优选地,作为整体,选自
最进一步优选地,作为整体,选自
C为其中:R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
优选地,R13选自C1-C6卤代烷基(例如二氟甲基);优选地,R13选自
进一步优选地,R13选自
R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;
优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;
p选自0、1、2;优选地,p为2;
Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
更优选地,R14选自
更优选地,R14选自
最优选地,作为整体,选自
最优选地,作为整体,选自
在本发明的第十三个方面,本发明提供了式VI-1所示的化合物,或其对映异构体、非对映异构体、消 旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VI-1,
其中B和C的定义如本发明的第一至第十二个方面中任一项所限定。
在本发明的第十四个方面,本发明提供了式VI-2所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VI-2,
其中B和C的定义如本发明的中第一至第十二个方面中任一项所限定。
在本发明的第十五个方面,本发明提供了式VII-1的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-1,
其中A、B、Rd、Re、Rf的定义如本发明的中第一至第十二个方面中任一项所限定。
本发明的第十六个方面,本发明提供了式VII-1-1的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-1-1,
其中A、B、Re、Rf、Rg、p的定义如本发明第十五个方面中所限定。
本发明的第十七个方面,本发明提供了式VII-1-2化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-1-2,
其中各个Rx独立地选自卤素、C1-C6烷氧基、羟基、氨基、C1-C6烷基、氰基,s选自0、1、2、3,或者两个Rx可与其连接的C原子形成C1-C6环烷基,Ry选自H、C1-C6烷基,A、B、Re、Rf的定义如本发明第十五个方面中所限定。
本发明的第十八个方面,本发明提供了式VII-2-1化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-2-1,
其中B、Re、Rf、Rg、p的定义如本发明第十六个方面中所限定。
本发明的第十九个方面,本发明提供了式VII-2-2的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-2-2,
其中B、Re、Rf、Rx、Ry、s的定义如本发明第十七个方面中所限定。
本发明的第二十个方面,本发明提供了式VII-3-1化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-3-1,
其中A、Rd、Re、Rf、Ra、Rb的定义如本发明第十五个方面中所限定。
本发明的第二十一个方面,本发明提供了式VII-3-2化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-3-2,
其中A、Rd、Re、Rf、Ra、Rb的定义本发明第十五个方面中所限定。
本发明的第二十二个方面,本发明提供了式VII-3-3化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-3-3,
其中A、Rd、Re、Rf、Ra、Rb的定义如本发明第十五个方面中所限定。
本发明的第二十三个方面,本发明提供了式VIII-1化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VIII-1化合物,
其中Rd、Re、Rf、Ra、Rb的定义如本发明第一至第十二个方面中任一项所限定。
本发明的第二十四个方面,本发明提供了式VIII-2化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VIII-2化合物,
其中Rd、Re、Rf、Ra、Rb的定义如本发明中第一至第十二个方面中任一项所限定。
本发明的第二十五个方面,本发明提供了式VIII-3化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VIII-3化合物,
其中Rd、Re、Rf、Ra、Rb的定义如本发明中第一至第十二个方面中任一项所限定。
在一些实施方案中,所述化合物选自:







在一些实施方案中,所述化合物选自:




在本发明的第二十六个方面,本发明提供了一种制备本发明的以上方面中任一项所述的式A化合物的方法,其中,式A中A为所述方法包括:
化合物A-1-B1经卤代反应获得化合物A-1-B2,化合物A-1-B2经取代反应获得化合物A-1-B3,化合物A-1-B3与化合物A-1-C1经成环反应获得化合物A-1;
其中其中X1为卤素(如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C的范围如本发明第一至第二十五个方面中任一项所述。
本发明的第二十七个方面,本发明提供了一种化合物A-C-1的制备方法包括:
化合物A-1-C1经硝化反应获得化合物A-1-C2,化合物A-1-C2经还原反应获得化合物A-1-C3,化合物A-1-C3经叠氮化获得化合物A-C-1,Rd、Re、Rf和C的范围如本发明第一至第二十五个方面中任一项所述。
本发明的第二十八个方面,本发明提供了一种制备本发明的以上方面中任一项所述的式A化合物的方法,其中,A为所述方法包括:
化合物A-2-B1经偶联反应获得化合物A-2-B2,化合物A-2-B2与化合物A-2-C2经偶联反应获得化合物A-2,其中X2和X3各自独立地为卤素(例如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C如本发明第一至第二十五个方面中任一项所述。
本发明的第二十九个方面,本发明提供了一种化合物A-2-C2的制备方法包括:
化合物A-2-C1经卤代反应获得化合物A-2-C2,其中X3为卤素(例如Cl、Br、I),Rd、Re、Rf、C如本发明第一至第二十五个方面中任一项所述。
本发明的第三十个方面,本发明提供了一种制备本发明第一至第二十五个方面中任一项所述式A化合物的方法,其特征在于:式A中A为所述方法包括:
化合物A-3-C1经氰化反应获得化合物A-3-C2,与A-3-B2发生环化反应得到A-3
其中X4为卤素(例如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C如本发明第一至第二十五个方面中任一项所述。
本发明的第三十一个方面,本发明提供了一种化合物A-3-B2的制备方法包括:
化合物A-3-B1经酰化反应获得化合物A-3-B2,其中Ra、Rb、B如权利要求1-27中所述。
在本发明的第三十二个方面,本发明提供了药物组合物,其包含前述的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,以及任选的药学上可以接受的辅料。
在本发明的第三十三个方面,本发明提供了PROTAC分子,其包含:弹头部分、连接酶结合部分和连接链,所述弹头部分为前述的化合物、或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,所述连接链分别与所述弹头部分和所述连接酶结合部分进行共价连接。
在一些实施方案中,所述连接酶结合部分为E3泛素连接酶结合部分。
在本发明的第三十四个方面,本发明提供了前述的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,或者前述药物组合物,或者前述的PROTAC分子在制备药物中的用途,所述药物用于治疗和/或预防与IRAK4激酶相关的疾病。
在一些实施方案中,所述与IRAK4激酶相关的疾病为癌症或自身免疫性疾病。
在一些实施方案中,所述自身免疫性疾病选自类风湿性关节炎、骨关节炎、慢性阻塞性肺疾病、系统性红斑狼疮、银屑病、溃疡性结肠炎、肠道应激综合症,或其任意组合。
在一些实施方案中,所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、华氏巨球蛋白血症,或其任意组合。
在本发明的第三十五个方面,本发明提供了前述的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,或者前述药物组合物,或者前述的PROTAC分子,其用于治疗和/或预防与IRAK4激酶相关的疾病。
在一些实施方案中,所述与IRAK4激酶相关的疾病为癌症或自身免疫性疾病。
在一些实施方案中,所述自身免疫性疾病选自类风湿性关节炎、骨关节炎、慢性阻塞性肺疾病、系统性红斑狼疮、银屑病、溃疡性结肠炎、肠道应激综合症,或其任意组合。
在一些实施方案中,所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、华氏巨球蛋白血症,或其任意组合。
在本发明的三十六方面,本发明提供了治疗和/或预防与IRAK4激酶相关的疾病的方法,其包括:给与受试者有效量的前述的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,或者前述药物组合物,或 者前述的PROTAC分子。
在一些实施方案中,所述与IRAK4激酶相关的疾病为癌症或自身免疫性疾病。
在一些实施方案中,所述自身免疫性疾病选自类风湿性关节炎、骨关节炎、慢性阻塞性肺疾病、系统性红斑狼疮、银屑病、溃疡性结肠炎、肠道应激综合症,或其任意组合。
在一些实施方案中,所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、华氏巨球蛋白血症,或其任意组合。
具体实施方式
应该理解,此处采用的术语目的在于描述具体的实施方案,并非意在限制。此外,尽管类似或者等价于此处描述的任何方法、装置和材料均可用于实施或者测试本发明,但是现在描述的是优选的方法、装置和材料。
本发明中,除非以其他方式明确指出,在本文中通篇采用的描述方式“…各自独立地选自”既可以是指在不同基团中,相同或不同的符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同或不同的符号之间所表达的具体选项之间互相不影响。
本发明化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
术语“烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如“C1-C6烷基”是指具有1至6个碳原子的烷基,优选“C1-C4烷基”,更优选“C1-C3烷基”。“C1-C6烷基”的实例包括但不限于甲基、乙基、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基、叔丁基)、戊基(例如正戊基、异戊基、新戊基)等。
术语“环烷基”是指饱和烃单价环,含有3-15个环碳原子或3-10个环碳原子,例如可以为“C3-C7环烷基”、“C4-C9环烷基”、“C3-C6环烷基”,环烷基可以呈单环、稠环、桥环或螺环等形式。示范性的环烷基实例包括但不限于以下部分:
等。术语“C3-C6环烷基”的示例包括
卤素指的是氟、氯、溴或碘。
术语“杂烷基”是指如上文所述的任意烷基(例如C1-C6烷基、C1-C4烷基、C1-C3烷基等)中的一个或多个骨架碳原子被杂原子(N、O或S)取代所形成的基团。
术语“烷氧基”是指如上文所述的任意烷基(例如C1-C6烷基、C1-C4烷基、C1-C3烷基等)通过O原子连接到分子的其余结构部分,示例如C1-C6烷氧基、C1-C4烷氧基、C1-C3烷氧基,具体如甲氧基、乙氧基等。
术语“C1-C6卤代烷基”指的是任意上述烷基(例如C1-C6烷基、C1-C4烷基、C1-C3烷基等)中的一个或多个氢原子被卤素(优选氟、氯)替代得到的基团,例如,单氟甲基、二氟甲基、二氟乙基、三氟甲基等。
术语“6-10元芳基”和“6-10元芳环”可互换使用并且是指芳香族6-10元单环或二环基团。具体示例如苯基、萘基,优选苯基。
杂原子指的是N、O或S。
术语“杂芳基”和“杂芳环”可互换使用并且是指在至少一个环中具有至少一个杂原子(N、O或S)的被取代的和未被取代的芳香族5-元或6-元单环基团、8-元、9-元或10-元二环基团和11-元至14-元三环基团,该含杂原子环任选还具有1个、2个或3个选自N、O或S的杂原子。其中,在至少一个环中具有至少一个杂原子(N、O或S)的被取代的和未被取代的芳香族8-元、9-元或10-元二环基团和11-元至14-元三环基团即为“稠杂芳基”或“稠杂芳环”。为二环或三环的杂芳基或杂芳环,需要二环或三环整体结构形成芳香体系。杂芳基或杂芳环可在任一环的任一可用氮或碳原子上连接。且本领域技术人员可以理解,稠环中每两个环之间共用两个相邻的原子(优选碳原子)。
示例性单环杂芳基或单环杂芳环包括但不限于:吡咯基/环、吡唑基/环、咪唑基/环、噁唑基/环、异噁唑基/环、噻唑基/环、噻二唑基/环、异噻唑基/环、呋喃基/环、噻吩基/环、恶二唑基/环、吡啶基/环、吡嗪基/环、嘧啶基/环、哒嗪基/环、三嗪基/环、三氮唑基/环、哒嗪基/环、2-吡啶酮等。
示例性二环杂芳基包括但不限于:吲哚基、5-氮杂吲哚基、吡咯并[2,3-d]嘧啶基、5,6-二氮杂吲哚基、6-氮杂吲哚基、7-氮杂吲哚基、吡唑并[3,4-b]吡啶基、吡咯并[2,3-c]哒嗪基、噻吩并[2,3-d]咪唑基、噻吩并[2,3-d]咪唑基、吡唑并[3,4-c]吡啶基、苯并噻唑基、苯并咪唑基、苯并噁唑基、苯并噻吩基、喹啉基、异喹啉基、苯并呋喃基、吲嗪基、喹喔啉基、吲唑基、吡咯并嘧啶基、呋喃并吡啶基、异吲哚基等,优选如
示例性的“9元杂芳基”包括但不限于 等。
术语“杂环”、“杂环的”或“杂环基”可互换使用并且是指被取代的和未被取代的3-元至7-元(优选4-7元、更优选5-6元)单环基团、7-元至11-元二环基团和10-元至15-元三环基团,其中可以包含一个或多个双键,但不构成芳香环;其中至少一个环具有至少一个杂原子(N、O或S)。完成二环和三环基团的稠环、桥环或螺环可仅含有碳原子且可为饱和或部分饱和,但不构成芳香环。杂环基团可在任何可用氮或碳原子上连接。示范性的杂环实例包括但不限于以下部分:
示例性单环杂环基包括氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂环庚三烯基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、1,3-二氧杂环戊烷基等,优选如
其中,“饱和杂环基”指的是上述定义的杂环中不含有不饱和键,如不含有双键,例如,“4-9元饱和杂环”的示例包括但不限于六氢嘧啶,六氢吡嗪,
例如,“6元饱和杂环基”的示例包括但不限于吗啉基、哌嗪基、哌啶基、四氢吡喃基、六氢嘧啶基、六氢吡嗪基,具体如
从所有上述描述中,对本领域技术人员显而易见的是,其名称是复合名称的任意基团,例如“羟基C1-C6烷基”,应该指的是常规地从左向右从其衍生的部分例如从被羟基取代的“C1-C6烷基”来构建,其中“C1-C6烷基”如上文所定义。具体地,“羟基C1-C6烷基”例如可以为羟甲基。其余类似的复合基团可以参照前述内容进行理解。
术语“直接键”指的是其两边的基团直接相连,例如,式A所示的结构式中,若L1为直接键,则式A所示的结构式为
术语“被取代”或“被取代基…所取代”是指指定原子或基团上的任一或多个氢被指定基团的选择替代,条件为不超过指定原子的正常价态。
“B选自6-10元杂芳基、6-10元芳基,且B被取代基Ra、Rb所取代”指的是B可以是6-10元杂芳基,且所述6-10元杂芳基被2个取代基即取代基Ra、Rb所取代,B也可以是6-10元芳基,且所述6-10元芳基被2个取代基即取代基Ra、Rb所取代,并且,所述6-10元杂芳基和所述6-10元芳基的取代基各自独立,相互不受影响,即所述6-10元杂芳基的取代基和所述6-10元芳基的取代基可以相同,也可以不同。另外,若Ra、Rb均为氢,则本领域技术人员可以理解,实际上所述6-10元杂芳基或所述6-10元芳基没有被取代。其余类似的定义可以参照前述内容进行理解。
“Rd选自C3-C6环烷基,所述C3-C6环烷基任选地被1个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代”指的是所述C3-C6环烷基可以不被取代基取代,也可以被1个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代。其余类似的定义可以参照前述内容进行理解。
“B为苯基,且B被取代基Ra、Rb所取代”,且“Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基)”时,其指的是,Ra、Rb和与Ra、Rb分别相连的苯环上的相邻的两个碳原子一起,形成5元杂环,且所述5元杂环可以不被取代,也可以在任意位置被1个取代基所取代,且这1个取代基选自C1-C6烷基(如叔丁基)。例如,若B为苯基,B被取代基Ra、Rb所取代,且Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的取代基为叔丁基时,其表示,B整体可以为也可以为等等,其中,中的虚线双键表示该5元杂环与苯环进行稠合的位点。其余类似的定义可以参照前述内容进行理解。
“C选自5-6元杂芳基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代”指的是C可以不被取代,也可以被取代,被取代时,取代基可以仅为Rd、Re或Rf,取代基也可以为Rd、Re、Rf中的任意两个的组合,取代基还可以为Rd、Re和Rf。其余类似的定义可以参照前述内容进行理解。
“R1且“R2、R3和与它们共同相连的N原子一起形成6元饱和杂环基”,其指的是,R2、R3和与R2、R3共同相连的N原子一起形成6元饱和杂环基,例如,若所述6元饱和杂环基为则1号N原子即为与R2、R3共同相连的N原子。
本发明中,“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状,可以是预防性的;和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状;(b)抑制疾病的症状,即阻止其发展;或(c)缓解疾病的症状,即,导致疾病或症状退化。
本发明中,“受试者”指脊椎动物。在某些实施方案中,脊椎动物指哺乳动物。哺乳动物包括,但不限于,牲畜(诸如牛)、宠物(诸如猫、犬、和马)、灵长类动物、小鼠和大鼠。在某些实施方案中,哺乳动物指人。
本发明中,“有效量”指在必需的剂量和时间上有效实现期望的治疗或预防效果的量。本发明的物质/分子的“治疗有效量”可根据诸如个体的疾病状态、年龄、性别和体重及该物质/分子在个体中引发期望应答的能力等因素而变化。治疗有效量还涵盖该物质/分子的治疗有益效果胜过任何有毒或有害后果的量。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然,由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的,因此预防有效量会低于治疗有效量。在癌症的情况中,药物的治疗有效量可减少癌细胞数;缩小肿瘤体积;抑制(即一定程度的减缓,优选停止)癌细胞浸润到周围器官中;抑制(即一定程度的减缓,优选停止)肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻与癌症有关的一种或多种症状。
本发明涉及的药物组合物可以包含药学上可接受的辅料,辅料包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂等等。
本发明所述药物组合物可以根据不同给药途径而制备成各种形式。例如,所述的药物组合物可以以下面的任意方式施用:口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服或静脉内用药方式。
本发明所述的化合物任选地还可与其它一种或多种活性成分联合使用,其各自用量和比例可由本领域技术人员根据具体病症和患者具体情况以及临床需要等而进行调整。
如本文所使用,除非另外说明,术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物,或者它们在它们不反应的形式中不具有或仅具有较低活性。通常可以使用公知的方法制备前药,例如Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
本文所述的化合物中的立体异构体,当以化学名称特别指定为(R)-或(S)-异构体时,应分别理解为主要构型为(R)-异构体或(S)-异构体。任何不对称碳原子可以存在于(R)-、(S)-或(R、S)-构型中,优选以(R)-或(S)-构型存在。
本文所述化合物包括本文所述的所有化合物所有可能的互变异构体。术语“互变异构体”指的是因分子中某一原子在两个位置迅速移动而产生的官能团异构体,例如非常典型的烯醇式-酮式互变异构体。
本文所述化合物包括本文所述的所有化合物所有可能的同位素标记化合物。术语“同位素标记化合物”指的是该化合物中任一个原子被其同位素原子代替而得到的化合物。
“溶剂化物”或“溶剂合物”可以互换使用,指的是以与某种溶剂分子的组合存在的化合物。该组合可以 包括化学计量的量的某种溶剂,例如,当溶剂为水时,形成“水合物”,如一水合物或二水合物,或者可以包括任意量的水;又如,当溶剂是醇时,如甲醇或乙醇,可以形成“醇化物”,其也可以为化学计量的或非化学计量的。在本文中使用的术语“溶剂合物”指的是固体形式,即,在溶剂的溶液中的化合物虽然其可以为溶剂化的,但是它不是如本文中使用的术语的溶剂合物。
如本文使用的,术语“代谢产物”是指化合物代谢时形成的化合物的衍生物。术语"代谢"是指特定物质被生物体改变的过程的总和(包括但不限于,水解反应和酶催化反应)。
如本文所使用的,术语“酯”是指,本发明所提供的化合物中存在的-COOH与适当的醇形成的酯,或者本发明所提供的化合物中存在的-OH与适当的酸(例如,羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于,甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下,可以发生水解反应生成相应的酸或醇。
如本文中所使用的,术语“药学上可接受的盐”是指,(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐,并且包括但不限于,碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等;无机碱盐,如铵盐;有机碱盐,如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及,(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH2)与适当的无机或者有机阴离子(酸)形成的盐,并且包括但不限于,氢卤酸盐,如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等;无机酸盐,如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对苯磺酸盐等;有机酸盐,如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等;氨基酸盐,如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
如本文中所使用的,术语“晶型”是指物质的晶体结构。物质在结晶时由于受各种因素影响,使分子内或分子间键合方式发生改变,致使分子或原子在晶格空间排列不同,形成不同的晶体结构。本发明化合物可以一种晶体结构存在,也可以多种晶体结构存在,即具有“多晶型”。本发明化合物可以不同的晶型存在。
实施例
本发明还提供了制备相应化合物的方法,可以使用多种合成方法制备本文所述的化合物,包括下述的方法,本发明的化合物或者其药学上可接受的盐,异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法,或通过本领域技术人员理解对这些方法的变化方法合成,优选方法包括但不限于下述方法。
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明,除非特别说明,所有的温度为℃。本申请部分化合物的命名根据chemdraw命名翻译得到。
实施例1:
(1R,4R)-5-(3-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(1A)的合成
1)第一步 化合物1-2的制备
室温下,向三口瓶中加入化合物1-1(5.00g,52.04mmol),N,N-二甲基甲酰胺(100mL)搅拌至溶解,依次加入溴代环己烷(12.7g,78.1mmol)和碳酸钾(14.4g,104mmol),反应液100℃下搅拌16小时。向反应液中加入水,用乙酸乙酯萃取(300mL×3),饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-20%乙酸乙酯/石油醚)得到化合物1-2(1.3g)。LC-MS:m/z:179.0(M+H)+
2)第二步 化合物1-3的制备
室温下,向三口瓶中加入化合物1-2(1.30g,7.29mmol),二氯甲烷(20mL),充分搅拌。冰浴下逐滴滴加二乙胺基三氟化硫(10.58g,65.65mmol)。反应液搅拌16小时,缓慢恢复室温。反应液缓慢加入冰水中,用碳酸氢钠调节酸碱至中性,用乙酸乙酯萃取(50mL×3),饱和食盐水洗涤(20mL×1),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-30%二氯甲烷/石油醚)得到化合物1-3(1g)。LC-MS:m/z:201.0(M+H)+
3)第三步 化合物1-4的制备
冰浴冷却下,向单口瓶中加入化合物1-3(1.00g,4.99mmol),加入浓硫酸(5mL)搅拌均匀后,向反应液加入浓硝酸。反应液0℃搅拌5分钟后,加热至120℃后反应2小时。将反应液缓慢加入至冰水中,用碳酸氢钠调节酸碱至中性,用乙酸乙酯萃取(50mL×3),饱和食盐水洗涤(10mL×1),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-25%乙酸乙酯/石油醚)得到化合物1-4(700mg)。LC-MS:m/z:246.0(M+H)+
4)第四步 化合物1-5的制备
室温下,向单口瓶中加入化合物1-4(700mg,2.85mmol),加入乙醇(10mL)搅拌至溶解,向反 应液中加入100mg钯炭(10%),用氢气置换体系三次,反应液室温搅拌2小时。用硅藻土过滤反应液,滤饼用乙酸乙酯冲洗(10mL×3),滤液减压浓缩,产品1-5(600mg)直接用于下一步反应。LC-MS:m/z:216.0(M+H)+
5)第五步 化合物1-6的制备
冰浴下,向三口瓶中加入化合物1-5(600mg,2.79mmol),和乙腈(5mL)搅拌均匀。氮气置换体系3次,加入亚硝酸叔丁酯(431.18mg,4.18mmol),反应液冰浴下搅拌0.5小时。加入叠氮基三甲基硅烷(642.30mg,5.58mmol)。反应液搅拌16小时,缓慢恢复至室温。向反应液中加入水,用二氯甲烷萃取(20mL×3),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-5%乙酸乙酯/石油醚)得到化合物1-6(400mg)。LC-MS:m/z:241.9(M+H)+
6)第六步 化合物1-8的制备
室温下,向单口瓶中加入化合物1-7(3.02g,19.54mmol),加入乙睛(30mL)搅拌至溶解。室温下,依次加入N,N-二异丙基乙胺(6.89g,53.28mmol)和化合物(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(2.41g,17.76mmol)。反应液在60℃下搅拌4小时。向反应液中加入水,用乙酸乙酯(100mL)萃取2次,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,减压浓缩。粗品经柱层析纯化(30-60%乙酸乙酯/石油醚)化合物1-8(3.84g)。
LC-MS:m/z:217.1(M+H)+
7)第七步 化合物1-9的制备
室温下,向单口瓶中加入化合物1-8(1.02g,4.62mmol)和乙睛(10mL),搅拌至溶解。加入N-碘代丁二酰亚胺(1.56g,6.94mmol)。反应液在室温下搅拌18小时。反应液加入饱和的硫代硫酸钠水溶液(20ml)淬灭后,用乙酸乙酯(50mL)萃取2次,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩。粗品经柱层析纯化(30-80%乙酸乙酯/石油醚)得到化合物1-9(1.4g)。LC-MS:m/z:343.0(M+H)+
8)第八步 化合物1-10的制备
室温下,向单口瓶中加入化合物1-9(1.00g,2.93mmol),加入四氢呋喃(10mL)搅拌至溶解。加入三甲基乙炔基硅(285mg,2.93mmol),三乙胺(1.25mL,8.77mmol),碘化亚铜(55.1mg,0.29mmol),双三苯基磷二氯化钯(205mg,0.29mmol)氮气置换体系3次。反应液室温搅拌12小时。向反应液中加入水,用乙酸乙酯(200mL)萃取2次。饱和食盐水(100mL)洗涤,无水硫酸钠干燥,减压浓缩。粗品用甲醇(10ml)溶解后,加入碳酸钾(810mg,5.85mmol),反应液室温搅拌2小时,将反应液减压浓缩,粗品经柱层析纯化(0-40%乙酸乙酯/石油醚)得到化合物1-10(800mg)。LC-MS:m/z:241.1(M+H)+
9)第九步 化合物1A的制备
室温下,向单口瓶中加入化合物1-10(100mg,0.41mmol),化合物1-6(100.41mg,0.41mmol)加入乙醇(5mL)和水(2ml)搅拌至溶解。向反应液中加入维生素C钠(8.21mg,0.04mmol)和五水硫酸铜(10.35mg,0.04mmol)。反应液室温搅拌18小时。向反应液中加入水,用乙酸乙酯(100mL)萃取2次,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,减压浓缩。粗品经高效液相(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min),制备得到化合物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)+
实施例2
(1R,4R)-5-(3-(1'-环己基-3'-(二氟甲基)-1'-[1,4'-双吡唑]-4-基)吡唑[1,5-a]嘧啶-5-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(2A)的制备
1)第一步 化合物2-1的制备
冰浴下,向单口瓶中加入化合物1-3(700mg,3.50mmol),加入二氯甲烷(15mL)搅拌至溶解。0℃下,加入N-溴代丁二酰亚胺(933mg,5.24mmol)。反应液室温下搅拌24小时。向反应液中加入水,用二氯甲烷萃取(20mL×2),饱和食盐水洗涤(10mL×1),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-2%二氯甲烷/石油醚)得到化合物2-1(400mg)。LC-MS:m/z:279.0(M+H)+
2)第二步 化合物2-3的制备
室温下,向化合物2-2(1.00g,4.30mmol)的N,N-二甲基甲酰胺(15mL)溶液中,加入N,N-二异丙基乙胺(3.56mL,21.51mmol)和(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(0.58g,4.30mmol),所得混和物100℃搅拌4小时。反应液减压浓缩,剩余物经快速柱层析纯化(乙酸乙酯/石油醚=1/3),得到化合物2-3(960mg)。LC-MS:m/z:296.7(M+H)+
3)第三步 化合物2-4的制备
室温下,向微波管中依次加入化合物2-3(250mg,0.85mmol),N,N-二甲基甲酰胺(5mL)和水(1mL),1H-吡唑-4-硼酸(94.78mg,0.85mmol),碳酸钠(270.27mg,2.55mmol)和四(三苯基膦)钯(98.23mg,0.09mmol)。氮气吹扫3分钟后密封,将微波管放入微波仪器中,在120℃下搅拌1小时后冷却至室温。反应液减压浓缩,剩余物经柱层析纯化(0-10%乙酸乙酯/石油醚)得到化合物2-4(100mg)。LC-MS:m/z:282.8(M+H)+
4)第四步 化合物2A的制备
室温下,向微波管中依次加入化合物2-4(100mg,0.35mmol),化合物2-1(118.65mg,0.43mmol),N,N-二甲基甲酰胺(5mL),反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺(10.08mg,0.07mmol),碘化亚铜(10.12mg,0.05mmol)和磷酸钾(225.56mg,1.06mmol)。氮气吹扫3分钟后密封。将微波管放入微波仪器中,在120℃下搅拌4小时后冷却至室温。反应液减压浓缩,剩余物经高效液相液相(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min)制备得到化合物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)+
实施例3
3-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-6-腈(3A) 的制备
1)第一步 化合物3-2的制备
室温下,向微波管中加入,化合物3-1(1.00g,5.05mmol),N,N-二甲基甲酰胺(10mL),氰化锌(0.47g,4.04mmol),三(二亚苄基丙酮)二钯(0.46g,0.50mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.15g,0.25mmol),氮气置换体系3次,反应在130℃微波反应器中反应30分钟。向反应液中加入水(20mL),乙酸乙酯萃取(20mL×2),无水硫酸钠干燥,减压浓缩,粗品经柱层析提纯(0-50%,石油醚/乙酸乙酯),得到化合物3-2(350mg)。LC-MS:m/z:144.8(M+H)+
2)第二步 化合物3-3的制备
室温下,向50mL单口瓶中加入化合物3-2(350mg,2.43mmol),N,N-二甲基甲酰胺(5mL),N-碘代丁二酰亚胺(600mg,2.67mmol),反应在25℃下搅拌3小时。将反应液倒入10%硫代硫酸钠溶液中(30mL),用乙酸乙酯萃取(30mL×2),无水硫酸钠干燥,减压浓缩,粗品经柱层析提纯(0-50%,石油醚/乙酸乙酯),得到化合物3-3(210mg)。LC-MS:m/z:270.8(M+H)+
3)第三步 化合物3-4的制备
室温下,向单口瓶中加入化合物3-3(200mg,0.740mmol),四氢呋喃(5mL),碘化亚铜(14.1mg,0.07mmol),三乙胺(0.31mL,2.22mmol),二(三苯基膦)二氯化钯(51.9mg,0.07mmol),三甲基硅基乙炔(0.21mL,1.48mmol),搅拌至溶解。氮气置换体系3次,反应在25℃下搅拌16小时。反应液加水(20mL)稀释,用乙酸乙酯萃取(20mL×2),用无水硫酸钠干燥,减压浓缩,粗品经柱层析提纯(0-20%,石油醚/乙酸乙酯),得到化合物3-4(150mg)。LC-MS:m/z:240.9(M+H)+
4)第四步 化合物3-5的制备
室温下,向单口瓶中加入化合物3-4(110mg,0.46mmol),甲醇(2mL),碳酸钾(127mg,0.92mmol),反应在25℃下搅拌30分钟,反应液减压蒸干,粗品直接用于下一步反应。
LC-MS:m/z:168.8(M+H)+
5)第五步 化合物3A的制备
室温下,向单口瓶中加入化合物3-5(50.0mg,0.300mmol),叔丁醇(1mL),水(1mL),化合物1-6(86.0mg,0.360mmol),五水硫酸铜(7.42mg,0.30mmol),抗坏血酸钠(5.89mg,0.30mmol),反应在25℃下搅拌3小时。反应液加水(5mL)稀释,用乙酸乙酯萃取(20mL×2),无水硫酸钠干燥,减压浓缩,粗品经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)制备得到化合物3A(70mg)。LC-MS:m/z:410.2(M+H)+.1H 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,1H),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).
实施例4
4-(3-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-5-基)吗啉(4A)的制备
1)第一步 化合物4-1的制备
室温下,向单口瓶中依次加入化合物1-7(5.00g,32.56mmol)和乙腈(50mL),搅拌至溶解。依次加入吗啉(4.25g,48.84mmol)和N,N-二异丙基乙胺(12.63g,97.68mmol)。氮气置换3次,反应液80℃下搅拌18小时。反应液减压浓缩,剩余物经柱层析纯化(0-1%甲醇/二氯甲烷)得到化合物4-1(6.00g)。LC-MS:m/z:205.4(M+H)+
2)第二步 化合物4-2的制备
室温下,向单口瓶中加入化合物4-1(2g,9.79mmol)和乙腈(25mL),搅拌至溶解。加入N-碘代丁二酰亚胺(3.30g,14.69mmol),氮气置换3次,反应液25℃下搅拌18小时。反应液减压浓缩,剩余物经柱层析纯化(0-1%甲醇/二氯甲烷)得到化合物4-2(2.0g)。LC-MS:m/z:330.9(M+H)+
3)第三步 化合物4-3的制备
室温下,向单口瓶中依次加入化合物4-2(500mg,1.51mmol)和四氢呋喃(10mL),搅拌至溶解。依次加入三甲基乙炔基硅(743.80mg,7.57mmol),碘化亚铜(28.84mg,0.15mmol),三乙胺(459.77mg,4.54mmol)和双三苯基磷二氯化钯(106.31mg,0.15mmol)。氮气置换3次,反应液30℃下搅拌18小时。反应液减压浓缩,剩余物经柱层析纯化(0-2%二氯甲烷/石油醚)得到化合物4-3((340mg)。LC-MS:m/z:300.8(M+H)+
4)第四步 化合物4-4的制备
室温下,向单口瓶中依次加入化合物4-3(300mg,1.00mmol)和无水甲醇(10mL),搅拌至溶解。加入碳酸钾(276.00mg,2.00mmol),反应液25℃下搅拌1小时。减压浓缩,得到化合物4-4(250mg,0.88mmol,87.75%)。无需纯化,直接进行下一步。LC-MS:m/z:228.9(M+H)+
5)第五步 化合物4A的制备
室温下,向50mL单口瓶中依次加入化合物4-5(200mg,0.83mmol),叔丁醇(8mL)和水(5mL),搅拌至溶解。依次加入五水硫酸铜(62.2mg,0.25mmol),化合物1-6(284.17mg,1.24mmol)和维生素C钠(49.3mg,0.25mmol)。氮气置换3次,反应液25℃下搅拌3小时。反应液减压浓缩,剩余物经高效液相(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min)制备得到化合物4A(82mg)。
1H 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)+
实施例5
2-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)-6-(三氟甲基)吡啶(11A)的制备
1)第一步 化合物11-2的制备
室温下,向单口瓶中依次加入化合物11-1(1.00g,4.42mmol)和三乙胺(10mL),搅拌至溶解。依次加入碘化亚铜(80.1mg,0.44mmol),乙炔基三甲基硅烷(800mg,8.85mmol)和二(三苯基膦)二氯化钯(310mg,0.44mmol)。氮气置换3次,反应液30℃下搅拌18小时。反应液减压浓缩,剩余物经柱层析纯化(石油醚/乙酸乙酯=10/1至3/1)得到化合物11-2(450mg)。LC-MS:m/z:244.0(M+H)+
2)第二步 化合物11A的制备
室温下,向单口瓶中加入化合物11-2(430mg,1.77mmol),1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑(554mg,2.30mmol),碳酸钾(489mg,3.53mmol),五水硫酸铜和抗坏血酸钠(140mg,0.710mmol)溶于水(4mL)和甲醇(4mL)的混合溶剂体系中,搅拌至溶解,反应液30℃下搅拌4小时。反应液减压浓缩,反应液减压浓缩,剩余物经高效液相制备(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min)得到化合物11A(640mg)。
1H 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)+
实施例6
(1R,4r)-4-(4-(4-(5-(((1R、4r)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基(25A)的制备

1)第一步 化合物25-2的制备
冰浴下,向化合物25-1(300mg,1.09mmol)的乙腈(8mL)溶液中加入亚硝酸异戊酯(153mg,1.31mmol)。反应液搅拌1小时。向反应液中加入叠氮基三甲基硅烷(188mg,1.64mmol)。反应液在室温下搅拌16小时。将反应液倒入水(30mL)中,用乙酸乙酯萃取(30mL×3),饱和食盐水洗涤(50mL),无水硫酸钠干燥。减压浓缩,得到化合物25-2(325mg)。无需纯化,直接进行下一步。LC-MS:m/z:300.1(M+H)+
2)第二步 化合物25-3的制备
向化合物25-2(325mg,1.09mmol)的乙醇(8mL)和水(5mL)混合溶液中依次加入维生素C钠(40mg,0.22mmol),五水合硫酸铜(50mg,0.22mmol)和化合物1-10(240mg,1.09mmol)。反应液在室温下搅拌2小时。将反应液中倒入水(30mL)中,用乙酸乙酯萃取(30mL×3),饱和食盐水洗涤(50mL),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-8%甲醇/二氯甲烷)得到化合物25-3(320mg)。LC-MS:m/z:540.2(M+H)+
3)第三步 化合物25-4的制备
向三口瓶中加入化合物25-3(320mg,0.59mmol),加入四氢呋喃(5mL)搅拌至溶解。氮气置换体系3次混合物,冷却至-50℃,向反应液逐滴加入氢化锂铝的四氢呋喃溶液(0.60mL,0.60mmol,1.0M)。反应液在-50℃搅拌1小时。向反应液中加入水(20mL),用乙酸乙酯萃取(20mL×3)。饱和食盐水洗涤(50mL×1),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化(0-10%甲醇/二氯甲烷)得到化合物25-4(200mg)。LC-MS:m/z:512.2(M+H)+
步骤4)化合物25A的制备
向化合物25-4(200mg,0.39mmol)的二氯甲烷(8mL)溶液中加入戴斯马丁氧化剂(250mg,0.59mmol)。反应液在室温下搅拌30分钟。向反应液中加入水(15mL),用二氯甲烷萃取(15mL×3)。饱和食盐水洗涤(50mL),无水硫酸钠干燥。减压浓缩,得到化合物25A(180mg)。LC-MS:m/z:510.1(M+H)+
实施例7
4-(3-(5-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-4H-1,2,4-三唑-3-基)吡唑并[1,5-a]嘧啶-5-基)吗啉(27A)的制备

1)第一步 化合物27-2的制备
向单口瓶中加入化合物27-1(10.0g,44.3mmol),加入乙腈(100mL)搅拌至溶解。室温下,依次加入N,N-二异丙基乙胺(22.0mL,133mmol)和吗啉(7.72g,88.6mmol)。反应混合液回流搅拌2小时。反应液降至室温,加水(300mL)稀释,用乙酸乙酯(100mL×3)萃取,饱和食盐水洗涤(300mL),无水硫酸钠干燥。减压浓缩,剩余物经柱层析纯化经硅胶柱分离纯化(0~40%乙酸乙酯/二氯甲烷)得到化合物27-2(9.54g)。LC-MS:m/z:277(M+H)+
1H 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).
2)第二步 化合物27-3的制备
向单口瓶中依次加入化合物27-2(2.00g,7.24mmol),水合肼(7.25mL,145mmol,98%)和乙醇(20mL)。反应混合液在45℃搅拌30小时。反应液降至室温,减压浓缩。残留物重结晶(石油醚/乙酸乙酯=1/1,10mL)得到化合物27-3(1.5g)LC-MS:m/z:263(M+H)+
1H 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).
3)第三步 化合物27-4的制备
室温下,向单口瓶中加入化合物2-1(1.30g,4.66mmol)和N,N-二甲基甲酰胺(20mL)搅拌至溶解。再向反应液中加入锌粉(0.30g,4.66mmol),氰化锌(0.34g,4.66mmol)和1,1-二(二苯膦基)二茂铁二氯化钯(0.34g,0.46mmol)。反应液在120℃下搅拌18小时。向反应液中加水(30mL)稀释并用乙酸乙酯(50mL)萃取3次。将有机相合并,用盐水(50mL)洗涤1次,用无水硫酸钠干燥,减压浓缩。粗品经柱层析纯化(0-70%乙酸乙酯/石油醚)得到化合物27-4(600mg)。LC-MS:m/z:225.9(M+H)+
4)第四步 化合物27A的制备
向微波管中依次加入化合物27-3(100mg,0.38mmol),化合物27-4(85.9mg,0.38mmol),碳酸钾(158mg,1.14mmol)和正丁醇(2mL)。反应液微波150℃加热30小时。反应液过滤,滤液减压浓缩。残留物硅胶板分离(石油醚/乙酸乙酯=1/2)然后经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)制备得到27A(2mg)。
1H 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)+
实施例8
4-(3-(5-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1,3,4-噻二唑-2-基)吡唑[1,5-a]嘧啶-5-基)吗啉(28A)的制备
1)第一步 化合物28-2的制备
室温下,向单口瓶中加入化合物28-1(3.75g,19.71mmol,毕得)和N,N-二甲基甲酰胺(15mL)搅拌至溶解。然后依次加入溴代环己烷(4.93mL,39.41mmol)和碳酸钾(4.09g,29.51mmol)。反应液在80℃下搅拌18小时。向反应液中加水(100mL)稀释并用乙酸乙酯(100mL)萃取3次。将有机相用饱和食盐水(150mL)洗涤1次,用无水硫酸钠干燥,减压浓缩。粗品经柱层析纯化(0-25%乙酸乙酯/石油醚)得到化合物28-2(1.61g)。
LC-MS:m/z:273.2(M+H)+
2)第二步 化合物28-3的制备
室温下,向单口瓶中加入化合物28-2(1.79g,19.71mmol),四氢呋喃(10mL),水(10mL)和甲醇(5mL)搅拌至溶解。再向反应液中加入氢氧化锂(0.83g,19.7mmol)。反应液在40℃下搅拌2小时。反应液减压浓缩,向水相中加入2.0M稀盐酸调至pH=2-3,向反应液中加水(100mL)稀释并用乙酸乙酯(100mL)萃取3次。将有机相用盐水(100mL)洗涤1次,用无水硫酸钠干燥,减压浓缩得到化合物28-3(1.51g)。
LC-MS:m/z:245.1(M+H)+
3)第三步 化合物28-4的制备
向单口瓶中加入化合物28-3(190mg,0.78mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(444.88mg,1.17mmol),加入四氢呋喃(5mL)搅拌至溶解。室温搅拌2小时后,依次加入N,N-二异丙基乙胺(0.39mL,2.34mmol)和化合物28-3(245.48mg,0.94mmol)。反应混合液室温下搅拌10小时。反应完成后,加水(10mL)淬灭,用乙酸乙酯(5mL×2)萃取,有机层合并,饱和食盐水洗涤(15mL),无水硫酸钠干燥,减压蒸馏,经柱层析纯化(0~5%甲醇/二氯甲烷)得到化合物28-4(300mg)。
LC-MS:m/z:489(M+H)+
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=8.0Hz,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).
4)第四步 化合物28A的制备
向微波管中加入化合物28-4(150mg,0.31mmol),劳森试剂(149mg,0.37mmol)和甲苯(2.5mL)。反应混合液回流搅拌6小时。反应完成后,加水(10mL)淬灭,用乙酸乙酯(5mL×2)萃取,有机层合并,饱和食盐水洗涤(15mL),无水硫酸钠干燥,减压蒸馏,剩余物经高效液相(Waters-2545,色谱 柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)制备得到化合物28A(70.1mg)。LC-MS:m/z:487(M+H)+1H 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).
实施例9
1-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]-1H-吡咯并[2,3-b]吡啶-5-腈(43A)的制备
1)第一步 化合物43-1的制备
室温下,向单口瓶中加入化合物43-1(0.500g,3.49mmol,毕得),甲苯(10mL)搅拌至溶解,依次加入43-1a(1.10g,4.19mmol,毕得),1,10-菲啰啉(0.11mL,0.70mmol),磷酸钾(1.48g,6.98mmol)和无水硫酸铜(0.060g,0.35mmol),反应液在氮气气氛下80℃搅拌12小时,反应混合物冷却,加水(30mL),用乙酸乙酯萃取(50mL×3),有机层合并,饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-30%石油醚/乙酸乙酯)得到化合物43-2((1.0g)。1H 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).
2)第二步 化合物43-3的制备
冰浴下,向三口瓶中加入化合物43-2(100mg,0.31mmol),加入四氢呋喃(2mL)搅拌,反应液在0℃缓慢滴加四丁基氟化铵-四氢呋喃溶液(0.15mL,0.46mmol,3.0mol/L),室温搅拌6小时,向反应液中加入饱和氯化铵水溶液(5mL),用乙酸乙酯萃取(10mL×3),饱和食盐水洗涤(10mL),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-15%石油醚/乙酸乙酯)得到化合物43-3(45mg)。LC-MS:m/z:168.0(M+H)+
3)第三步 化合物43A的制备
室温下,向单口瓶中加入化合物43-3(40.0mg,0.17mmol),化合物1-6(33.26mg,0.20mmol)加入乙醇(2mL)搅拌,加入抗坏血酸钠(3.28mg,0.02mmol)和五水硫酸铜(4.14mg,0.02mmol),反应液室温搅拌3小时,减压浓缩。粗品经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min),制备得到化合物43A(20mg,0.05mmol)。1H 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=53.3Hz,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)。
实施例10
4-(1-(1-(1-(环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)吗啉(45A)的制备
1)第一步 化合物45-2的制备
25℃下,向单口瓶中加入化合物45-1(1.00g,5.08mmol,毕得),甲苯(10mL),43-1a(1.46g,5.58mmol,毕得),磷酸三钾(2.15g,10.1mmol),1,10-菲罗啉(0.180g,1.02mmol),五水硫酸铜(0.080g,0.510mmol),体系置换氮气3次,反应在80℃下,搅拌18小时。将反应液旋干,加水(20mL)稀释,乙酸乙酯(20mL)萃取3次,合并有机相,无水硫酸钠干燥,旋干。剩余物经柱层析纯化(乙酸乙酯/石油醚=1/100至1/1),得到化合物45-2(1.40g)。1H 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).
2)第二步 化合物45-3的制备
25℃下,向单口瓶中加入化合物45-2(400mg,1.06mmol),甲苯(4mL),吗啉(0.370mL,4.24mmol),醋酸钯(118mg,0.530mmol),三叔丁基膦(0.130mL,0.530mmol)叔丁醇钾(356mg,3.18mmol),反应在80℃下搅拌1小时。将反应液通过硅藻土过滤,滤液加饱和氯化钠溶液稀释,用乙酸乙酯(10mL)萃取3次,合并有机相,无水硫酸钠干燥,旋干。剩余物经柱层析纯化(乙酸乙酯:石油醚=1:100to 1:1),得到化合物45-3(250mg)。1HNMR(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).
3)第三步 化合物45-4的制备
25℃下,向单口瓶中加入化合物45-3(300mg,0.780mmol),四氢呋喃(3mL),四丁基氟化铵溶液(1M,0.940mL,0.940mmol)。反应在25℃下搅拌30分钟。反应液加入饱和氯化铵溶液(20mL)淬灭反应,用乙酸乙酯萃取(10mL×2),合并有机相用无水硫酸钠干燥,减压浓缩,剩余物经柱层析纯化(乙酸乙酯:石油醚=1:100to 1:1),得到化合物45-4(150mg)。LC-MS:m/z:228.0(M+H)+
4)第四步 化合物45A的制备
室温下,向单口瓶中加入化合物45-4(30.0mg,0.130mmol),叔丁醇(1mL),水(1mL),化合物1-6(3.18mg,0.130mmol),五水硫酸铜(3.29mg,0.013mmol),抗坏血酸钠(2.62mg,0.013mmol),反应在室温下搅拌18小时。反应液过滤,滤饼用甲醇(5mL)洗涤,滤饼干燥。残余物通过高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物45A(17.0mg)。LC-MS:m/z:469.2(M+H)+
1H 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)
实施例11
(1R,4R)-5-(3-(1-(3-(二氟甲基)-1-甲基-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(46A)的制备
1)第一步 化合物46-2的制备
冰浴下,向三口瓶中加入化合物46-1(50mg,0.340mmol,毕得),乙腈(2mL)搅拌至溶解,氮气置换体系三次,0℃下缓慢滴加亚硝酸叔丁酯(0.090mL,0.680mmol),冰浴下搅拌30分钟,0℃下缓慢滴加叠氮基三甲基硅烷(0.070mL,0.510mmol),反应液室温下搅拌3小时。向反应液中加入水,用乙酸乙酯萃取(10mL×3),饱和食盐水洗涤(5mL×1),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-30%石油醚/乙酸乙酯)得到化合物46-2(45mg)。LC-MS:m/z:174.0[M+1]+
2)第二步 化合物46A的制备
室温下,向单口瓶中加入化合物46-2(45mg,0.260mmol),加入乙醇(2mL)和水(1mL)搅拌,加入化合物1-10(74.9mg,0.310mmol),五水硫酸铜(6.49mg,0.030mmol),抗坏血酸钠(5.15mg,0.030mmol)反应液室温搅拌3小时,向反应液中加入水,用乙酸乙酯萃取(10mL×3),饱和食盐水洗涤(5mL),无水硫酸钠干燥,减压浓缩。粗品经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min),制备得到化合物46A(5mg)。1H 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]+
实施例12
3-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑并[1,5-a]嘧啶(56A)的制备

1)第一步 化合物56A的制备
室温下,向单口瓶中加入化合物56-1(60mg,0.21mmol,采用专利申请“WO2015108490 A2”中说明书第111页的中间体3-ethynylpyrazolo[l,5-a]pyrimidine公开的方法制备而得),化合物1-6(51mg,0.21mmol)加入四氢呋喃(1.5mL)搅拌至溶解。向反应液中加入碘化亚铜(12mg,0.06mmol)和三乙胺(64mg,0.63mmol)。反应液氮气氛围下室温搅拌18小时。反应液减压浓缩得到粗产物。粗品经高效液相(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min),制备得到化合物56A(2.5mg)。1H NMR(400MHz,DMSO-d6)δ9.24(d,J=6.0Hz,1H),8.72(d,J=10.8Hz,4H),7.45-7.05(m,2H),4.32-4.26(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]+.
实施例13
1-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)-1H-吡咯并[2,3-b]吡啶-5-羧酸(66A)的制备
1)第一步 化合物66A的制备
室温下,向单口瓶中加入,化合物43A(50.0mg,0.120mmol),乙醇(1mL),水(1mL),氢氧化钠(24.0mg,0.600mmol)反应在100℃下反应2小时。反应液经高效液相纯化(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min),得到化合物66A(23.0mg)。LC-MS:m/z:428.0(M+H)+1H 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=53.3Hz,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).
实施例14
1-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺(65A)的制备
合成路线:
1)第一步 化合物65A的制备
室温下,向25mL单口瓶中加入,化合物43A(50.0mg,0.120mmol),二甲亚砜(1mL),碳酸钾(33.8mg,0.240mmol),搅拌至溶解,加入双氧水(30%,0.05mL,0.61mmol)反应在室温下反应5分钟。反应液经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物65A(20.0mg,0.050mmol)。LC-MS:m/z:427.0(M+H)+.1H 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=17.3Hz,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).
实施例15
(7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡咯并[1,2-b]哒嗪-3-基)(哌嗪-1-基)甲酮(64A)的制备
1)第一步 化合物64-1的制备
室温下,向单口瓶中加入化合物61A(80mg,0.19mmol),DCM(5mL)搅拌至溶解,依次加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(142.34mg,0.37mmol),N,N-二异丙基乙胺(0.05mL,0.28mmol)和1-叔丁氧羰基哌嗪(41.83mg,0.22mmol),反应液25℃下搅拌3小时向反应液中加入水(20mL),用乙酸乙酯萃取(30mL×3),饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-15%二氯甲烷/甲醇)得到化合物64-1(90mg)。LC-MS:m/z:596.7(M+H)+
2)第二步 化合物64A的制备
室温下,向单口瓶中加入化合物64-1(30mg,0.05mmol),加入二氯甲烷(2mL)和三氟乙酸(1ml)搅拌,反应液室温搅拌0.5小时,减压浓缩。粗品经高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min),制备得到化合 物64A(20mg)。1HNMR(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)+。实施例16
7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡咯并[1,2-b]哒嗪-3-碳腈(29A)的制备
1)第一步 化合物29-2的制备
室温下,向乙腈(10mL)中加入化合物29-1(300mg,2.10mmol,采用专利申请“WO2015117563 A1”中说明书第75页的中间体pyrrolo[1,2-b]pyndazine-3-carbonitrile公开的方法制备而得),N-碘代丁二酰亚胺(707mg,3.14mmol)。将反应液在60℃搅拌1小时。TLC监测反应完全,向反应液中小心加入饱和亚硫酸钠溶液(10mL)。然后混合物用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL×2)洗涤,用无水硫酸钠干燥,过滤并减压浓缩。剩余物经快速色谱柱(石油醚/乙酸乙酯=10/1)得到化合物29-2(270mg)。1H 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).
2)第二步 化合物29-3的制备
将化合物29-2(1.16g,4.31mmol)加入到四氢呋喃(10mL)中,再向其中加入碘化亚铜(0.08g,0.43mmol),双三苯基磷二氯化钯(0.30g,0.43mmol)和三乙胺(1.20mL,8.62mmol),接着置换氮气,再向其中加入三甲基乙炔基硅(6.14mL,43.11mmol),室温搅拌过夜。将反应体系加入水中,然后乙酸乙酯(15ml X 3)萃取,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,有机相合并浓缩。经快速分离柱(石油醚/乙酸乙酯=20/1)纯化得到化合物29-3(816mg)。1H 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).
3)第三步 化合物29-4的制备
将化合物29-3(816mg,3.41mmol)和碳酸钾(1413.47mg,10.23mmol)加入到甲醇(10mL)中,室温搅拌2h。向反应体系中加水,然后乙酸乙酯(15mL X 3)萃取,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,过滤,有机相浓缩。经Flash正向柱(EA:PE=5%)纯化得到产物29-4(175mg,1.05mmol)。1H 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).
4)第四步 化合物29A的制备
氮气保护下,将化合物29-3(175mg,1.05mmol)和化合物1-6(252.55mg,1.05mmol)加入到乙醇(8mL)和水(4mL)的混合溶液中,接着再加入五水硫酸铜(0.01mL,0.10mmol)和维生素C钠(20.74mg,0.10mmol),室温搅拌过夜。反应液减压蒸馏,残留物柱层析纯化(MeOH/DCM=1/20);得到产物29A(230mg)。 LC-MS:m/z:409.0(M+H)+
实施例17
7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡咯并[1,2-b]哒嗪-3-甲酰胺(60A)的制备
1)第一步 化合物60A的制备
将化合物29A(100mg,0.24mmol)加入到氨水(1mL)乙醇(1mL)的混合溶剂中,然后滴加双氧水(0.03mL,0.98mmol,30%),室温搅拌反应16h。向反应体系中加入饱和的硫代硫酸钠溶液淬灭,然后乙酸乙酯(10mL X 3)萃取,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,过滤,有机相浓缩。残留物通过高效液相(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)制备,得到化合物60A(30mg,0.07mmol)。LC-MS:m/z:427.0(M+H)+1H 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=53.3Hz,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).
实施例18
7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡咯并[1,2-b]哒嗪-3-羧酸(61A)的制备
1)第一步 化合物61A的制备
将化合物29A(50mg,0.12mmol)加入到乙醇(2mL)和水(2mL)的混合溶液中,接着加入氢氧化钠(48.97mg,1.22mmol),回流搅拌2h。将反应体系浓缩除掉有机溶剂,然后用HCl(2N)调节pH值到4-5, 有大量固体析出,过滤,滤饼干燥。得到产物61A(25mg,0.06mmol)。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,2H),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)+
实施例19
4-(3-(1-(3-(二氟甲基)-1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)吗啉(69A)的制备
1)第一步 化合物69-2的制备
冰浴下,向三口瓶中加入化合物69-1(1.04g,3.29mmol,采用专利申请“WO2022161414 A1”中说明书第140页的步骤5产物公开的方法制备而得),乙腈(25mL)搅拌至溶解,0℃下缓慢滴加亚硝酸叔丁酯(0.47mL,3.94mmol),冰浴下搅拌30分钟,0℃下缓慢滴加叠氮基三甲基硅烷(0.65mL,4.93mmol),反应液室温下搅拌3小时。向反应液中加入水(40mL),用乙酸乙酯萃取(25mL×3),饱和食盐水洗涤(15mL×1),无水硫酸钠干燥,减压浓缩。得到化合物69-2(1.05g,3.07mmol,93.29%))。无需纯化直接用于下一步。
LC-MS:m/z:287.1(M+H-55)+
2)第二步 化合物69-3的制备
室温下,向单口瓶中加入化合物69-2(300mg,0.88mmol),加入乙醇(4mL)和水(4mL)搅拌,加入化合物69-2a(200mg,0.88mmol),五水硫酸铜(21.9mg,0.09mmol),抗坏血酸钠(17.36mg,0.09mmol)反应液室温搅拌3小时,向反应液中加入水(20mL),用乙酸乙酯萃取(15mL×3),饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,减压浓缩。剩余物经柱层析纯化(0-5%二氯甲烷/甲醇)得到化合物69-3(195mg,0.34mmol,39.00%)。LC-MS:m/z:571.4(M+H)+
3)第三步 化合物69A的制备
室温下,向单口瓶口瓶中加入化合物69-3(175mg,0.31mmol)和二氯甲烷(3mL),滴加氯化氢/二氧六环(4.0M,3mL,12.00mmol)。反应混合液在25℃下搅拌1小时。减压浓缩。残留物经高效液相(色谱柱:Waters-SunFire-C18-10μm-19*250mm;流动相:水(含有10mmol/L盐酸)和乙腈,梯度配比:乙腈40%-50%,流速:30mL/min),制备得到化合物69A(53mg,0.11mmol,36.73%)。1H 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,1H),6.81(d,J=7.9Hz,1H),4.75-4.57(m,1H),3.73(s,8H),3.42(d,J=12.9Hz,2H),3.10(q,J=11.9Hz,2H),2.39-2.14(m,4H).LC-MS:m/z:471.0(M+H)+.
实施例20
7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]-N-(吡咯烷-3-基)吡咯并[1,2-b]哒嗪-3-甲酰胺(67A)的制备
1)第一步 化合物67-1的制备
将化合物61A(100mg,0.23mmol),3-氨基吡咯烷-1-羧酸叔丁酯(52.3mg,0.28mmol,毕得)溶于二氯甲烷(5mL)中,加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(107mg,0.28mmol)和三乙胺(0.10mL,0.70mmol),室温搅拌反应2小时后,反应液加入水(15mL),二氯甲烷(15mL×3)萃取,有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物直接作为下一步原料,无需纯化,得到标题化合物67-1(145mg)。MS m/z(ESI):596.5[M+1]+
2)第二步 化合物67A的制备
将化合物67-1(125mg,0.21mmol)溶于氯化氢二氧六环(5mL,4M),室温搅拌反应1小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到标题化合物67A(30mg)。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).
实施例21
7-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]-N-(4,4-二氟吡咯烷-3-基)吡咯并[1,2-b]哒嗪-3-甲酰胺(68A)的制备
1)第一步 化合物68-1的制备
将化合物64-1(100mg,0.23mmol),4-氨基-3,3-二氟吡咯烷-1-羧酸叔丁酯(62.4mg,0.28mmol,毕得)溶于二氯甲烷(5mL)中,加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(107mg,0.28mmol)和三乙胺(0.10mL,0.70mmol),室温搅拌反应2小时后,反应液加入15mL水,乙酸乙酯(15mL×3)萃取,有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物直接作为下一步原料,无需 纯化,得到化合物68-1(150mg)。MS m/z(ESI):632.4[M+1]+。
2)第二步 化合物68A的制备
将化合物68-1(130mg,0.21mmol)溶于盐酸(5mL,4M in 1,4-dioxane),室温搅拌反应1小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物68A(50mg)。MS m/z(ESI):532.2[M+1]+1H 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).
实施例22
4-(3-(1-(3-(二氟甲基)-1-((2S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3-三唑-4基)吡唑[1,5-a]嘧啶-5-基)吗啉(79A)的制备
1)第一步 化合物79-2的制备
室温下,向单口瓶中加入化合物79-1(9.09g,42.6mmol,乐研),再加入甲醇(100mL),将反应体系置于冰浴中冷却。向快速搅拌的反应液中分批加入硼氢化钠(3.22g,85.2mmol),加完后自然回复至25℃继续搅拌30分钟。冰浴环境下向反应体系中滴加饱和氯化铵溶液(100mL),并使用乙酸乙酯(80mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(50mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到化合物79-2(9.54g)。MS m/z(ESI):160.2[M-55]+
2)第二步 化合物79-3的制备
室温下向单口瓶中加入化合物79-2(9.54g,42.1mmol),再加入二氯甲烷(100mL),将反应体系置于冰浴中冷却并置换氮气三次。按顺序加入三乙胺(17.5mL,126mmol)和甲基磺酰氯(3.91mL,50.5mmol),加完后自然回复至25℃继续搅拌2小时。反应体系使用饱和碳酸氢钠溶液(200mL)淬灭,并使用二氯甲烷(150mL×3)萃取,收集二氯甲烷层使用饱和食盐水(50mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到化合物79-3(12.5g)。MS m/z(ESI):238.0[M-55]+
3)第三步 化合物79-5的制备
室温下向单口瓶中加入化合物79-3(5.00g,8.52mmol)、79-4(1.25g,7.67mmol)和碳酸铯(8.33g,25.6mmol),再加入N,N-二甲基甲酰胺(50mL),将反应置换氮气三次,80℃条件下反应18小时。将反应液倾入水(300mL) 中,并使用乙酸乙酯(100mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(50mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到粗品。粗品采用硅胶柱色谱法以洗脱剂体系(洗脱液:乙酸乙酯/石油醚=0%-40%)纯化得到化合物79-5(1.30g)。MS m/z(ESI):305.2[M-55]+1H 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).
4)第四步 化合物79-6的制备
室温下向单口瓶中加入化合物79-5(430mg,1.19mmol),钯碳(100mg,0.0900mmol),再加入甲醇(5mL),将反应置换氢气三次,25℃氢气条件下反应18小时。将反应液过滤浓缩后得到化合物79-6(400mg)。MS m/z(ESI):275.2[M-55]+
5)第五步 化合物79-7的制备
室温下向单口瓶中加入化合物79-6(400mg,1.21mmol),再加入乙腈(5mL),将反应体系置于冰浴下缓慢滴加亚硝酸叔丁酯(0.220mL,1.82mmol)并搅拌1小时。再向反应体系中缓慢滴加叠氮基三甲基硅烷(0.240mL,1.82mmol),随后自然恢复至25℃继续搅拌1小时。将反应液倾入水(30mL)中,并使用乙酸乙酯(10mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(10mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到标题化合物粗品79-7(431mg)。粗品无需纯化即可进行下一步反应。MS m/z(ESI):301.2[M-55]+
6)第六步 化合物79-8的制备
室温下向单口瓶中加入化合物79-7(431mg,1.21mmol)、化合物4-5(304mg,1.33mmol)、五水硫酸铜(30.2mg,0.120mmol)和维生素C钠(24.0mg,0.120mmol),再加入乙醇(6mL)和水(3mL),25℃条件下反应2小时。将反应液倾入水(50mL)中,并使用乙酸乙酯(30mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(30mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到残余物。残余物采用硅胶柱色谱法以洗脱剂体系(洗脱液:乙酸乙酯/石油醚=40%-100%)纯化得到化合物79-8(340mg)。MS m/z(ESI):585.4[M+1]+
7)第七步 化合物79A的制备
室温下向单口瓶中加入化合物79-8(100mg,0.170mmol),再加入二氧六环(2mL),冰浴下滴加浓度为4.00mol/L的盐酸二氧六环溶液(2mL),25℃条件下反应1.5小时。将反应液浓缩,加入水(1mL),用氨水(1mL)中和体系,此时有固体析出,抽滤得到滤饼为粗品。粗品用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10.0mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min)纯化得到化合物79A(53.1mg)。MS m/z(ESI):485.2[M+1]+1H 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=7.9Hz,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).
实施例23
4-(3-(3-二氟甲基)-1-(2R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-5-基)吗啉盐酸盐(80A)的制备

1)第一步 化合物80-2的制备
将化合物80-1(3.00g,14.1mmol)溶于甲醇(30mL),向反应液中加入硼氢化钠(0.55g,14.5mmol)。反应液在25℃下搅拌2小时。将反应液倒入水中(30mL),水相用乙酸乙酯(30mL x 3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥并过滤。滤液减压浓缩,残余物用硅胶柱色谱法(二氯甲烷/甲醇=20/1至10/1)纯化得到化合物80-2(2.80g)。MS m/z:160.0[M-55]+
2)第二步 化合物80-3的制备
将化合物80-2(2.80g,13.0mmol)溶于二氯甲烷(40mL)中。向反应液中依次加入三乙胺(4.00g,39.5mmol)和甲基磺酰氯(1.80g,15.7mmol)。反应液在0℃下搅拌1小时。将反应液倒入水(30mL)中,水相用二氯甲烷(30mL x 3)萃取。合并的有机相用饱和食盐水(80mL)洗涤,无水硫酸钠干燥并过滤。滤液减压浓缩得到化合物80-3(3.20g)。
3)第三步 化合物80-4的制备
将化合物79-4(1.70g,10.4mmol)和化合物80-3(3.20g,20.2mmol)溶于N,N-二甲基甲酰胺(80mL)中,加入碳酸铯(10.5g,32.2mmol)。反应液在80℃下搅拌18小时。将反应液倒入水(100mL)中,水相用乙酸乙酯(80mL×3)萃取。合并的有机相用饱和食盐水(80mL)洗涤,无水硫酸钠干燥并过滤。滤液减压浓缩,残余物用硅胶柱色谱法以(石油醚/乙酸乙酯=5/1至3/1)纯化得到化合物80-4(1.10g)。MS m/z(ESI):305.0[M-55]+
4)第四步 化合物80-5的制备
将化合物80-4(1.10g,3.05mmol)溶于甲醇(10mL)中,加入湿钯碳(150mg,10%)。反应液用氢气球置换三次后,反应液在25℃下搅拌2小时。将反应液过滤,滤液减压浓缩得到化合物80-5(950mg)。MS m/z(ESI):275.1[M-55]+
5)第五步 化合物80-6的制备
将化合物80-5(900mg,2.72mmol)溶于乙腈(20mL),在0℃下加入亚硝酸异戊酯(500mg,4.27mmol,毕得)。反应液搅拌30分钟后,加入叠氮基三甲基硅烷(470mg,4.08mmol)。反应液在25℃下搅拌18小时。反应液倒入水中(30mL),水相用乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥和过滤。滤液减压浓缩得到化合物80-6(900mg)。MS m/z(ESI):301.0[M-55]+
6)第六步 化合物80-7的制备
将化合物80-6(900mg,2.53mmol)溶于乙醇(20mL)和水(5mL)中。向反应液中依次加入维生素C钠(50mg,0.25mmol,安耐吉),五水硫酸铜(65mg,0.26mmol,安耐吉)和化合物4-5(650mg,2.85mmol)。反应液在25℃下搅拌18小时。将反应液倒入水(50mL)中,水相用乙酸乙酯(30mL x 3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥并过滤。滤液减压浓缩,残余物用硅胶柱色谱法(石油醚/乙酸乙酯=1/1至0/1)纯化得到化合物80-7(520mg)。MS m/z(ESI):585.4[M+H]+
7)第七步 化合物80A的制备
将化合物80-7(80mg,0.14mmol)溶于乙酸乙酯(3mL)中,向反应液中加入盐酸的乙酸乙酯溶液(1mL,4M)。反应液在25℃搅拌2小时,将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱: SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈30%-70%,流速:30mL/min)纯化得到标题化合物80A(20.0mg)。MS m/z(ESI):485.2[M+H]+1H 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).
实施例24
4-(3-(3-二氟甲基)-1-(2R,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-5-基)吗啉异构体1(72A)和4-(3-(3-二氟甲基)-1-(2R,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-5-基)吗啉异构体2(73A)的制备
1)第一步 化合物72-1和73-1的制备
化合物80-7(320mg,0.55mmol)经手性拆分(WATERS 150 preparative SFC(SFC-26),色谱柱:Chiral Cel OX,250×30mm,ID,10μm;流动相:二氧化碳和乙醇,梯度配比:乙醇30-50%,流速:150mL/min)得到化合物72-1(120mg,保留时间:3.345分钟))和化合物73-1(160mg,保留时间:3.661分钟)。MS m/z:585.3[M+H]+.
2)第二步 化合物72A的制备
将化合物72-1(120mg,0.210mmol)溶于二氯甲烷(3mL)中,向反应液中加入三氟乙酸(1mL)。反应液在25℃搅拌2小时,将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈30%-70%,流速:30mL/min)纯化得到化合物72A(45mg)。MS m/z(ESI):485.3[M+H]+。1H 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).
3)第三步 化合物73A的制备
将化合物73-1(140mg,0.241mmol)溶于二氯甲烷(3mL)中,向反应液中加入三氟乙酸(1mL)。反应液在25℃搅拌2小时,将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈30%-70%,流速:30mL/min)纯化得到化合物73A(55mg)。MS m/z(ESI):485.3[M+H]+1H 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).
实施例25
(S)-4-(3-(1-(1-环己基-3-(二氟甲基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)-3-甲基吗啉(82A)的制备
1)第一步 化合物82-1的制备
将化合物1-7(1.00g,6.51mmol,毕得)溶于乙腈(40mL)中,加入1-7a(990mg,9.77mmol,毕得),N,N-二异丙基乙胺(4.32mL,26.1mmol),60℃搅拌反应2小时后,反应液加入水(40ml),乙酸乙酯萃取(40mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以(二氯甲烷/甲醇=100/1至30/1)纯化得到化合物82-1(642mg)。MS m/z(ESI):219.2[M+1]+
2)第二步 化合物82-2的制备
将化合物82-1(642mg,2.94mmol)溶于二氯甲烷(30mL)中,0度下加入N-碘代丁二酰亚胺(728mg,3.24mmol),0度下搅拌反应2小时后,反应液加入到饱和碳酸氢钠溶液(40ml)中淬灭,二氯甲烷萃取(25mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=100/1至5/1)纯化得到化合物82-2(700mg)。MS m/z(ESI):345.1[M+1]+
3)第三步 化合物82-3的制备
将化合物82-2(1.10g,0.09mmol)溶于四氢呋喃(10mL)中,依次加入碘化亚铜(600mg,0.32mmol)和双(三苯基膦)二氯化钯(220mg,0.32mmol)和三乙胺(0.89mL,6.39mmol),置换氮气三次,再加入三甲基乙炔基硅(4.55mL,31.96mmol)。室温搅拌反应12小时后,反应液加入水(40ml),乙酸乙酯萃取(30mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=100/1至20/1)纯化得到化合物82-3(700mg)。MS m/z(ESI):315.6[M+1]+
4)第四步 化合物82-4的制备
将化合物82-3(650mg,2.07mmol)溶于甲醇(30mL)中,加入碳酸钾(571mg,4.13mmol)室温搅拌反应1小时后,反应液直接减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=100/1至1/1)纯化得到化合物82-4(320mg)。MS m/z(ESI):243.1[M+1]+
5)第五步 化合物82A的制备
将化合物82-4(200mg,0.83mmol),1-6(200mg,0.83mmol)溶于水(4mL)和乙醇(4mL)的混合溶液,加入五水硫酸铜(20.6mg,0.08mmol),维C钠(16.4mg,0.08mmol),室温搅拌反应12小时后,减压浓缩除去乙醇,在向反应液加入水(15mL),乙酸乙酯萃取(15mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤 除去干燥剂后滤液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物82A(75mg)。MS m/z(ESI):484.5[M+1]+1H 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).
实施例26
(2S)-4-(3-{1-[1-环己基-3-(二氟甲基)-1H-吡唑-4-基]-1H-1,2,3-三唑-4-基}吡唑并[1,5-a]嘧啶-5-基)-2-甲基吗啉(83A)的制备
1)第一步 化合物83-1的制备
室温下,向单口瓶中依次加入化合物1-7(1.00g,,6.51mmol,上海毕得),N,N-二甲基甲酰胺(8mL),充分混合均匀后继续加入(2S)-2-甲基吗啉盐酸(93.7mg,680umol,上海皓鸿)和碳酸铯(3.18g,9.70mmol)。反应液在100℃下搅拌16个小时。向反应液加入20mL的水,然后用50mL的乙酸乙酯萃取2次,有机相用无水硫酸钠干燥过滤后减压浓缩,剩余物经硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=0~3/2)得到化合物83-1(1.15g)。1H 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)
2)第二步 化合物83-2的制备
室温下,向单口瓶中依次加入化合物83-1(1.05g,4.81mmol),乙腈(10mL),搅拌至溶解,然后向反应瓶中加入事先溶解于10mL乙腈的N-碘代丁二酰亚胺(1.62g,7.22mmol)溶液。反应液25℃下搅拌6个小时。向反应液加入20mL饱和亚硫酸钠水溶液,然后用50mL的乙酸乙酯萃取2次,有机相用无水硫酸钠干燥后过滤、减压浓缩,剩余物经硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=0~3/2)得到化合物83-2(1.58g)。MS m/z(ESI):345.2[M+1]+
3)第三步 化合物83-3的制备
室温下,向单口瓶中依次加入化合物83-2(1.58g,4.59mmol),四氢呋喃(12mL),搅拌至溶解,然后向反应瓶中加入碘化亚铜(90.0mg,460umol),双(三苯基膦)二氯化钯(320mg,46umol),随后加入三乙胺(1.91mL,13.8mmol)和乙炔基三甲基硅烷(1.31mL,9.18mmol)。向反应液中通氮气约1分钟尽量赶走空气,随后迅速拧紧瓶盖,25℃下搅拌6个小时。向反应液加入10mL水,然后用20mL的乙酸乙酯萃取2次,有机相用无水硫酸钠干燥后过滤、减压浓缩,剩余物经硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=1/4~4/1)得到 化合物83-3(830mg)。MS m/z(ESI):315.2[M+1]+
4)第四步 化合物83-4的制备
室温下,向单口瓶中依次加入化合物83-3(770mg,2.45mmol),甲醇(10mL),搅拌至溶解,然后向反应瓶中加入碳酸钾(677mg,4.90mmol)。反应液25℃下搅拌1个小时。向反应液加入20mL水,然后用50mL的乙酸乙酯萃取2次,有机相用无水硫酸钠干燥后过滤、减压浓缩得到化合物83-4(547mg)。
MS m/z(ESI):243.3[M+1]+
5)第五步 化合物83的制备
室温下,向单口瓶中依次加入化合物83-4(150mg,620umol),叔丁醇(1.2mL)和水(1.2mL),搅拌均匀,然后向反应瓶中加入抗坏血酸钠(12.3mg,60.0umol),氧化亚铜(39.4mg,500umol),随后加入化合物1-6(149mg,620umol)。反应液80℃下搅拌2个小时。向反应液加入10mL水,然后用20mL的乙酸乙酯萃取2次,有机相用无水硫酸钠干燥后过滤、减压浓缩,剩余物经高效液相色谱法(CAS-CD-SEMI-PREP-S,色谱柱:Phenomenex luna C18150*25mm*10um;流动相:水(含有甲酸)和乙腈,梯度配比:乙腈50%-80%,流速:25mL/min)纯化得到化合物83(88.2mg)。MS m/z(ESI):484.4[M+1]+.1H 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),3.95–3.91(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)
实施例27
7-(1-(3-(二氟甲基)-1-(哌啶-4-基)-1H-吡唑-4-基)~1H-1,2,3-三唑-4基)吡咯并[1,2-b]哒嗪-3-甲酰胺(84A)的制备
1)第一步 化合物84-1的制备
将化合物29-3(300mg,1.79mmol)溶于二甲亚砜(0.6mL)和乙醇(3mL)中,在0℃下,加入氢氧化钠(86.0mg,2.15mmol),过氧化氢(0.2mL,30%水溶液),反应液保持0℃,搅拌反应30分钟后,反应液加入水(15mL),乙酸乙酯(10mL×3)萃取。合并的有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以(二氯甲烷/甲醇=100/1至20/1)纯化得到化合物84-1(254mg)。MS m/z(ESI):186.1[M+1]+
2)第二步 化合物84-2的制备
将化合物84-1(200mg,1.08mmol),69-2(555mg,1.62mmol)溶于水(4mL)和乙醇(4mL)的混合溶液,加入五水硫酸铜(27.0mg,0.11mmol),维生素C钠(21.4mg,0.11mmol),室温搅拌反应12小时后,减压浓缩除去乙醇,在向反应液加入水(30mL),乙酸乙酯萃取(15mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=100/1至20/1)纯化得到化合物84-2(435mg)。MS m/z(ESI):528.3[M+1]+
3)第五步 化合物84A的制备
将化合物84-2(100mg,0.19mmol)溶于二氯甲烷(3mL)中,加入盐酸(3mL,4M in 1,4-dioxane),室温搅拌反应1小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到标题化合物84A(70mg)。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).
实施例28
4-(3-(1-(3-(二氟甲基)-1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)吗啉(85A)的制备
1)第一步 化合物85-2的制备
室温下向单口瓶中加入化合物85-1(1.88g,8.20mmol)和4-二甲氨基吡啶(200mg,1.64mmol),再加入二氯甲烷(20mL),将反应体系置于冰浴中冷却并置换氮气三次。按顺序加入三乙胺(2.27mL,16.4mmol)和对甲苯磺酰氯(2.34g,12.3mmol),加完后40℃条件下反应18小时。向反应体系中加入二氯甲烷(200mL),并使用水(50mL×3)洗涤二氯甲烷层,收集二氯甲烷层使用饱和食盐水(50mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到化合物85-2(3.07g)。MS m/z(ESI):406.2[M+23]+
2)第二步 化合物85-3的制备
室温下向单口瓶中加入化合物85-2(3.07g,8.01mmol)、79-4(1.31g,8.01mmol)和碳酸铯(7.82g,24.0mmol),再加入DMF(31mL),将反应置换氮气三次,80℃条件下反应18小时。将反应液倾入水(300mL)中,并使用乙酸乙酯(100mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(50mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到粗品。粗品采用硅胶柱色谱法以洗脱剂体系(洗脱液:乙酸乙酯/石油醚=0%-40%)纯化得到标题化合物85-3(830mg)。MS m/z(ESI):319.2[M-55]+1H 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).
3)第三步 化合物85-4的制备
室温下向单口瓶中加入化合物85-3(830mg,2.22mmol),钯碳(165mg),再加入甲醇(8mL),将反应置换氢气三次,25℃氢气条件下反应18小时。将反应液过滤浓缩后得到标题化合物85-4(690mg)。MS m/z(ESI):289.2[M-55]+
4)第四步 化合物85-5的制备
室温下向单口瓶中加入化合物85-4(200mg,0.580mmol),再加入乙腈(2mL),将反应体系置于冰浴下缓慢滴加亚硝酸叔丁酯(0.100mL,0.870mmol)并搅拌1小时。再向反应体系中缓慢滴加叠氮基三甲基硅烷(0.110mL,0.870mmol),随后自然恢复至室温继续搅拌1小时。将反应液倾入水(30mL)中,并使用乙酸乙酯(10mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(10mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到化合物粗品85-5(215mg)。粗品无需纯化即可进行下一步反应。MS m/z(ESI):315.2[M-55]+
5)第五步 化合物85-6的制备
室温下向单口瓶中加入化合物85-5(215mg,0.580mmol)、4-5(146mg,0.640mmol)、五水硫酸铜(14.5mg,0.0600mmol)和维生素C钠(11.5mg,0.060mmol),再加入乙醇(3mL)和水(1.5mL),25℃条件下反应1.5小 时。将反应液倾入水(50mL)中,并使用乙酸乙酯(30mL×3)萃取,收集乙酸乙酯层使用饱和食盐水(30mL)洗涤,并使用无水硫酸钠干燥,过滤浓缩后得到粗品。粗品采用硅胶柱色谱法以洗脱剂体系(洗脱液:乙酸乙酯/石油醚=1/3-1/1)纯化得到标题化合物85-6(145mg)。MS m/z(ESI):599.4[M+1]+
6)第六步 化合物85A的制备
室温下向单口瓶中加入化合物85-6(40mg,0.0700mmol),再加入二氧六环(0.5mL),冰浴下滴加浓度为4.00mol/L的盐酸二氧六环溶液(0.5mL),25℃条件下反应1.5小时。将反应液浓缩,加入甲醇(1mL),用氨水(1mL)中和体系,经制备纯化得到化合物85A(12.7mg)。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=7.9Hz,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).
实施例29
(R)-4-(3-(1-(3-(二氟甲基)-1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)吗啉异构体1盐酸盐(86A)&(S)-4-(3-(1-(3-(二氟甲基)-1-(2,2-二甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)吗啉异构体2盐酸盐(87A)的制备
1)第一步 化合物86-1和87-1的制备
化合物85-6(450mg,0.750mmol)经手性拆分(WATERS 150 preparative SFC(SFC-26),色谱柱:ChiralCel OX,250×30mm I.D.,10μm;流动相:二氧化碳和乙醇,梯度配比:乙醇40%,流速:150mL/min)得到化合物86-1(200mg,保留时间:3.920分钟)和化合物87-1(191mg,保留时间:4.946分钟)。MS m/z(ESI):599.3[M+1]+
2)第二步 化合物86A的制备
室温下向单口瓶中加入化合物86-1(200mg,0.330mmol),再加入二氯甲烷(2mL),再加入浓度为2.00mol/L的盐酸乙酸乙酯溶液(4mL),25℃条件下反应3小时。将反应液浓缩到标题化合物86A(179mg)。MS m/z(ESI):499.2[M+1]+1HNMR(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).
3)第三步 化合物87A的制备
将化合物87-1(191mg,0.320mmol)溶于二氯甲烷(4mL)中,慢慢滴加氯化氢二氧六环溶液(4mL,4.0M),25℃下搅拌2小时。将混合物浓缩得到标题化合物87A(169mg)。MS m/z(ESI):499.4[M+1]+1H 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).
实施例30
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-(3,3-二甲基吗啉基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基)环己基)甲醇(88A)的制备
1)第一步 化合物88-2的制备
将化合物88-1(3.00g,12.2mmol,采用专利申请“WO2022161414 A1”中说明书第137页的中间体步骤6化合物公开的方法制备而得)溶于乙腈(35mL),在0℃下加入亚硝酸异戊酯(2.10g,17.9mmol,毕得)。反应液在搅拌30分钟后,加入叠氮基三甲基硅烷(2.00g,17.4mmol)。反应液在25℃下搅拌18小时。反应液倒入水中(30mL),水相用乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥和过滤。滤液减压浓缩得到化合物88-2(3.00g)。MS m/z(ESI):272.1[M+H]+
2)第二步 化合物88-3的制备
将5-氯吡唑并[1,5-a]嘧啶1-7(2.00g,13.0mmol),3,3-二甲基吗啉(1.80g,15.6mmol),N,N-二异丙基乙胺(6.47mL,39.07mmol),及N-甲基吡咯烷酮(15mL)在130℃条件下反应18小时,之后反应液与水(100mL)混合,乙酸乙酯萃取(100mL×2),有机相合并,用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法(石油醚/乙酸乙酯=100/1至1/1)纯化得到化合物88-3(1.0g)。MS m/z(ESI):233.1[M+1]+
3)第三步 化合物88-4的制备
在将碘代丁二酰亚胺(1.94g,8.61mmol)加入到含有化合物88-3(1.00g,4.30mmol),及乙腈(15mL)的溶液中。在25℃条件下反应18小时,之后反应液用饱和亚硫酸钠溶液(50mL)淬灭,乙酸乙酯萃取(50mL×2),有机相合并,用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法(石油 醚/乙酸乙酯=100/1至1/1)纯化得到化合物88-4(600mg)。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).
4)第四步 化合物88-5的制备
在氮气保护下将双三苯基磷二氯化钯(235mg,0.34mmol)加入到含有化合物88-4(600mg,1.68mmol),三甲基乙炔基硅(2.40mL,16.8mmol),三乙胺(0.70mL,5.03mmol)及四氢呋喃(10mL)的溶液中。反应用氮气置换三次,然后在25℃条件下反应18小时,之后反应液用水(20mL)淬灭,乙酸乙酯萃取(20mL×2),有机相合并,用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法(石油醚/乙酸乙酯=100/1至1/1)纯化得到化合物88-5(400mg)。MS m/z(ESI):329.2[M+1]+
5)第五步 化合物88-6的制备
将碳酸钾(337mg,2.45mmol)加入到含有化合物88-5(400mg,1.22mmol)及甲醇(5mL)的溶液中。反应在25℃下搅拌2小时。将反应液用水(20mL)淬灭,二氯甲烷萃取(20mL×2),有机相合并,用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法(石油醚/乙酸乙酯=100/1至1/1)纯化得到化合物88-6(260mg)。MS m/z(ESI):[M+23]+
6)第六步 化合物88A的制备
将维生素C钠(8.00mg,0.04mmol)加入到包含化合物88-2(158.76mg,0.59mmol),化合物88-6(100mg,0.39mmol),五水硫酸铜(9.80mg,0.04mmol),乙醇(1mL)和水(1mL)的溶液中,氮气置换三次,然后在25℃条件下搅拌18小时。之后反应液用水(5mL)淬灭,乙酸乙酯萃取(5mL×2),有机相合并,用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用高效液相色谱法(A:0.1%FA/H2O B:ACN,色谱柱:Wetch-Ultimate-XB-C18-10μm-21.2*150mm;流动相:水(含有0.1%甲酸)和乙腈,梯度配比:乙腈25%-45%,流速:25mL/min)纯化得到化合物88A(150mg)。MS m/z(ESI):528.4[M+1]+1H 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),1.93–1.86(m,2H),1.84–1.74(m,2H),1.53(s,6H),1.49–1.39(m,1H),1.20–1.05(m,2H).
实施例31
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-(2,2-二甲基吗啉基)吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基环己基)甲醇(89A)的制备
1)第一步 化合物89-1的制备
将化合物1-7(1.00g,6.51mmol,毕得)溶于乙腈(15mL)中,加入2,2-甲基吗啉(900mg,7.81mmol,毕得),碳酸铯(6.36g,19.5mmol),80℃搅拌反应12小时后,反应液加入水(40ml),乙酸乙酯萃取(30mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱 剂体系(二氯甲烷/甲醇=100/1至20/1)纯化得到化合物89-1(1.2g)。MS m/z(ESI):233.5[M+1]+
2)第二步 化合物89-2的制备
将化合物89-1(1.00g,4.30mmol)溶于乙腈(20mL)中,0℃下加入N-碘代丁二酰亚胺(970mg,4.30mmol),室温下搅拌反应1小时后,反应液加入到饱和碳酸氢钠溶液(100ml)中淬灭,乙酸乙酯萃取(60mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=100/1至20/1)纯化得到化合物89-2(1.7g)。MS m/z(ESI):359.1[M+1]+
3)第三步 化合物89-3的制备
将化合物89-2(1.70g,4.75mmol)溶于四氢呋喃(20mL)中,依次加入碘化亚铜(90mg,0.47mmol)和双(三苯基膦)二氯化钯(330mg,0.47mmol)和三乙胺(1.97mL,14.2mmol),置换氮气三次,再加入三甲基乙炔基硅(6.76mL,47.5mmol)。室温搅拌反应12小时后,反应液加入水(50ml),乙酸乙酯萃取(40mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=100/1至20/1)纯化得到化合物89-3(1g)。MS m/z(ESI):329.2[M+1]+
4)第四步 化合物89-4的制备
将化合物89-3(800mg,2.44mmol)溶于甲醇(12mL)中,加入碳酸钾(673mg,4.87mmol)室温搅拌反应2小时后,反应液直接减压浓缩,残余物用硅胶柱色谱法以(二氯甲烷/甲醇=100/1至20/1)纯化得到化合物89-4(400mg)。MS m/z(ESI):257.2[M+1]+
5)第五步 化合物89A的制备
将化合物89-4(100mg,0.39mmol),88-2(159mg,0.59mmol)溶于水(2.5mL)和乙醇(2.5mL)的混合溶液,加入五水硫酸铜(9.74mg,0.04mmol),维C钠(7.73mg,0.04mmol),室温搅拌反应12小时后,减压浓缩除去乙醇,在向反应液加入水(15mL),乙酸乙酯萃取(15mL×3),有机相合并,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物89A(96mg)。MS m/z(ESI):528.4[M+1]+1H 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).
实施例32
((1r,4r)-4-(4-(4-(5-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基]环己基)甲醇(90A)的制备
1)第一步 化合物90-1的制备
将化合物1-7(2.00g,13.0mmol,毕得)和6-氮杂-2-氧杂螺[3.3]庚烷(1.68g,17.0mmol,毕得)溶于乙腈(20mL)中,加入N,N-二异丙基乙胺(6.5mL,39.1mmol)。反应液在80℃下,搅拌12小时后,反应液减压浓缩得到残留物。残留物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=100/1至30/1)纯化得到化合物90-1(2.8g)。MS m/z(ESI):217.1。[M+1]+1H 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).
2)第二步 化合物90-2的制备
将化合物90-1(500mg,2.31mmol)溶于二氯甲烷(10mL)中,加入N-碘代丁二酰亚胺(624mg,2.77mmol)。反应液在25℃下,搅拌4小时后,反应液倒入饱和碳酸氢钠水溶液(10mL)和饱和亚硫酸钠水溶液(10mL)中,水相分液后,用二氯甲烷萃取(20mL×3)。合并的有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残留物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=100/1至30/1)纯化得到化合物90-2(680mg)。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).
3)第三步 化合物90-3的制备
将化合物90-2(580mg,1.70mmol),三乙胺(0.7mL,5.09mmol),三甲基乙炔基硅(2.4mL,17.0mmol),双三苯基磷二氯化钯(119mg,0.17mmol)和碘化亚铜(32.3mg,0.17mmol),溶于四氢呋喃(10mL)中。反应液氮气置换三次。反应液在25℃,氮气保护下,搅拌12小时后,反应液减压浓缩,残留物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=100/1至30/1)纯化得到化合物90-3(464mg)。MS m/z(ESI):313.2[M+1]+1H 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).
4)第四步 化合物90-4的制备
将化合物90-3(110mg,0.35mmol)溶于四氢呋喃(5mL)中,加入四丁基氟化铵(0.5mL,0.46mmol,1.0M四氢呋喃溶液)。反应液在25℃下,搅拌1小时后,反应液减压浓缩,残留物用二氯甲烷(10mL)溶解,有机相用饱和碳酸氢钠水溶液(5mL×3)洗涤,硫酸钠干燥。过滤除去干燥剂后滤液减压浓缩得到化合物90-4(84.6mg)。MS m/z(ESI):241.1[M+1]+
5)第五步 化合物90A的制备
将化合物90-4(84.6mg,0.35mmol),化合物88-2(95.5mg,0.35mmol)和五水硫酸铜(8.79mg,0.04mmol)溶于水(2mL)和乙醇(2mL)中,加入维生素C钠(6.97mg,0.04mmol)。反应液在25℃下,搅拌12小时后,反应液减压浓缩得到残留物。残留物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-T C18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物90A(70.3mg)。MS m/z(ESI):512.3[M+1]+1H 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).
实施例33
4-(3-(1-(3-(二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基)吡唑并[1,5-a]嘧啶-5-基)硫代吗啉1,1-二氧化物(91A)的制备

1)第一步 化合物91-1的制备
将化合物1-7(1.02g,6.51mmol)溶于N-甲基吡咯烷酮(10mL)。依次加入N,N-二异丙基乙胺(3.24mL,19.5mmol)和硫代吗啉-1,1-二氧化物(1.32g,9.77mmol)。反应液在130℃下搅拌18小时。将反应液混合物过滤得到化合物91-1(3.84g)。MS m/z(ESI):253.1[M+1]+
2)第二步 化合物92-2的制备
将化合物91-1(900mg,3.57mmol)溶于乙腈(10mL)和二氯甲烷(10mL)中。加入N-碘代丁二酰亚胺(882mg,3.92mmol)。反应液在25℃下搅拌18小时。将反应液混合物过滤得到化合物92-2(1.10g)。MS m/z(ESI):379.0[M+1]+
3)第三步 化合物91-3的制备
将化合物91-2(500mg,1.32mmol),三乙胺(0.6mL,3.97mmol),三甲基乙炔基硅(1.9mL,13.2mmol),双三苯基磷二氯化钯(92.8mg,0.13mmol)和碘化亚铜(25.2mg,0.13mmol),溶于四氢呋喃(15mL)中。反应液氮气置换三次。反应液在25℃,氮气保护下,搅拌12小时后,反应液减压浓缩,残留物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=100/1至20/1)纯化得到化合物91-3(420mg)。MS m/z(ESI):349.0[M+1]+
4)第四步 化合物91-4的制备
将化合物91-3(390mg,1.12mmol)溶于四氢呋喃(15mL)中,加入四丁基氟化铵(1.3mL,1.34mmol,1.0M四氢呋喃溶液)。反应液在25℃下,搅拌1小时后,反应液减压浓缩,残留物用二氯甲烷(10mL)溶解,有机相用饱和碳酸氢钠水溶液(5mL×2)洗涤,硫酸钠干燥。过滤除去干燥剂后滤液减压浓缩得到化合物91-4(260mg)。MS m/z(ESI):277.1[M+1]+1H 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).
5)第五步 化合物91A的制备
将化合物91-4(50.0mg,0.18mmol)和化合物88-2(51.2mg,0.19mmol)溶于水(1.5mL)和乙醇(1.5mL)中,加入五水硫酸铜(4.52mg,0.02mmol)和维生素C钠(3.58mg,0.02mmol)。反应液在25℃下,搅拌12小时后,反应液减压浓缩得到残留物。残留物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-T C18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物91A(25.7mg)。MS m/z(ESI):548.4[M+1]+1H 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),1.93–1.86(m,2H),1.85–1.75(m,2H),1.50–1.41(m,1H),1.19–1.08(m,2H).
实施例34
4-((3-(1-(3-(二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)氨基)-2-甲基丁烷-2-醇(92A)的制备
1)第一步 化合物92-2的制备
将化合物92-1(2.30g,13.0mmol,采用专利申请“WO2015108490 A2”中说明书第102页的中间体5-chloro-3-ethynylpyrazolo[l,5-a]pyrimidine的合成方法制备而得),88-2(3.51g,13.0mmol)溶于水(40mL)和乙醇(40mL)的混合溶液,加入五水硫酸铜(320mg,1.30mmol),维C钠(260mg,1.30mmol),室温搅拌反应12小时后,减压浓缩除去乙醇,在向反应液加入水(50mL),有大量的固体析出,过滤,滤饼用(石油醚/乙酸乙酯=1/1)洗涤两次,过滤,滤饼直接作为下一步原料,无需纯化,得到化合物92-2(2.30g)。MS m/z(ESI):449.1[M+1]+
2)第二步 化合物92A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入4-氨基-2-甲基-丁-2-醇(23.0mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物92A(12mg)。MS m/z(ESI):516.3[M+1]+1HNMR(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),4.30–4.22(m,1H),3.54–3.46(m,2H),3.32–3.27(m,2H),2.19–2.12(m,2H),1.90(d,J=13.1Hz,2H),1.85–1.70(m,4H),1.55–1.47(m,1H),1.20–1.11(m,8H).
实施例35
1-(3-(1-(3-二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基吡唑并[1,5-a]嘧啶-5-基)-4-甲基哌啶-4-醇(93A)的制备

1)第一步 化合物93A的制备
室温下向单口瓶中依次加入化合物92-2(50.0mg,0.110mmol),4-甲基-4-羟基哌啶(19.3mg,0.170mmol,乐研)和乙腈(1mL),搅拌下加入N,N-二异丙基乙胺(27.7μL,0.170mmol),将反应体系置换氮气三次,80℃条件下反应2小时。反应液用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈24%-95%流速:25mL/min)纯化得到化合物93A(30.1mg)。MS m/z(ESI):528.3[M+1]+1H 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).
实施例36
((1r,4r)-4-(4-(4-(5-((环丙基甲基)氨基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑1-基)环己基)甲醇(94A)的制备
1)第一步 化合物94A的制备
向92-2(50.0mg,0.110mmol)的乙腈(3mL)溶液中加入环丙基甲胺(0.030mL,0.340mmol)和N,N-二异丙基乙胺(58.0mg,0.450mmol),混合物在80℃,氮气氛围下搅拌反应3小时。反应液减压浓缩后用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈30%-95%,流速:25mL/min)纯化得到化合物94A(30.0mg)。MS m/z(ESI):484.2[M+1]+1HNMR(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).
实施例37
(1R,4R)-4-(3-二氟甲基)-4-(4-(5-(4-甲基哌嗪-1-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基)环己基甲醇甲酸盐(95A)的制备

1)第一步 化合物95A的制备
将化合物92-2(50mg,0.11mmol)溶于乙腈(3mL)中,依次加入N-甲基哌嗪(20mg,0.20mmol)和N,N-二异丙基乙胺(20mg,0.23mmol)。反应液在80℃搅拌2小时,将反应液过滤,滤液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈30%-70%,流速:30mL/min)纯化得到化合物95A甲酸盐(35mg)。MS m/z(ESI):513.4[M+H]+1H NMR(400MHz,DMSO-d6):δ8.72(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.36(s,1H),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).
实施例38
1-(3-(1-(3-二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基吡唑并[1,5-a]嘧啶-5-基)氮杂环丁烷-3-醇(96A)
1)第一步 化合物96A的制备
室温下向单口瓶中依次加入化合物92-2(50.0mg,0.110mmol),3-羟基氮杂环丁烷盐酸盐(18.3mg,0.170mmol,乐研)和乙腈(1mL),搅拌下加入N,N-二异丙基乙胺(27.3μL,0.170mmol),将反应体系置换氮气三次,80℃条件下反应2小时。反应液用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈19%-95%流速:25mL/min)纯化得到化合物96A(12.0mg)。MS m/z(ESI):486.2[M+1]+1H 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).
实施例39
1-(3-(1-(3-二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)哌啶-4-醇(97A)的制备
1)第一步 化合物97A的制备
25℃下,将化合物92-2(50.0mg,0.11mmol)溶于乙腈(1mL)中,加入化合物4-羟基哌啶(0.010mL,0.20mmol),N,N-二异丙基乙胺(43.1mg,0.33mmol),反应在60℃搅拌2小时后,将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物97A(20.0mg)。MS m/z(ESI):514.3[M+1]+1H NMR(400MHz,DMSO-d6):δ8.65–8.62(m,2H),8.48(s,1H),8.29(s,1H),7.17(t,J=53.1Hz,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).
实施例40
((1r,4r)-4-(4-(4-(5-(1,4-氧杂环戊-4-基)吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基]环己基)甲醇(98A)的制备
1)第一步 化合物98A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入1,4-氧杂氮杂环庚烷(22.3mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物98A(22mg)。MS m/z(ESI):514.4[M+1]+1H 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).
实施例41
((1r,4r)-4-(4-(4-(5-(8-氧杂-3-氮杂双环[3.2.1]辛-3-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1- 基)-3-(二氟甲基)-1H-吡唑1-基)环己基)甲醇(99A)的制备
1)第一步 化合物99A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入8-氧杂-3-氮杂双环[3.2.1]辛烷(33.3mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物99A(17mg)。MS m/z(ESI):526.3[M+1]+1H 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).
实施例42
1-(3-(1-(3-二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)哌啶-3-醇(100A)的制备
1)第一步 化合物100A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入3-羟基哌啶(23.0mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物100A(27mg)。MS m/z(ESI):514.3[M+1]+1H 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),3.25–3.20(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).
实施例43
1-(3-(1-(3-二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶 -5-基)吡咯烷-3-醇(101A)的制备
1)第一步 化合物101A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入3-羟基吡咯烷(19.2mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物101A(15mg)。MS m/z(ESI):500.3[M+1]+
1H 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).
实施例44
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-(4-(二甲基氨基)哌啶-1-基)吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基环己基)甲醇(102A)的制备
1)第一步 化合物102A的合成
将化合物92-2(80mg,0.18mmol),化合物4-二甲氨基哌啶(46mg,0.36mmol,毕得)溶于乙腈(2mL)中,加入N,N-二异丙基乙胺(0.060mL,0.36mmol),80℃搅拌反应2小时后,反应液中加入水(10mL),乙酸乙酯(20mL×3)萃取,有机相合并,用饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物102A(15.0mg)。MS m/z(ESI):541.8[M+1]+1HNMR(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).
实施例45
((1r,4r)-4-(4-(4-(5-((S)-3-氨基哌啶-1-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基]环己基)甲醇(103A)的制备
1)第一步 化合物103-1的合成
将化合物92-2(60mg,0.13mmol),化合物(S)-3-Boc-氨基哌啶(27mg,0.13mmol)溶于乙腈(2mL)中,加入N,N-二异丙基乙胺(0.07mL,0.40mmol),80℃搅拌反应2小时后,反应液中加入水(10mL),乙酸乙酯(20mL×3)萃取,有机相合并,用饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤除去干燥剂后滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=40/1至15/1)纯化得到标题化合物103-1(30mg)。MS m/z(ESI):611.5[M-1]-
2)化合物103A的合成
将三氟乙酸(1.0mL)加入到含有化合物103-1(25mg,0.040mmol)及二氯甲烷(2mL)的溶液中。反应液在25℃下搅拌一个小时。将反应液浓缩,残留物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物103A(10mg)。MS m/z(ESI):513.4[M+1]+1H 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).
实施例46
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-吗啉并吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基]环己基)甲醇(104A)的制备

1)第一步 化合物104A的制备
将化合物88-2(2.20g,8.11mmol)溶于乙醇(30mL)和水(10mL)中。向反应液中依次加入维生素C钠(0.33g,1.67mmol,安耐吉),五水硫酸铜(0.41g,1.64mmol,安耐吉)和化合物4-5(1.86g,8.15mmol)。反应液在25℃下搅拌18小时。将反应液过滤,固体收集并用混合溶剂(石油醚/乙酸乙酯=1/1,30mL)打浆,得化合物104A(3.20g)。MS m/z(ESI):500.4[M+1]+1H 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).
实施例47
((1R,4r)-4-(4-(4-(5-((1R,4r)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲醇(105A)的制备
1)第一步 化合物105A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(29.8mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物105A(15mg)。MS m/z(ESI):512.3[M+1]+1HNMR(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).
实施例48
((1r,4r)-4-(4-(4-(5-(((R)-3-氨基哌啶-1-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基]环己基)甲醇(106A)的制备
1)第一步 化合物106-1的制备
室温下,向化合物92-2(50.0mg,0.11mmol)的乙腈(1mL)溶液中,加入N,N-二异丙基乙基胺(43.1mg,0.33mmol),化合物(R)-3-Boc-氨基哌啶(44.6mg,0.22mmol)。反应在80℃下,搅拌3小时。反应液减压浓缩,残余物用硅胶柱色谱法以(二氯甲烷/甲醇=100/1至10/1)纯化得到标题化合物106-1(30.0mg)。MS m/z(ESI):613.8[M+1]+
2)第二步 化合物106A的制备
将化合物106-1(30.0mg,0.05mmol)溶于氯化氢二氧六环溶液(1mL,4M)中。在25℃下,搅拌1小时,反应液减压蒸干。残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-T C18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化得到化合物106A(21.3mg)。MS m/z(ESI):514.0[M+1]+
实施例49
(1R,2S)-2-((3-(1-(3-(二氟甲基)-1-((1R,4S)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)氨基)环己烷-1-醇(107A)的制备
1)第一步 化合物107A的制备
将化合物92-2(50.0mg,0.11mmol)溶于乙腈(3mL)中,加入(1R,2S)-2-氨基环己醇盐酸盐(33.4mg,0.22mmol,毕得),N,N-二异丙基乙胺(43.2mg,0.33mmol),80℃搅拌反应2小时后,直接将反应液减压浓 缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物107A(7mg)。MS m/z(ESI):528.3[M+1]+1H 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=7.6Hz,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).
实施例50
((1r,4r)-4-(4-(4-(5-(5-氨基-3,3-二氟哌啶-1-基)吡唑并[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-3-(二氟甲基)-1H-吡唑-1-基环己基)甲醇(108A)的制备
1)第一步 化合物108-1的制备
将化合物92-2(100mg,0.22mmol)溶于乙腈(5mL)中,加入N-(5,5-二氟哌啶-3-基)氨基甲酸叔丁酯(105mg,0.45mmol,江苏艾康),N,N-二异丙基乙胺(86.4mg,0.67mmol),80℃搅拌反应2小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物108-1(100mg)。MS m/z(ESI):649.5[M+1]+
2)第二步 化合物108A的制备
将化合物108-1(100mg,0.15mmol)溶于二氯甲烷(5mL)中,加入氯化氢二氧六环(5mL,4M),室温搅拌反应1小时后,直接将反应液减压浓缩,残余物用高效液相色谱法(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水(含有10mmol/L甲酸)和乙腈,梯度配比:乙腈38%-45%,流速:30mL/min)纯化,得到化合物108A(25mg)。MS m/z(ESI):549.5[M+1]+1H 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).
实施例51
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-((2S,6S)-2,6-二甲基吗啉基)吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基环己基)甲醇(109A)

1)第一步 化合物109A的制备
向化合物92-2(45.0mg,0.100mmol)的乙腈(2mL)溶液中加入(2S,6S)-2,6-二甲基吗啉(23.0mg,0.200mmol)和N,N-二异丙基乙胺(52.0mg,0.400mmol),混合物在80℃氮气氛围下搅拌反应2小时。反应液减压浓缩后用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-SunFire-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈30%-95%,流速:25mL/min)纯化得到化合物109A(35.0mg)。MS m/z(ESI):528.3[M+1]+1HNMR(400MHz,DMSO-d6)δ8.74(d,J=8.0Hz,1H),8.68(s,1H),8.52(s,1H),8.36(s,1H),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).
实施例52
((1r,4r)-4-(3-(二氟甲基)-4-(4-(5-(哌嗪-1-基)吡唑[1,5-a]嘧啶-3-基)-1H-1,2,3-三唑-1-基)-1H-吡唑-1-基环己基)甲醇(110A)的制备
1)第一步 化合物110A的制备
向92-2(50.0mg,0.110mmol)的乙腈(2mL)溶液中加入哌嗪(48.0mg,0.56mmol)和N,N-二异丙基乙胺(144mg,1.11mmol),混合物在80℃氮气氛围下搅拌反应2小时。反应液减压浓缩后用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-SunFire-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈20%-95%,流速:25mL/min)纯化得到化合物110A(35.0mg)。MS m/z(ESI):499.2[M+1]+1H 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).
实施例53
(1S,2R)-2-((3-(1-(3-(二氟甲基)-1-((1r,4R)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑并[1,5-a]嘧啶-5-基)氨基)环己-1-醇(111A)的制备
1)第一步 化合物111A的制备
向92-2(100mg,0.220mmol)的乙腈(2mL)溶液中加入(1S,2R)-2-氨基环己醇盐酸盐(101mg,0.670mmol)和N,N-二异丙基乙胺(173mg,1.34mmol),混合物在80℃氮气氛围下搅拌反应2小时。反应液减压浓缩后用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-SunFire-C18-10μm-19*250mm;流动相:水(含有10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈42%-95%,流速:20mL/min)纯化得到标题化合物111A(50.0mg)。MS m/z(ESI):528.3[M+1]+1HNMR(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).
实施例54
(S)-1-(3-(1-(3-(二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑并[1,5-a]嘧啶-5-基)哌啶-3-醇(112A)的制备
1)第一步 化合物112A的制备
室温下向单口瓶中依次加入化合物92-2(50.0mg,0.110mmol),(S)-3-羟基哌啶盐酸盐(18.3mg,0.170mmol)和乙腈(1mL),搅拌下加入N,N-二异丙基乙胺(27.3μL,0.170mmol),将反应体系置换氮气三次,80℃条件下反应18小时。反应液用高效液相色谱法(Gilson_306_1741,色谱柱:Waters-Xbridge-C18-10μm-19*250mm;流动相:水(含有26.5mmol/L甲酸)和乙腈,梯度配比:乙腈21%-95%流速:25mL/min)纯化得到化合物112A(10.1mg)。MS m/z(ESI):514.2[M+1]+1H 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),4.15–4.03(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).
实施例55
(R)-1-(3-(1-(3-(二氟甲基)-1-((1r,4r)-4-(羟甲基)环己基)-1H-吡唑-4-基)-1H-1,2,3-三唑-4-基]吡唑[1,5-a]嘧啶-5-基)哌啶-3-醇(113A)的制备
1)第一步 化合物113A的制备
室温下向单口瓶中依次加入化合物92-2(50.0mg,0.110mmol),(R)-3-羟基哌啶盐酸盐(17.0mg,0.170mmol)和乙腈(2mL),搅拌下加入N,N-二异丙基乙胺(60.0μL,0.39mmol),将反应体系置换氮气三次,80℃条件下反应1小时。反应液过滤之后,滤液用高效液相色谱法(A:0.1%FA/H2O B:ACN,色谱柱:Wetch-Ultimate-XB-C18-10μm-21.2*150mm;流动相:水(含有0.1%甲酸)和乙腈,梯度配比:乙腈25%-45%,流速:25mL/min)纯化得到化合物113A(30mg)。MS m/z(ESI):514.2[M+1]+1H NMR(400MHz,DMSO-d6):δ8.71–8.63(m,2H),8.50(s,1H),8.34(s,1H),7.20(t,J=52.8Hz,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).
测试例
测试例1、IRAK4激酶抑制实验方法:
本实验使用Cisbio HTRF KinEASE-STK SI试剂盒(62S1PEB),实验/检测缓冲液,STK Substrate 1-biotin,Streptavidin-XL665,STK Antibody-Crypatete皆包含在试剂盒内。
使用Echo 665在384板(PerkinElmer 6008280)中加入化合物/DMSO后添加5μL实验缓冲液[1体积5X激酶缓冲液+20mM氯化镁(Sigma)溶液+1mM DTT(Alfa Aesar)溶液+4体积去离子水]溶解的2倍反应浓度的IRAK4激酶蛋白(终浓度:10nM),密封浅孔板,震荡后1000rpm离心1分钟,室温孵育5分钟;然后加入5μL实验缓冲液配制的2倍反应浓度STK Substrate 1-biotin(终浓度:1μM)和ATP(Sigma A1852)(终浓度:200μM)1:1混合物,密封浅孔板,震荡后1000rpm离心1分钟,37℃孵育2小时后加入10μL检测缓冲液溶解的Streptavidin-XL665(终浓度:62.5nM)和STK-antibody-cryptate的1:1混合液,密封浅孔板,震荡后1000rpm离心1分钟,室温孵育1小时后,使用酶标仪在620nm/665nm波长下读取数值。使用Prism 9.3软件对数据进行分析,四参数Logistic方程拟合IRAK4激酶抑制的IC50值。
实验结果显示,本发明的化合物对IRAK4激酶的抑制活性优异,本发明代表性化合物IC50值如下表所示。
表1本发明代表性化合物IRAK4激酶抑制活性

在表1中,A表示:>5000nM;B表示1000-5000nM;C表示100-1000nM;D表示<100nM。
测试例2、HiBit荧光检测蛋白降解的方法:
利用HiBiT标签技术,将含有HiBiT标签连接到IRAK4质粒上,将质粒通过转染到HEK293T细胞中,检测HiBiT荧光水平来表征化合物对IRAK4的降解水平。1mL的新鲜培养基,300000个HEK293T细胞接种到6孔板(Corning 3516),放置在37℃,5%CO2的恒温培养箱中过夜。3μL X-tremeGENETM 9 DNA Transfection Reagent(Roche#06365787001),1μgpcdna3.1-IRAK4-HiBiT加入到200μL Opti-MEM(Gibico31985062)中并轻轻混匀,取出过夜孵育的6孔板,室温静置15分钟后,逐滴加入到6孔板中。瞬时转染6小时后,用胰酶消化细胞,1000rpm离心3分钟,用40μL新鲜培养基,5000个HEK293T细胞接种到384孔板(Corning 3765),放置在37℃,5%CO2的恒温培养箱中过夜。然后用Echo 655 Liquid Handler将40nL化合物加入到384孔板,最高终浓度10μM,1:3系列稀释,共10个浓度。37℃,5%CO2培养24小时。取出384孔板,平衡至室温。每孔加入40μLHiBiT Lytic Detection System(Promega N3030),室温孵育15分钟,用EnVision Xcite Multilabel Reader(PerkinElmer 2105-0020)记录荧光值。使用Prism 9.3软件对数据进行分析,四参数Logistic方程拟合IRAK4降解的DC50值。
实验结果表明,包含本发明化合物的PROTAC分子对IRAK4具有优异的降解水平。

Claims (22)

  1. 式A所示化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,
    其中:
    A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;
    进一步优选地,A选自 任选地被取代基Rk所取代,其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点;
    更进一步优选地,A选自 其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点;
    更进一步优选地,A选自其中#R1表示连接R1的连接位点,$L1表示连接L1的连接位点;
    Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
    Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
    B选自6-10元杂芳基、6-10元芳基,且B任选地被取代基Ra、Rb中的至少一个所取代;优选地,B被取代基Ra、Rb中的至少一个所取代;优选地,B选自9元杂芳基、吡啶基、苯基、嘧啶基,且B被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;优选地,B选自9元杂芳基、吡啶基、苯基,且B被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;
    更优选地,B选自吡啶基、苯基、嘧啶基,且B被取代基Ra、Rb中的至少一个所取代;
    更优选地,B选自吡啶基、苯基,且B被取代基Ra、Rb中的至少一个所取代;
    进一步优选地,B选自且B被取代基Ra、Rb所取代;
    进一步优选地,B选自且B被取代基Ra、Rb所取代;
    Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基)、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),其中,所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Cy1为任选被Rcy1和Rcy2所取代的5-7元杂环基,更优选地,Cy1为任选被Rcy1和Rcy2所取代的6元杂环基,进一步优选地,Cy1为任选被Rcy1和Rcy2所取代的吗啉、哌嗪、硫代吗啉;
    Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;
    优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
    优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、 C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个选自F、Cl、Br、甲基的取代基所取代;进一步优选地,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代;
    优选地,Ra选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、F、Cl、Br所取代;
    m选自0、1、2、3;优选地,m选自0、1;
    n选自0、1、2、3;优选地,n选自0、1;
    p选自0、1、2、3;优选地,p选自0、1;
    更优选地,m为0且n为0;
    更优选地,Ra选自氢、氰基、羧基、(优选)、 (优选)、(优选)、 (优选)、 (优选)、(优选)、(优选)、
    更优选地,Ra选自氢、氰基、羧基、(优选 (优选)、(优选 )、 (优选)、(优选)、(优选);
    更优选地,Ra选自氢、氰基、
    更优选地,Ra选自氢、氰基、
    Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、优选地,Rb选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);优选地,Ra、Rb和与它们分别相连的碳原子一起形成
    Rc选自氢、C1-C6烷基;优选地,Rc选自C1-C6烷基;
    最优选地,B作为整体,选自:
    (优选)、(优选)、 (优选)、(优选)、(优选)、
    最进一步优选地,B作为整体,选自 (优选)、(优选)、 (优选)、(优选)、、(优选 )、
    最进一步优选地,B作为整体,选自 (优选)、(优选 (优选)、(优选(优选)、
    最更进一步优选地,B作为整体,选自
    L1选自直接键、C1-C6烷基、优选地,L1选自直接键、 优选地,L1选自直接键、亚甲基、优选地,L1选自直接键、优选地,L1选自直接键;
    R1选自
    C选自5-6元杂芳基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基、噁唑基、呋喃基、1,2,3-三唑基、1,2,4-三唑基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C选自吡唑基、噻唑基、吡啶基、吡咯基、噁唑基、呋喃基、1,2,3-三唑基、1,2,4-三唑基,且C任选地被取代基Rd、Re、Rf中的至少一个所取代;
    Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基、所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被C1-C6烷基、1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    优选地,Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基、所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被、1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    优选地,Rd选自C1-C6烷基、C3-C6环烷基、苯基、吡啶基、吗啉基、哌嗪基、哌啶基,所述C3-C6环烷基、苯基、吡啶基、吗啉基、哌嗪基、哌啶基各自独立任选地被1-2个选自C1-C6烷基、卤素、烷氧 基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    优选地,Rd选自C3-C6环烷基、苯基、吗啉基、哌啶基,所述C3-C6环烷基、苯基、吗啉基、哌啶基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    更优选地,Rd选自C1-C6烷基、苯基、吗啉基、哌嗪基、哌啶基,所述苯基、吗啉基、哌嗪基、哌啶基任选地被C1-C6烷基(优选甲基)取代;更优选地,Rd选自苯基、吗啉基、哌啶基;p选自0、1、2;Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基;
    进一步优选地,Rd选自甲基、乙基、异丙基、 哌嗪基、哌啶基、
    进一步优选地,Rd选自哌嗪基;
    进一步优选地,Rd选自
    Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基;优选地,Re选自氢、甲基、F3C-、-NHCH3
    优选地,Re选自氢、甲基、F3C-、
    或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
    优选地,Re、Rf和与它们分别相连的碳原子一起形成
    各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
    更优选地,Re、Rf和与它们分别相连的碳原子一起形成
    R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子;
    优选地,R2、R3各自独立地选自氢、甲基、乙基、丙基、
    或者优选地,R2、R3和与它们共同相连的N原子一起形成
    最优选地,R1作为整体,选自:
    最进一步优选地,R1作为整体,选自:

    最更进一步优选地,R1作为整体,选自:
    最进一步优选的,R1作为整体,选自
  2. 权利要求1所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式i,
    其中:
    A1选自5元杂芳环,且所述5元杂芳环任选地被取代基Rk所取代;优选地,A1选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A1选自1,2,3-三唑环、1,2,4- 三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环;进一步优选地,A1选自 其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;更进一步优选地,A1选自其中#R11表示连接R11的连接位点,$L1表示连接L1的连接位点;
    Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
    Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
    B1选自6-10元杂芳基、6-10元芳基,且B1任选地被取代基Ra、Rb中的至少一个所取代;优选地,B1被取代基Ra、Rb中的至少一个所取代;优选地,B1选自9元杂芳基、吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;优选地,B1选自9元杂芳基、吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;更优选地,B1选自 吡啶基、苯基、嘧啶基,且B1被取代基Ra、Rb中的至少一个所取代;更优选地,B1选自吡啶基、苯基,且B1被取代基Ra、Rb中的至少一个所取代;
    进一步优选地,B1选自且B1被取代基Ra、Rb所取代;
    进一步优选地,B1选自且B1被取代基Ra、Rb所取代;Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷 基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、(其中Cy1为任选被Rcy1和Rcy2所取代的4-9元杂环基),-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代,所述C4-C9环烷基、4-9元饱和杂环基任选地被C1-C6烷基、卤素、羟基、氰基所取代;
    优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉基、哌嗪基、硫代吗啉基;
    Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
    优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;进一步优选地,Cy2选自吡咯烷基,所述吡咯烷基任选被1-3个(如1个或2个或3个)F取代;
    优选地,Ra选自氢、卤素、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自羟基、C3-C6环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,Ra选自氢、氰基、羧基、C1-C6卤代烷基(例如三氟甲基)、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;;
    优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基)、所述任选地被C1-C6烷基(优选甲基)、卤素(如F、Cl、Br)所取代;
    m选自0、1、2、3;优选地,m选自0、1;
    n选自0、1、2、3;优选地,n选自0、1;
    p选自0、1、2、3;优选地,p选自0、1;
    更优选地,Ra选自氢、氰基、羧基、(优选)、 (优选)、(优选)、 (优选)、 (优选)、(优选)、(优选)、
    更优选地,Ra选自氢、氰基、(优选(优选)、(优选)、
    Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、优选地,Rb选自氢、氰基、Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    或者,Ra、Rb和与它们分别相连的碳原子一起形成取代或未取代的5元杂环,取代基选自C1-C6烷基(如叔丁基);
    优选地,Ra、Rb和与它们分别相连的碳原子一起形成
    Rc选自氢、C1-C6烷基;优选地,Rc选自C1-C6烷基;
    最优选地,B1作为整体,选自:
    (优选)、(优选)、 (优选)、(优选)、(优选)、
    最优选地,B1作为整体,选自:
    (优选)、(优选)、 (优选)、(优选 )、(优选)、
    最更进一步优选地,B1作为整体,选自
    L1选自直接键、C1-C6烷基、优选地,L1选自直接键、优选地,L1选自直接键、亚甲基、优选地,L1选自直接键、
    R11选自
    C1选自5-6元杂芳基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;优选地,C1选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、咪唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C1选自吡唑基、噻唑基、吡啶基、吡咯基,且C1任选地被取代基Rd、Re、Rf中的至少一个所取代;
    Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、4-7元饱和杂环基、所述C3-C7环烷基和4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、所述C3-C7环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    优选地,Rd选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;优选地,Rd选自4-7元饱和杂环基,所述4-7元饱和杂环基任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;更 优选地,Rd选自C1-C6烷基、
    或者更优选地,Rd选自吡咯基、哌啶基、咪唑烷基、哌嗪基,所述吡咯基、哌啶基、咪唑烷基、哌嗪基任选地被1-2个选自卤素、C1-C6烷氧基、C1-C6烷基(优选甲基)取代;更优选地,Rd选自p选自0、1、2;
    或者更优选地,Rd选自吡咯基、哌啶基,所述吡咯基、哌啶基任选地被1-2个选自卤素、C1-C6烷基(优选甲基)取代;
    Rg选自氢、氨基、羟基、羟基C1-C6烷基、甲酰基;
    进一步优选地,Rd选自甲基、乙基、异丙基、哌啶基、进一步优选地,Rd选自进一步优选地,Rd选自
    Rh、Ri各自独立地选自氢、C1-C6烷基、C3-C6环烷基;
    优选地,Rh、Ri各自独立地选自氢、甲基、乙基、异丙基、环丙基;
    优选地,Re选自氢、甲基、-NHCH3;优选地,Re选自氢、甲基、F3C-、
    或者,Re、Rf和与它们分别相连的碳原子一起形成取代或未取代的5-9元杂环,取代基选自C1-C6烷基(如乙基)、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
    优选地,Re、Rf和与它们分别相连的碳原子一起形成
    各Rj独立地选自氢、C1-C6烷基、烷氧基(例如C1-C6烷氧基)、C3-C6环烷基、氨基、羟基;
    更优选地,Re、Rf和与它们分别相连的碳原子一起形成
    R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成5-6元饱和杂环基,优选地,所述5-6元饱和杂环基含有2-3个杂原子,且所述杂原子选自N、S、O原子;优选地,R2、R3各自独立地选自氢、甲基、乙基、丙基、或者优选地,R2、R3和与它们共同相连的N原子一起形成
    最优选地,R11作为整体,选自:
    最优选地,R11作为整体,选自:
    最优选地,R11作为整体,
  3. 权利要求2所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式i-1,

    其中:A1、B1、R11的定义如权利要求2所限定。
  4. 权利要求2-3任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式i-1-1,
    其中:A1、B1、C1的定义如权利要求2所限定。
  5. 权利要求1所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式ii,
    其中:A2选自6元杂芳环,且所述6元杂芳环任选地被取代基Rk所取代;优选地,A2选自6元杂芳环,所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述6元杂芳环任选地被取代基Rk所取代;更优选地,A2选自2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;进一步优选地,A2选自任选地被取代基Rk所取代,其中#R12表示连接R12的连接位点,$B2表示连接B2的连接位点;
    更进一步优选地,A2选自 其中#R12表示连接R12的连接位点,$B2表示连接B2的连接位点;
    Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
    Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
    进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
    B2选自6-10元杂芳基,且B2任选地被取代基Ra、Rb中的至少一个所取代;优选地,B2被取代基Ra、Rb中的至少一个所取代;优选地,B2选自9元杂芳基,且B2被取代基Ra、Rb中的至少一个所取代;优选地,所述9元杂芳基含有1-4个杂原子,所述杂原子选自N、O、S原子;更优选地,B2选自 且B2被取代基Ra、Rb中的至少一个所取代;
    Ra选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基);优选地,Ra选自氢、氰基、C1-C6卤代烷基(例如三氟甲基);更优选地,Ra选自氢、氰基、
    Rb选自氢、卤素、氨基、氰基、羧基、C1-C6烷基、C1-C6卤代烷基(例如三氟甲基)、优选地,Rb选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    最优选地,B2作为整体,选自
    R12选自
    C2选自5-6元杂芳基,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;
    优选地,C2选自5-6元杂芳基,所述5-6元杂芳基含有1-3个杂原子,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;更优选地,C2选自吡咯基、噁唑基、呋喃基、1,2,3-三唑基、1,2,4-三唑基,且C2任选地被取代基Rd、Re、Rf中的至少一个所取代;
    Rd、Re、Rf各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基(例如二氟甲基)、C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基,所述C3-C7环烷基、6-10元芳基、5-6元杂芳基、4-7元饱和杂环基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;
    优选地,Rd选自C3-C6环烷基、苯基、吗啉基、哌嗪基,所述C3-C6环烷基、苯基、吗啉基、哌嗪基各自独立任选地被1-2个选自卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代;更优选地,Rd选自C3-C6环烷基、苯基、吗啉基、哌嗪基;进一步优选地,Rd选自哌嗪基;
    优选地,Re选自氢、甲基、F3C-、
    最优选地,R12作为整体,选自:
  6. 权利要求1所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式I,

    其中:A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮、哒嗪环,且所述2-吡啶酮任选地被取代基Rk所取代;进一步优选地,A选自 任选地被取代基Rk所取代,其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
    更进一步优选地,A选自 其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
    更进一步优选地,A选自其中#C表示连接C的连接位点,$L1表示连接L1的连接位点;
    Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
    Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
    进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
    B选自(1)-(7)组中的任一个:
    (1)其中:R4选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷 基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    m1选自0、1、2、3;m1优选为0;n1选自0、1、2、3;n1优选为0、1;
    更优选地,R4选自氢、(优选)、(优选)、(优选)、(优选)、 (优选)、(优选)、(优选);
    R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    优选地,R5选自氢、氰基;
    最优选地,作为整体,选自 (优选)、(优选)、 (优选 )、(优选)、(优选 )、
    最进一步优选地,作为整体,选自 (优选)、(优选)、 (优选)(优选 )、(优选)、
    (2)其中:R6选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R6选自m2选自0、1、2、3;n2选自0、1、2、3;更优选地,R6
    R7选自氢、C1-C6烷基;
    最优选地,作为整体,为
    (3)其中:R8、R9、R10、R11中,任意一个选自氰基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基,其余为氢;优选地,R8、R9、R10、R11中,R8、R9或R11选自氰基、C1-C6卤代烷基(例如三氟甲基)、其余为氢;m3选自0、1、2、3;n3选自0、1、2、3;最优选地,作为整体,选自
    (4)其中:R12选自氢、C1-C6烷基;优选地,R12选自C1-C6烷基;
    (5)其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
    优选地,R22选自氢、m4选自0、1、2、3;n4选自0、1、2、3;更优选地,R22选自氢、
    R23选自氢、C1-C6烷基、氰基、羧基、 优选地,R23选自氢、C1-C6烷基、氰基、优选地,R23选自氢、氰基、羧基、优选地,R23选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    最优选地,作为整体,选自
    最进一步优选地,作为整体,选自
    最更进一步优选地,作为整体,选自
    (6)其中:R24选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R24选自m5选自0、1、2、3;n5选自0、1、2、3;更优选地,R24
    (7)其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R25选自氢、m6选自0、1、2、3;n6选自0、1、2、3;更优选地,R25选自氢、优选地,R25为氢;
    R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、C1-C6烷基、氰基、
    优选地,R26选自氢、C1-C6烷基、
    最优选地,作为整体,选自
    最进一步优选地,作为整体,选自
    L1选自直接键、C1-C6烷基、优选地,L1选自直接键、优选地,L1选自直接键;
    C选自(1)-(10)组中的任一个:
    (1)其中:R13选自C1-C6卤代烷基(例如二氟甲基)、Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
    优选地,R13选自三氟甲基、优选地,R13选自更优选地,R13选自
    R14选自C3-C6环烷基、哌啶基,所述C3-C6环烷基和哌啶基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基的取代基所取代;优选地,R14选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代;
    优选地,R14选自p选自0、1、2;Rg选自氢、羟基C1-C6烷基、甲酰基;
    或者,优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)取代;更优选地,R14选自最优选地,作为整体,选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
    (2)其中:R15选自C1-C6卤代烷基;R16选自C3-C6环烷基;
    最优选地,作为整体,为
    (3)其中:R17选自氢、C1-C6烷基;优选地,作为整体,为
    (4)其中:R18选自氢、C1-C6烷基;优选地,R18选自C1-C6烷基;最优选地,作为整体,为
    (5)其中:R19选自氢、C1-C6烷基;优选地,R19选自C1-C6烷基;最优选地,作为整体,为
    (6)其中:R20选自C3-C6环烷基;最优选地,作为整体,为
    (7)其中:R27选自苯基、C3-C6环烷基;最优选地,作为整体,选自
    (8)其中:R28选自6元饱和杂环基;优选地,R28为吗啉基;最优选地,作为整体,为
    (9)其中:R29选自C3-C6烷基;最优选地,作为整体,为
    (10)其中:R30选自C3-C6环烷基;R31选自C1-C6烷基;最优选地,作为整体,为
  7. 权利要求6所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式I-1,
    其中,A、B、C的定义如权利要求6所限定。
  8. 权利要求6-7任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式I-1-1,
    其中:A选自5-6元杂芳环,且所述5-6元杂芳环任选地被取代基Rk所取代;优选地,A选自5元杂芳环、6元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;所述6元杂芳环含有1-2个杂原子,且至少有1个杂原子为N原子,且所述5元杂芳环和6元杂芳环任选地被取代基Rk所取代;更优选地,A选自1,2,3-三唑环、1,2,4-三唑环、吡唑环、咪唑环、1,3,4-噻二唑环、1,3,4-噁二唑环、2-吡啶酮环、哒嗪环,且所述2-吡啶酮环任选地被取代基Rk所取代;
    进一步优选地,A选自 任选地被取代基Rk所取代,其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    更进一步优选地,A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    Rk选自C1-C6烷基、C3-C7环烷基、RpRqN-、C1-C6卤代烷基、C1-C6杂烷基(例如C1-C6烷氧基)、4-9元杂环基(例如5-6元饱和杂环基)、6-10元芳基、5-10元杂芳基;优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、4-9元饱和杂环基(例如5-6元饱和杂环基);更优选地,Rk选自C1-C6烷基、C3-C6环烷基、RpRqN-、C1-C6卤代烷基、吗啉基;
    Rp、Rq各自独立地选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基;优选地,Rp、Rq各自独立地选自氢、C1-C6烷基;
    进一步优选地,Rk选自异丙基、环丙基、二甲氨基、二氟甲基、
    B选自(1)-(7)组中的任一个:
    (1)其中:R4选自氢、C1-C6烷基、C4-C9环烷基、4-9元饱和杂环基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;n1选自0、1、2、3;
    更优选地,R4选自氢、(优选(优选)、(优选)、 (优选)、(优选)、(优选);
    R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、C1-C6烷基、优选地,R5选自氢、氰基、优选地,R5选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    最优选地,作为整体,选自 (优选)、(优选)、 (优选 )、(优选)、(优选 )、
    最优选地,作为整体,选自 (优选)、(优选)、 (优选)、(优选 )、(优选)、
    最进一步优选地,作为整体,选自 (优选)、(优选)、 (优选 )、(优选)、(优选 )、
    最更进一步优选地,作为整体,选自
    (2)其中:R6选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R6选自m2选自0、1、2、3;n2选自0、1、2、3;更优选地,R6
    R7选自氢、C1-C6烷基;最优选地,作为整体,为
    (3)其中:R8、R9、R10、R11中,任意一个选自氰基、C1-C6卤代烷基(例如三氟甲基)、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基,其余为氢;
    优选地,R8、R9、R10、R11中,R8、R9或R11选自氰基、C1-C6卤代烷基(例如三氟甲基)、其余为氢;m3选自0、1、2、3;n3选自0、1、2、3;
    最优选地,作为整体,选自
    (4)其中:R12选自氢、C1-C6烷基;优选地,R12选自C1-C6烷基;
    (5)其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R22选自氢、m4选自0、1、2、3;m4优选0;n4选自0、1、2、3;n4优选0、1;更优选地,R22选自氢、
    R23选自氢、C1-C6烷基、氰基、(其中Cy1为任选被Rcy1和Rcy2所取 代的4-9元杂环基)、(其中Rz为H或C1-C6烷基,Cy2为5-7元杂环基、C3-C7环烷基或C6-C10芳基,所述5-7元杂环基、C3-C7环烷基或C6-C10芳基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代);
    优选地,Cy1为5-7元杂环基,更优选地,Cy1为6元杂环基,进一步优选地,Cy1为吗啉、哌嗪、硫代吗啉;
    Rcy1和Rcy2各自独立地选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、卤素、羟基、硝基、氰基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、氧代;优选地、Rcy1和Rcy2各自独立地选自C1-C6烷基、卤素、羟基、氨基、氧代,进一步优选地Rcy1和Rcy2各自独立地选自氧代;
    优选地,Cy2为5-7元杂环基,所述5-7元杂环基任选被1-3个选自卤素、C1-C6烷基、C1-C6烷氧基、CN、羟基的取代基所取代;进一步优选地,Cy2选自氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基,所述氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基任选被1-3个选自卤素、C1-C6烷基的取代基所取代基;进一步优选地,Cy2选自吡咯烷基、咪唑烷基、哌啶基,所述吡咯烷基、咪唑烷基、哌啶基任选被1-3个F、Cl、Br、甲基所取代;优选地,R23选自氢、C1-C6烷基、氰基、
    优选地,R23选自氢、氰基、优选地,R23选自氢、氰基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    最优选地,作为整体,选自
    最优选地,作为整体,选自
    最进一步优选地,作为整体,选自
    (6)其中:R24选自氢、C1-C6烷基、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
    优选地,R24选自m5选自0、1、2、3;n5选自0、1、2、3;更优选地,R24
    (7)其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;优选地,R25选自氢、m6选自0、1、2、3;m6优选0;n6选自0、1、2、3;n6优选0、1;
    更优选地,R25选自氢、
    R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、C1-C6烷基、氰基、优选地,R26选自氢、氰基、
    最优选地,作为整体,选自
    最优选地,作为整体,选自
    最进一步优选地,作为整体,选自
    C选自(1)-(11)组中的任一个:
    (1)其中:R13选自C1-C6卤代烷基(例如二氟甲基)、
    Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
    优选地,R13选自进一步优选地,R13选自
    R14选自C3-C6环烷基,所述C3-C6环烷基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基的取代基所取代;或者R14选自苯基、吗啉基、哌嗪基、哌啶基,所述苯基、吗啉基、哌嗪基、哌啶基任选地被1-2个选自C1-C6烷基、卤素、烷氧基(例如C1-C6烷氧基)、羟基、氨基、羟基C1-C6烷基(例如羟甲基)、氨基C1-C6烷基、甲酰基的取代基所取代优选地,R14选自p选自0、1、2;
    或者优选地,R14选自哌啶基,所述哌啶基任选地被1-2个选自C1-C6烷基(优选甲基)、卤素、羟基、氨基的取代基所取代
    Rg选自氢、羟基C1-C6烷基、甲酰基;
    更优选地,R14选自
    更优选地,R14选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
    (2)其中:R15选自C1-C6卤代烷基;R16选自C3-C6环烷基;最优选地,作为整体,为
    (3)其中:R17选自氢、C1-C6烷基;优选地,作为整体,为
    (4)其中:R18选自氢、C1-C6烷基;优选地,R18选自C1-C6烷基;最优选地,作为整体,为
    (5)其中:R19选自氢、C1-C6烷基;优选地,R19选自C1-C6烷基;最优选地,作为整体,为
    (6)其中:R20选自C3-C6环烷基;最优选地,作为整体,为
    (7)其中:R27选自苯基、C3-C6环烷基;最优选地,作为整体,选自
    (8)其中:R28选自6元饱和杂环基;优选地,R28为吗啉基;
    最优选地,作为整体,为
    (9)其中:R29选自C3-C6烷基;最优选地,作为整体,为
    (10)其中:R30选自C3-C6环烷基;R31选自C1-C6烷基;
    最优选地,作为整体,为
    (11)其中:R32选自苯基、C3-C6环烷基;R33选自C1-C6烷基、C1-C6卤代烷基(例如三氟甲基、二氟甲基);最优选地,作为整体,选自
  9. 权利要求1所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式II,
    其中:
    A选自5元杂芳环;优选地,A选自5元杂芳环,所述5元杂芳环含有2-3个杂原子,且至少有2个杂原子为N原子;更优选地,A选自1,2,3-三唑环、咪唑环;最优选地,A选自 其中#R31表示连接羰基的连接位点,$B11表示连接稠环双环的连接位点;
    R2、R3各自独立地选自氢、C1-C6烷基、C3-C6环烷基;或者,R2、R3和与它们共同相连的N原子一起形成6元饱和杂环基,优选地,所述6元饱和杂环基含有2个杂原子,且所述杂原子为N原子;优选地,R2、R3各自独立地选自氢、甲基、乙基、异丙基、
    或者优选地,R2、R3和与它们共同相连的N原子一起形成最优选地,整体选自
    R21选自C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
    优选地,R21选自m7选自0、1、2、3;n7选自0、1、2、3;
    优选地,R21选自
  10. 权利要求1-9任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式III,
    其中:
    A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    B为其中:R4选自氢、C1-C6烷基、C4-C9环烷基、4-9元饱和杂环基、-NRNaRNb(其中RNa和RNb各自独立地选自H、C1-C6烷基,所述C1-C6环烷基可任选被1-3个选自卤素、羟基、C3-C6环烷基、C3-C6卤代环烷基、4-7元杂环基的取代基所取代),所述C4-C9环烷基、4-9元饱和杂环基任选地被1-3个选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、羟基、羟基-C1-C6烷基-、氰基、氧代、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    优选地,R4选自氢、 所述 任选地被1-3个选自C1-C6烷基、卤素、羟基、氰基、-NH2、-N(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)的取代基所取代;
    n1选自0、1、2、3;优选地n1为0;
    更优选地,R4选自氢、 (优选)、(优选 )、(优选)、
    更进一步优选地,R4选自氢、
    R5选自氢、氰基、C1-C6烷基、
    优选地,R5选自氢、氰基;
    优选地,作为整体,选自 (优选)、(优选)、 (优选)、(优选)、(优选)、
    进一步优选地,作为整体,选自 (优选)、(优选)、 (优选)、(优选)、(优选)、
    进一步优选地,作为整体,选自
    C为其中:R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、
    Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
    优选地,R13选自C1-C6卤代烷基(例如二氟甲基);优选地,R13选自进一步优选地,R13选自
    R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;
    p选自0、1、2;优选地,p为2;
    Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
    更优选地,R14选自
    更优选地,R14选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
  11. 权利要求1-9任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式IV,
    其中:
    A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    B为其中:R22选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
    优选地,R22选自氢、m4选自0、1、2、3;优选地,m4选自0;n4选自0、1、2、3;优选地,n4选自0、1;更优选地,R22选自氢、
    R23选自氢、C1-C6烷基、氰基、羧基、优选地,R23选自氢、羧基、
    Rl、Rm各自独立地选自氢、C1-C6烷基、C3-C6环烷基;优选地,Rl、Rm各自独立地选自氢、C1-C6烷基;
    最优选地,作为整体,选自
    C为其中:R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、
    Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;
    优选地,R13选自C1-C6卤代烷基(例如二氟甲基);优选地,R13选自进一步优选地,R13选自
    R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;
    p选自0、1、2;优选地,p为2;
    Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
    更优选地,R14选自
    更优选地,R14选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
  12. 权利要求1-9任一项所述的化合物,或所述化合物的立体异构体、互变异构体、前药、晶型、水合物、同位素标记化合物(氘代物)、代谢产物、酯、药学上可接受的盐或药学上可接受的溶剂合物,其中,所述化合物的结构式为式V,
    其中:
    A选自 其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    更进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    最进一步优选地,A选自其中#C表示连接C的连接位点,$B表示连接B的连接位点;
    B为其中:R25选自氢、C4-C9环烷基、C4-C9环烷基-C1-C6烷基、4-9元饱和杂环基、4-9元饱和杂环基-C1-C6烷基;
    优选地,R25选自氢、m6选自0、1、2、3;优选地,m6为0;n6选自0、1、2、3;优选地,n6为0、1;
    更优选地,R25选自氢、
    R26选自氢、C1-C6烷基、氰基、羧基、优选地,R26选自氢、氰基、羧基、
    最优选地,作为整体,选自
    最进一步优选地,作为整体,选自
    C为其中:
    R13选自C1-C6卤代烷基(例如二氟甲基或三氟甲基)、Rh、Ri各自独立地选自氢、C1-C6烷基;优选地,Rh、Ri各自独立地选自氢、甲基、异丙基;优选地,R13选自C1-C6卤代烷基(例如二氟甲基);优选地,R13选自
    进一步优选地,R13选自
    R14选自C3-C6环烷基、哌啶基、哌嗪基、吗啉基,所述C3-C6环烷基、哌啶基、哌嗪基、吗啉基任选地被1-2个选自羟基C1-C6烷基(例如羟甲基)、甲酰基、C1-C6烷基(优选甲基)的取代基所取代;
    优选地,R14选自哌啶基,所述哌啶基任选地被1-2个C1-C6烷基(优选甲基)的取代基所取代;p选自0、1、2;优选地,p为2;Rg选自氢、羟基C1-C6烷基、甲酰基;优选地,Rg为氢;
    更优选地,R14选自
    更优选地,R14选自
    最优选地,作为整体,选自
    最优选地,作为整体,选自
  13. 权利要求1-12任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VI-1或者式VI-2或者式VII-1或者式VII-1-1或者式VII-1-2,
    式VI-1、式VI-2、式VI-3中A、B、C、Rd、Re、Rf的定义如权利要求1-12中任一项所限定;
    式VII-1-1中,A、B、Re、Rf、Rg、p的定义如权利要求1-12中任一项所限定;
    式VII-1-2中,各个Rx独立地选自卤素、C1-C6烷氧基、羟基、氨基、C1-C6烷基、氰基,s选自0、1、2、3,或者两个Rx可与其连接的C原子形成C1-C6环烷基,Ry选自H、C1-C6烷基;A、B、Re、Rf的定义如权利要求1-12中任一项所限定。
  14. 权利要求1-13任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VII-2-1或者式VII-2-2或者式VII-3-1或者式VII-3-2或者式VII-3-3,
    式VII-2-1中,B、Re、Rf、Rg、p的定义如权利要求1-13中任一项所限定;
    式VII-2-2中,B、Re、Rf、Rx、Ry、s的定义如权利要求1-13中任一项所限定;
    式VII-3-1中,A、Rd、Re、Rf、Ra、Rb的定义如权利要求1-13中任一项所限定;
    式VII-3-2中,A、Rd、Re、Rf、Ra、Rb的定义如权利要求1-13中任一项所限定;
    式VII-3-3中,A、Rd、Re、Rf、Ra、Rb的定义如权利要求1-13中任一项所限定。
  15. 权利要求1-14中任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物的结构式为式VIII-1或者式VIII-2或者式VIII-3,
    式VIII-1中,Rd、Re、Rf、Ra、Rb的定义如权利要求1-14中任一项所限定;
    式VIII-2中,Rd、Re、Rf、Ra、Rb的定义如权利要求1-14中任一项所限定;
    式VIII-3中,Rd、Re、Rf、Ra、Rb的定义如权利要求1-14中任一项所限定。
  16. 权利要求1-15任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,其中,所述化合物选自:








    ;优选地,所述化合物选自:





  17. 一种制备权利要求1-16中任一项所述式A化合物的方法,其特征在于:
    式A中A为所述方法包括:
    化合物A-1-B1经卤代反应获得化合物A-1-B2,化合物A-1-B2经取代反应获得化合物A-1-B3,化合物A-1-B3与化合物A-1-C1经成环反应获得化合物A-1;
    其中X1为卤素(如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C的范围如权利要求1-27中任一项所述;
    优选地,所述化合物A-C-1的制备方法包括:
    化合物A-1-C1经硝化反应获得化合物A-1-C2,化合物A-1-C2经还原反应获得化合物A-1-C3,化合物A-1-C3经叠氮化获得化合物A-C-1,Rd、Re、Rf和C的范围如权利要求1-27中任一项所述。
  18. 一种制备权利要求1-16中任一项所述式A化合物的方法,其中,
    式A中A为所述方法包括:
    化合物A-2-B1经偶联反应获得化合物A-2-B2,化合物A-2-B2与化合物A-2-C2经偶联反应获得化合物A-2,其中X2和X3各自独立地为卤素(例如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C如权利要求1-16中任一项所述;
    优选地,所述化合物A-2-C2的制备方法包括:
    化合物A-2-C1经卤代反应获得化合物A-2-C2,其中X3为卤素(例如Cl、Br、I),Rd、Re、Rf、C如权利要求1-16中任一项所述;
    或者式A中A为所述方法包括:
    化合物A-3-C1经氰化反应获得化合物A-3-C2,与A-3-B2发生环化反应得到A-3;
    其中X4为卤素(例如Cl、Br、I),Ra、Rb、Rd、Re、Rf、B、C如权利要求1-16中任一项所述;
    优选地,所述A-3-B2的制备方法包括:
    化合物A-3-B1经酰化反应获得化合物A-3-B2,其中Ra、Rb、B如权利要求1-16中任一项所述。
  19. 一种药物组合物,其包含权利要求1-16任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,以及任选的药学上可以接受的辅料。
  20. 一种PROTAC分子,其包含:弹头部分、连接酶结合部分和连接链,所述弹头部分为权利要求1-16任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,所述连接链分别与所述弹头部分和所述连接酶结合部分进行共价连接;
    优选地,所述连接酶结合部分为E3泛素连接酶结合部分。
  21. 权利要求1-16任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,或者权利要求19所述的药物组合物,或者权利要求20所述的PROTAC分子在制备药物中的用途,所述药物用于治疗和/或预防与IRAK4激酶相关的疾病;
    优选地,所述与IRAK4激酶相关的疾病为癌症或自身免疫性疾病;
    优选地,所述自身免疫性疾病选自类风湿性关节炎、骨关节炎、慢性阻塞性肺疾病、系统性红斑狼疮、银屑病、溃疡性结肠炎、肠道应激综合症,或其任意组合;
    优选地,所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、华氏巨球蛋白血症,或其任意组合。
  22. 一种治疗和/或预防与IRAK4激酶相关的疾病的方法,包括向受试者施用有效量的权利要求1-16任一项所述的化合物,或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药,或者权利要求19所述的药物组合物,或者权利要求20所述的PROTAC分子;
    优选地,所述与IRAK4激酶相关的疾病为癌症或自身免疫性疾病;
    优选地,所述自身免疫性疾病选自类风湿性关节炎、骨关节炎、慢性阻塞性肺疾病、系统性红斑狼疮、银屑病、溃疡性结肠炎、肠道应激综合症,或其任意组合;
    优选地,所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、华氏巨球蛋白血症,或其任意组合。
PCT/CN2023/108727 2022-07-22 2023-07-21 一种抑制irak4活性的化合物及其应用 WO2024017381A1 (zh)

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Publication number Priority date Publication date Assignee Title
US20160152608A1 (en) * 2013-06-20 2016-06-02 Ab Science Benzimidazole derivatives as selective proteine kinase inhibitors
CN106749268A (zh) * 2015-11-24 2017-05-31 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN111560012A (zh) * 2019-02-14 2020-08-21 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
CN112480101A (zh) * 2019-09-12 2021-03-12 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160152608A1 (en) * 2013-06-20 2016-06-02 Ab Science Benzimidazole derivatives as selective proteine kinase inhibitors
CN106749268A (zh) * 2015-11-24 2017-05-31 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN111560012A (zh) * 2019-02-14 2020-08-21 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
CN112480101A (zh) * 2019-09-12 2021-03-12 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用

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