WO2022214044A1 - Amine-substituted pyridine fused ring compounds, preparation method therefor and use thereof - Google Patents

Amine-substituted pyridine fused ring compounds, preparation method therefor and use thereof Download PDF

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Publication number
WO2022214044A1
WO2022214044A1 PCT/CN2022/085658 CN2022085658W WO2022214044A1 WO 2022214044 A1 WO2022214044 A1 WO 2022214044A1 CN 2022085658 W CN2022085658 W CN 2022085658W WO 2022214044 A1 WO2022214044 A1 WO 2022214044A1
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alkyl
membered
group
heteroaryl
cycloalkyl
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PCT/CN2022/085658
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French (fr)
Chinese (zh)
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赵吉辰
周福生
林崇懒
张涛
杨华彬
李震
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Priority to CN202280033521.XA priority Critical patent/CN117279896A/en
Publication of WO2022214044A1 publication Critical patent/WO2022214044A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Hematopoietic progenitor kinase 1 is a hematopoietic system-specific serine/threonine protein kinase that belongs to the MAP4K family of mammalian ste20-related protein kinases. HPK1 is mainly expressed in hematopoietic tissues and cells. There are three activation modes of HPK1, namely serine phosphorylation, threonine phosphorylation or tyrosine phosphorylation. Previous studies have shown that in vitro HPK1-/- T cells have a lower TCR activation threshold, proliferate robustly, and produce more Th1 cytokines.
  • HPK1-/- mice develop more severe self when immunized with peptides derived from myelin oligodendrocyte glycoprotein (MOG) immune symptoms. Furthermore, in the PGE2-producing Lewis lung cancer tumor model, tumor development was significantly slower in HPK1-knockout mice compared with wild-type mice.
  • HPK1 can interact with many adaptor proteins, such as SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, CRK family, etc., and activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby Negative regulation of the TCR pathway.
  • the present invention provides an efficient HPK1 inhibitor with novel structure, which has the advantages of high activity, good selectivity, low toxicity and side effects, and has good physicochemical properties and drug-forming properties.
  • the first aspect of the present invention provides a compound represented by formula (A) or formula (D) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • Cy1 ring is C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C6-14 aryl or 5 to 20 membered heteroaryl; the 3 to 20 membered heterocyclyl, the 5 to 20 membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
  • R x is a substituent at a position on the Cy2 ring
  • R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl);
  • R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl);
  • the bond between R 2a and the carbon atom is a single bond ;
  • R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group;
  • the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms;
  • the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
  • R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl),
  • R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond;
  • the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected
  • Rx is in
  • Rx is in
  • R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
  • p1 is 0, 1 or 2;
  • R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl
  • each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • a compound of formula (A) or a pharmaceutically acceptable salt, solvate or prodrug thereof is prepared by a method comprising the steps of:
  • Rm and Rm' are selected from reactive groups known in the art.
  • R x is a substituent at a position on the Cy2 ring
  • Ry and Ry' are selected from reactive groups known in the art.
  • the boronic acid group or boronic acid ester group is selected from or -B(OH) 2 .
  • the third aspect of the present invention provides a compound represented by formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
  • Rx is wherein, when R 2a and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered The monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the said The 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2,
  • Rx is wherein R 2e and R 2f together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains a nitrogen atom and optionally 1 or 2 heterocyclic heteroaryl groups independently selected from N, O, S and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally Or 4 groups selected from S1 group are substituted;
  • R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered heteroaryl, -NH-C 6- 14 Aryl; wherein, the 3- to 20-membered heterocyclic group, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optionally replaced by 1, 2, 3 or 4 substituted with a group selected from the S3 group; the 3- to 20-membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
  • Rx is in
  • R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not 3 to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is replaced by 1 , 2, 3 or 4 groups selected from group S1; or
  • R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group
  • R 2a is deuterium
  • R 2b is hydrogen, Deuterium or C 1-6 alkyl (eg methyl) and the bond between R 2a and the carbon atom is a single bond
  • the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms
  • the 3- to 20-membered heterocyclic groups , the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected
  • R 2g , R 2h , R 2h' , R 2g' is hydrogen or deuterium or C 1-6 alkyl (eg methyl), at least one of R 2g , R 2h , R 2h' and R 2g' is deuterium;
  • the 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as a ring and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3, or 4 Replaced by
  • R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group;
  • R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group
  • the aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered
  • the monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group;
  • R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group
  • the aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered
  • the monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R x is a substituent at a position on the Cy2 ring
  • R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group,
  • the 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1;
  • R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group
  • R 2a is deuterium
  • R 2b is hydrogen, deuterium or methyl
  • the bond between R 2a and the carbon atom is a single bond
  • the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms
  • the cyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R x is a substituent at a position on the Cy2 ring
  • each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group,
  • each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • n hydrogen atoms on each of the above groups can be optionally substituted by R 1 ; n is 0, 1, 2 or 3; each R 1 is independently defined as before.
  • the Cy2 ring is selected from the group consisting of:
  • each R 2 is independently defined as above.
  • each of R x and R 2 is independently defined as above.
  • each of R x and R 2 is independently defined as above.
  • the hydrogen atoms on the ring in each of the above groups can be independently optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group;
  • Rx is selected from the group consisting of: In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  • Rx is selected from the group consisting of: In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  • Rx is Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 Monocyclic heterocyclyl.
  • Rx is Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 6-membered monocyclic heterocyclyl.
  • the boronic acid group or boronic acid ester group is selected from or -B(OH) 2 .
  • the compound of the present invention is selected from Table (I):
  • the 3- to 20-membered heterocyclic group is selected from the group consisting of: 3- to 6-membered monocyclic heterocyclic group, 7- to 11-membered spiro heterocyclic group, 6- to 10-membered condensed heterocyclic group Heterocyclyl, 6- to 14-membered bridged heterocyclyl.
  • each R a , each R b , each R a1 , each R b1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl base, -C 1-2 alkyl-hydroxyl, -C 1-2 alkyl-cyano, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterium Substituted C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C
  • each R d , each R d1 is each independently hydrogen, C 1-4 alkyl, or deuterated C 1-4 alkyl.
  • each R c , each R c1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy base, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterated C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-2 alkyl-3 to 6-membered monocyclic
  • the -C 1-2 alkyl- is unsubstituted; or the hydrogen atoms on the -C 1-2 alkyl- are each independently selected from halogen, cyano, hydroxyl, C 1- 4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, -CH 2 -hydroxyl group, -CH 2 -cyano group, phenyl group substituted or C 1-2 alkyl group Two hydrogen atoms of the same carbon atom are simultaneously substituted with -(CH 2 ) j - to form a cycloalkyl group, where j is 2, 3, 4, 5 or 6.
  • any 3 to 6 membered monocyclic heterocyclyl is selected from the group consisting of: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 3- to 6-membered monocyclic heterocyclic group is optionally replaced by 1, substituted with 2, 3 or 4 groups selected from group S1.
  • any one 5 or 6 membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine ;
  • the 5- or 6-membered monocyclic heteroaryl group is optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group.
  • Cy2 ring As described in this article, may be referred to as the Cy2 ring. may be referred to as the Cy1 ring.
  • a fourth aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be administered orally, by inhalation, rectally, nasally, bucally, topically, parenterally, such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • parenterally such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention may be formulated in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and cornstarch, although lubricants such as magnesium stearate may also be added.
  • Diluents used in capsule formulations typically include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations.
  • the compounds of the present invention can be prepared into different topical formulations according to different affected surfaces or organs
  • the compounds of the present invention when administered topically to the eye, may be formulated as a micronized suspension or solution in the form of an isotonic, pH, sterile, isotonic carrier, with or without the addition of a preservative such as Benzyl alkoxide chloride.
  • the compounds can also be formulated in the form of an ointment such as petrolatum ointment.
  • the compounds of the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
  • Useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium such as mono- or diglycerides.
  • Another aspect of the present invention provides the compound of the above-mentioned first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the above-mentioned fourth aspect in the preparation of prophylaxis and/or use in a medicament for the treatment of a disease or condition; a disease or condition associated with HPK1 activity.
  • the disease or disorder is cancer.
  • Another aspect of the present invention provides the compound described in the first, second or third aspect above, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition described in the fourth aspect above. Use in HPK1 inhibitors.
  • Another aspect of the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described in the first, second or third aspect or a pharmaceutically acceptable salt thereof, A stereoisomer, solvate or prodrug, or any combination of the above, or the step of administering the pharmaceutical composition of the fourth aspect above.
  • the term "subject” refers to an animal, particularly a mammal. People are preferred.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect.
  • the amount of a given drug depends on factors such as the particular dosing regimen, the type of disease or condition and its severity, the subject in need of treatment or the uniqueness of the host (e.g. body weight), however, the dose to be administered may be known in the art depending on the particular surrounding circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated method is routinely determined.
  • the administered dose is typically in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day.
  • the desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts with inorganic acids or organic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, caproic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • solvate and “solvate” refer to substances formed by combining a compound of the present invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include acetic acid and the like.
  • Solvates include stoichiometric amounts and non-stoichiometric amounts of solvates. Certain compounds of the present invention may exist in unsolvated as well as solvated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds described in the present invention may exist in stereoisomeric forms, and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc.
  • the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture.
  • a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation. And as a drug, a stereoisomer having excellent activity is preferable.
  • the compounds of the present invention have optical isomers derived from asymmetric carbons and the like, and if necessary, single isomers can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.
  • halophenyl refers to a phenyl group having only halogen as a substituent; excluding one substituent on the phenyl group which is a halogen and the other substituents being substituents other than halogen.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbyl group.
  • C 1-20 alkyl refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Preferably it is a C 1-10 alkyl group. More preferred are C1-6 alkyl groups (ie straight or branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferred is C 1-4 alkyl. More preferred is C 1-3 alkyl.
  • Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers, etc.
  • alkoxy refers to a group having the structure -O-alkyl, wherein alkyl is as defined above.
  • C 1-10 alkoxy refers to an alkoxy group having 1 to 10 carbon atoms. Preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy. More preferred is C 1-3 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein alkoxy is as defined above.
  • haloC 1-10 alkoxy refers to a haloalkoxy having 1 to 10 carbon atoms.
  • Preferred is halogenated C 1-6 alkoxy. More preferred is a halogenated C 1-4 alkoxy group. More preferred is a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • deuterated alkyl refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by deuterium atoms, wherein alkyl is as defined above.
  • deuterated C 1-10 alkyl refers to a deuterated alkyl group having 1 to 10 carbon atoms. Deuterated C 1-6 alkyl is preferred. More preferred is deuterated C 1-4 alkyl. More preferred is deuterated C 1-3 alkyl. Specific examples include, but are not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, monodeuteroethyl, 1,2-dideuteroethyl, trideuteroethyl, and the like.
  • deuterated alkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein alkoxy is as defined above .
  • deuterated C 1-10 alkoxy refers to a deuterated alkoxy group having 1 to 10 carbon atoms. Preferred is deuterated C 1-6 alkoxy. More preferred is deuterated C 1-4 alkoxy. More preferred is deuterated C 1-3 alkoxy.
  • Specific examples include, but are not limited to, tri-deuteriomethoxy, tri-deuteroethoxy, mono-deuteromethoxy, mono-deuteroethoxy, dideuteromethoxy, dideuteroethoxy, and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkanes and bridged cycloalkyl groups.
  • the ring carbon atoms of the cycloalkyl group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
  • 3 to 20 membered cycloalkyl or "C 3-20 cycloalkyl” refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. Preferably it is C 3-12 cycloalkyl, C 5-20 spirocycloalkyl, C 5-20 fused cycloalkyl or C 5-20 bridged cycloalkyl. More preferred is C 3-8 monocyclic cycloalkyl.
  • C 3-8 monocyclic cycloalkyl and “3- to 8-membered monocyclic cycloalkyl” refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms.
  • it is a C 3-6 monocyclic cycloalkyl group (ie, a 3- to 6-membered monocyclic cycloalkyl group) or a C 4-6 monocyclic cycloalkyl group (ie, a 4- to 6-membered monocyclic cycloalkyl group). More preferred is a C3, C4 , C5 or C6 monocyclic cycloalkyl.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, double-spirocycloalkyl groups and poly-spirocycloalkyl groups.
  • 5- to 20-membered spirocycloalkyl or "C 5-20 spirocycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the single ring sharing the spiro atoms is 3 to 8 membered Monocyclic cycloalkyl ring.
  • Preferred are 6 to 14 membered (ie C6-14 ) spirocycloalkyl. More preferred is a 6- to 14-membered monospirocycloalkyl. More preferred is a 7- to 11-membered (ie C7-11 ) spirocycloalkyl.
  • fused cycloalkyl and “fused cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group in which two or more monocyclic rings are formed by sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl.
  • the term “5 to 20 membered fused cycloalkyl” or " C5-20 fused cycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are 3 to 20 ring carbon atoms.
  • 8-membered monocyclic cycloalkyl ring Preferably it is a 6- to 14-membered (ie C 6-14 ) fused cycloalkyl group. More preferred is a 6- to 14-membered di-fused cycloalkyl group. More preferred is a 7- to 10-membered (ie C 7-10 ) fused cycloalkyl group. More preferred is a 7- to 10-membered di-fused cycloalkyl group.
  • fused cycloalkyl include, but are not limited to:
  • fused cycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
  • bridged cycloalkyl groups include, but are not limited to:
  • bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.
  • halocycloalkyl refers to a cycloalkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein cycloalkyl is as defined above.
  • haloC 3-8 monocyclic cycloalkyl refers to a halogenated monocyclic cycloalkyl having 3 to 8 ring carbon atoms. Preferably it is a halogenated C 3-6 monocyclic cycloalkyl. More preferred is a haloC3 , haloC4 , haloC5 or haloC6 monocyclic cycloalkyl. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclyl and bridged heterocyclyl.
  • the ring carbon atoms of the heterocyclic group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • the 3- to 20-membered heterocyclyl groups of the present invention include monocyclic heterocyclyl groups (eg, 3- to 8-membered monocyclic heterocyclyl groups), 5- to 20-membered spiro heterocyclyl groups, 5- to 20-membered fused heterocyclyl groups, and 5- to 20-membered fused heterocyclyl groups. to 20-membered bridged heterocyclyl.
  • a 4- to 6-membered monocyclic heterocyclyl group having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 5- or 6-membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the heteroatom is a sulfur atom
  • the ring carbon atoms of the monocyclic heterocyclyl may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclyl groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -one, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3
  • azetidinyl ie, tetrahydropyrrole
  • azepinyl ie, hexahydropyridine
  • morpholinyl morpholinyl
  • piperazinyl oxazolidine
  • 3 to 8 membered monocyclic heterocycloalkyl refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms.
  • it is a 3- to 6-membered monocyclic heterocycloalkyl, ie a saturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms.
  • heterocycloalkyl examples include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, Dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-dioxanyl.
  • spiroheterocyclyl and “spiroheterocyclyl ring” refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (referred to as a spiro atom).
  • the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • 5- to 20-membered spiroheterocyclyl refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocycles sharing the spiro atoms is a 3- to 8-membered monocyclic heterocyclyl ring and the other
  • the monocycle is a 3- to 8-membered monocyclic heterocyclyl ring or a 3- to 8-membered monocyclic cycloalkyl ring.
  • 7 to 11 membered spiroheterocyclyl groups having 7 to 11 ring atoms, of which 1 or 2 are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Shared pairs of adjacent ring atoms can be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
  • the term "5- to 20-membered fused heterocyclyl” refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein the monocycles sharing adjacent pairs of ring atoms are 3- to 8-membered monocyclic heterocyclyl rings.
  • Preferred is a 6- to 14-membered fused heterocyclic group having 6 to 14 ring atoms, of which 1 or 2 are heteroatoms.
  • fused heterocyclic groups include, but are not limited to:
  • fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • 5- to 20-membered bridged heterocyclyl refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected ring atoms, each monocyclic Rings can contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Preferred is a 6- to 14-membered bridged heterocyclyl group. More preferred is a 7- to 10-membered bridged heterocyclyl group.
  • Specific examples of bridged heterocyclyl groups include, but are not limited to:
  • bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • the above various types of heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • aryl As used herein, the terms “aryl”, “aryl ring” and “aromatic ring” are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic ring (rings connected to rings by covalent bonds, non-fused group) or all-carbon fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups in which at least one ring is aromatic, ie, has a conjugated pi-electron system.
  • C 6-14 aryl refers to an aryl group having 6 to 14 ring atoms. Preferably it is a C 6-10 aryl group.
  • the C 6-14 aryl group in the present invention includes a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group, wherein examples of the monocyclic aryl group include phenyl, and examples of the non-fused polycyclic aryl group include Biphenyl, etc.
  • the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings , non-limiting examples of which include naphthyl, anthracenyl, and the like.
  • the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.
  • heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaromatic ring” are used interchangeably to refer to a monocyclic or fused ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
  • the heteroaryl group has 6, 10 or 14 pi electrons shared and at least one ring in the group is aromatic.
  • the fused bicyclic heteroaryl group can be either a bicyclic group formed by condensing a single aryl ring (such as phenyl) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).
  • the 2 ring atoms connected arbitrarily on the above-mentioned monocyclic heteroaryl ring, including C-C, N-C, N-N, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring.
  • the 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably C-C, including without limitation the following forms:
  • Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a A polycyclic group formed by condensing multiple non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure) and the like.
  • a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cycl
  • the non-aromatic heterocycle includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be 2 oxo groups are substituted to form a cyclic lactam or cyclic lactone structure), etc.
  • the polycyclic group formed by condensing the above-mentioned monocyclic aryl ring and one or more non-aromatic heterocycles can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic aryl group Ring or non-aromatic heterocycle.
  • heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • hydroxy refers to -OH.
  • hydroxymethyl refers to -CH2OH and "hydroxyethyl” refers to -CH2CH2OH or -CH(OH ) CH3 .
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • benzyl refers to -CH2 -benzene.
  • acetyl refers to -COCH3 .
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and the substituted compound is stable.
  • optionally substituted or “optionally substituted” means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any group if If the label is on a bond (not the bond itself), it means that the bond labeled by the group is attached to the rest of the molecule.
  • any group or compound structural formula if a chemical bond connected to a double bond is drawn as It means that the group or compound can be a mixture of cis-isomer and trans-isomer.
  • Step 2 Add 7-bromoisoquinolin-1-amine (500mg, 2.24mmol), bis(pinacol)diboron (683mg, 2.69mmol), [1,1'-bis(2.69mmol) to a 50mL round-bottomed flask (diphenylphosphino)ferrocene]palladium dichloride (161 mg, 0.22 mmol), potassium acetate (658 mg, 6.72 mmol), 1,4-dioxane (15 mL), nitrogen replaced three times, the reaction was carried out at 95°C Reaction for 16h.
  • Step 3 Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.91 mmol), isoquinolin-1-amine-7-boronic acid (1.0 g, 3.82 mmol) to a 50 mL round-bottomed flask mmol), potassium carbonate (791 mg, 5.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (139 mg, 0.19 mmol), 1,4-dioxane (20 mL ) and water (5 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours.
  • Step four 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (294 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (8 mL) ) N-iodosuccinimide (262 mg, 1.17 mmol) was added in an ice bath, and the reaction was stirred at room temperature for 4 h. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum.
  • Step six 2-(6-(1-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl]isoquinolin-4-yl)isochroman-8 -yl) tert-butyl pyrrolidine-1-carboxylate (50mg, 0.086mmol) was dissolved in methanol (1ml), 4M hydrochloric acid dioxane solution (3ml) was added, and the reaction was stirred at room temperature for 1 hour.
  • reaction solution was concentrated, 7.0M ammonia methanol solution (4 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4- (8-(pyrrolidin-2yl)isochroman-6-yl)isoquinolin-1-amine (Z1, 20 mg, 78% yield), white solid.
  • Step 1 Add 1-(5-bromo-2-(tetrahydro-2H-pyran-4-yl)phenyl)-N,N-dimethylmethylamine (90mg, 0.30mmol) to a 5mL microwave tube , bispinacol borate (91mg, 0.36mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (22mg, 0.03mmol), potassium acetate (88mg, 0.90 mmol), 1,4-dioxane (2 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 120 °C for 30 min.
  • bispinacol borate 9mg, 0.36mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium 22mg, 0.03mmol
  • potassium acetate 88mg, 0.90 mmol
  • 1,4-dioxane (2
  • Step 2 Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (60mg, 0.15mmol) to a 5mL microwave tube, N, N-Dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroyl) Alk-2-yl)phenyl)methanamine (185 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.4 mL), purged with nitrogen for 1 min, and reacted at 100 °C for 1 h in a microwave reactor.
  • N N-Dimethyl-1-(2-(tetrahydro-2H-pyr
  • Step 1 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (160mg, 0.396mmol) and di-tert-butyl dicarbonate (305mg , 1.40mmol) was suspended in dichloromethane (10mL) at room temperature, added N,N-diisopropylethylamine (206mg, 1.60mmol) and 4-dimethylaminopyridine (8mg, 0.06mmol), the reaction was stirred at room temperature 18h. The reaction solution was concentrated, and water (10 mL) was added, followed by extraction with ethyl acetate (50 mL).
  • Step 2 Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl)amino)iso to a 50mL round-bottomed flask Quinoline (150 mg, 0.25 mmol), bispinacol borate (126 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27 mg, 0.038 mmol) ), potassium acetate (74 mg, 0.75 mmol), N,N-dimethylformamide (4 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 3 hours.
  • Step 3 1-(6-Chloro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethylamine (65mg, 0.25mmol), 7- (7-Fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (280mg, crude), potassium carbonate (103mg, 0.75mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy - Biphenyl (10 mg, 0.025 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II
  • Step 1 Dissolve tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate (35 mg, 0.1 mmol) in dichloromethane (0.2 mL), add trifluoroacetic acid dropwise with stirring (0.2 mL). The reaction was completed at room temperature for 2 hours. After the reaction solution was concentrated, it was dissolved in dichloromethane (1 mL), and 3 drops of aqueous formaldehyde solution were added to the system. After the reaction was stirred for 15 minutes, sodium triacetylborohydride (64 mg, 0.3 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction was completely converted.
  • Step 2 In a 10 mL sealed tube, 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (60 mg, 0.1 mmol), 5-bromo-2-(1-methylpiperidine) -4-yl)thiazole (30 mg, crude product) was dissolved in 1,4-dioxane (0.8 mL), an aqueous solution of potassium carbonate (41 mg, 0.3 mmol) (0.2 mL) and [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (7 mg, 0.01 mmol).
  • Step three 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(2-(1-methylpiperidin-4-yl)thiazol-5-yl)- 1-(Bis(tert-butyloxycarbonyl)amino)isoquinoline (70 mg, crude) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added with stirring. The reaction was stirred at room temperature for 4 hours.
  • Step 2 3-(3,6-Dihydro-2H-pyran-4-yl)thiophene-2-carbaldehyde (1.7g, 8.76mmol) and methylamine hydrochloride (2.96g, 43.80mmol) were suspended in acetonitrile (40 mL), sodium cyanoborohydride (1.1 g, 17.52 mmol) was added, and the reaction was allowed to react at room temperature for 24 hours. Adjust the pH of the reaction solution to 10 with 1M sodium hydroxide solution, spin off most of the acetonitrile, and extract with dichloromethane (40 mL ⁇ 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step six ((5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)methyl)(methyl)carbamate (1.25g, 3.20mmol) was dissolved in To formic acid (10 mL), 37% aqueous formaldehyde solution (4 mL) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 Add 1-(5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)-N,N-dimethylmethylamine (61mg, 0.20 mmol), bispinacol borate (76 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate ( 59 mg, 0.60 mmol), N,N-dimethylformamide (1.5 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 100 °C for 1 h.
  • Step 8 7-Fluoroimidazo[1,2-a]pyridine (3.0g, 22.06mmol) was suspended in acetonitrile (50mL), and N-bromosuccinimide (4.12g, 23.16mmol) was added under ice bath , and the reaction was stirred under ice bath for 1 h.
  • the reaction solution was added with saturated sodium thiosulfate (30 mL), saturated sodium bicarbonate (30 mL) and water (30 mL), and extracted with dichloromethane (50 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step 9 3-Bromo-7-fluoroimidazo[1,2-a]pyridine (3.0 g, 13.95 mmol) and isopropanol pinacol boronate (7.78 g, 41.85 mmol) were dissolved in tetrahydrofuran (60 mL) , isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (21.50mL, 27.90mmol, 1.3M) was added dropwise at 0°C under nitrogen protection, and the reaction was stirred at 0°C for 2h.
  • Step ten add 3-bromo-1,6-naphthyridine (700mg, 3.13mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaboran-2-yl)imidazo[1,2-a]pyridine (4.0 g, crude), sodium carbonate (1.33 g, 12.52 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (227 mg, 0.31 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, and reacted at 100° C. for 4 hours.
  • Step eleven 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,6-naphthyridin-5-amine (685 mg, 2.45 mmol) was dissolved in N,N-dimethyl N-iodosuccinimide (606 mg, 2.70 mmol) was added to N-iodosuccinimide (20 mL) in an ice bath, and the reaction was stirred at room temperature for 24 hours.
  • Step 12 add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-8-iodo-1,6-naphthyridin-5-amine (40 mg, 0.10 mmol), N,N-dimethyl-1-(3-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)thiophen-2-yl)methanamine (130 mg, crude), potassium carbonate (41 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (7 mg, 0.01 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C.
  • Step 2 Dissolve 2-(2-chloroacetyl)pyrrolidine-1-carboxylate tert-butyl ester (10g, 40.4mmol) in ethanol (200mL), add thiourea (3.07g, 40.4mmol) at room temperature, heat to The reaction was stirred at 90°C for 3 hours.
  • Step 4 Dissolve tert-butyl 2-(2-bromothiazol-4-yl)pyrrolidine-1-carboxylate (66.2 mg, 0.20 mmol) in dioxane (10 mL) and water (2 mL) at room temperature Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), under nitrogen The reaction was stirred at 100°C for 2 hours.
  • Step 2 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL), and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), stirred for 20 minutes, added acetic acid (5 mL), stirred at room temperature for 16 hours, and added sodium cyanoborohydride ( 260.8 mg, 4.14 mmol).
  • Step 3 2-Bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (49.4 mg, 0.20 mmol) was dissolved in dioxane (10 mL) and water (2 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-di Methoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), the reaction was stirred at 100 °C for 2 hours under nitrogen protection.
  • Step 4 2-(1-(bis(tert-butyloxycarbonyl)amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (56mg, 0.09mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (2mL) was added, and the reaction was carried out at room temperature for 1 The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (trifluoroacetic acid method) to obtain 2-(1-amino-7-(7-fluoroimidazo[1, 2-a]pyridin-3-yl)isoquinolin-4-yl)-N-methyl-4,5,6,7-tetrahydrobenzo[d]thia
  • Step 1 Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (900mg, 2.63mmol) was dissolved in dichloromethane ( 5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated, adjusted to pH 8 with saturated sodium bicarbonate (30 mL), a solid was precipitated, filtered, the filter cake was washed with water (10 mL), and dried in vacuo to obtain 2-amino-5-(tetrahydro-2H-pyran-4- (395 mg, yield: 62%), white solid.
  • ES-API: [M+H] + 243.1.
  • Step 2 copper bromide (950mg, 4.26mmol) was dissolved in acetonitrile (6mL), tert-butyl nitrite (219mg, 2.13mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5-( A suspension (7 mL) of methyl tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (345 mg, 1.42 mmol) in acetonitrile was stirred at 60°C for 2 hours. The reaction solution was poured into 1M aqueous sodium hydroxide solution (20 mL), and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 3 Methyl 2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (285 mg, 0.93 mmol) was dissolved in tetrahydrofuran (5 mL), and hydroboration was added dropwise under ice bath A solution of lithium in tetrahydrofuran (0.93 mL, 1.86 mmol, 2.0 M), the reaction was stirred under an ice bath for 30 minutes and at room temperature for an additional 2 hours. The reaction was quenched with water (8 mL) and 1.0 M dilute hydrochloric acid (4 mL) under ice bath, and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 4 (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (230 mg, 0.83 mmol) and triethylamine (210 mg, 2.08 mmol) were dissolved in dichloro Methane (10 mL) was added dropwise with methanesulfonyl chloride (142 mg, 1.24 mmol) under an ice bath, and the reaction was stirred under an ice bath for 2 hours.
  • Step 5 Methyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylmethanesulfonate (295 mg, 0.83 mmol) was dissolved in tetrahydrofuran (5 mL), room temperature A 2.0M solution of dimethylaminetetrahydrofuran (10 mL, 20.0 mmol) was added under it, and the reaction was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 6 Add 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N,N-dimethylmethanamine (45mg, 0.15mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (200 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, at 110 °C in a microwave reactor The reaction was carried out for 45 minutes.
  • Step 7 4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1 ,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (35 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added , at room temperature for 1 hour.
  • Step 1 copper bromide (637.1 mg, 2.85 mmol) was dissolved in anhydrous acetonitrile (5 mL), tert-butyl nitrite (392.4 mg, 3.81 mmol) was added, 2-amino-6 was added after stirring at room temperature for 2 minutes, 7-Dihydrobenzo[d]thiazol-4(5H)-one (400 mg, 2.38 mmol), the reaction solution was stirred at room temperature for 2 hours.
  • Step 2 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL) and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), after stirring for 20 minutes, acetic acid (5 mL) was added, and after stirring at room temperature for 16 hours, sodium cyanoborohydride ( 260.8 mg, 4.14 mmol).
  • Step 4 2-Bromo-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (52.2mg, 0.20mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2 ',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), phosphoric acid Potassium (127.2 mg, 0.60 mmol), and the reaction was stirred at 100 °C
  • Step 1 (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (300 mg, 1.08 mmol) was dissolved in dichloromethane (25 mL), added under ice bath Dess-Martin oxidizer (572 mg, 1.35 mmol) and the reaction was stirred at room temperature for 3 hours. Dichloromethane (25 mL) was added to the reaction solution, washed with saturated sodium bicarbonate solution (25 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 55mg, 0.14mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (147 mg, crude), potassium carbonate (58 mg, 0.42 mmol), [1,1'-bis(bis(bis)) Phenylphosphine)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor for 110 The reaction was carried out at
  • Step five (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7- Di-tert-butyl (7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (27 mg, 0.034 mmol) was dissolved in methanol (1 mL) and 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 16.0 mmol) was allowed to react at room temperature for 18 hours.
  • Step 2 Into a 5mL microwave tube, add: 1-(2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N,N-dimethylmethanamine (50mg, 0.17mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (128 mg, crude), potassium carbonate (71 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (13 mg, 0.017 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C.
  • Step 3 4-(4-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridine -3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (37 mg, 0.05 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added, The reaction was carried out at room temperature for 18 hours.
  • Step 1 2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carbaldehyde (500mg, 1.81mmol) and (S)-2-methylpropane-2-sulfinamide ( 439 mg, 3.62 mmol) was dissolved in dichloromethane (25 mL), titanium tetraethoxide (1.03 g, 4.53 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Saturated brine (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL ⁇ 2).
  • Step 2 (S,E)-N-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylene)-2-methylpropane-2- Sulfonamide (570 mg, 1.50 mmol) was dissolved in tetrahydrofuran (15 mL), and 0.5 M (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide tetrahydrofuran solution was added dropwise at -78°C under nitrogen protection (1.05 mL, 0.53 mmol) and the reaction was stirred at -78 °C for 30 minutes.
  • Step 4 (S)--2-Bromo-4-(pyrrolidin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole trifluoroacetate (2.5g, crude product) Dissolved in dichloromethane (15 mL), triethylamine (800 mg, 7.91 mmol) and di-tert-butyl dicarbonate (650 mg, 7.91 mmol) were added at 0°C, and the reaction was stirred at room temperature for 1 hour. Dichloromethane (25 mL) was added to the reaction solution, washed successively with water (10 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Add (S)-2-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)pyrrolidine-1-carboxylic acid tert-butyl into a 5mL microwave tube Ester (60 mg, 0.14 mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (130 mg, crude), potassium carbonate (60 mg, 0.43 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor The reaction was carried out at 110
  • Step 1 1-benzyl 2-methylpiperidine-1,2-dicarboxylate (5.0 g, 18.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), chloroiodomethane (15.9 g, 90.5 mmol) was added, Stir at room temperature for 2 minutes, cool down to -78 ° C and stir for 10 minutes, slowly add lithium diisopropylamide solution (45.3 mL, 2 M, 90.5 mmol) dropwise within 1.5 hours, keep the temperature below -70 ° C during the period, and drop after dropping in React at -78°C for 1 hour, then add acetic acid/tetrahydrofuran mixed solution (1:3, 80mL), stir at -78°C for 10 minutes, warm to room temperature, pour the reaction solution into water (50mL), add acetic acid Extracted with ethyl ester (200 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated by filtration and purified by si
  • Step 2 Benzyl 2-(2-chloroacetyl)piperidine-1-carboxylate (3.0g, 10.1mmol) was dissolved in ethanol (50mL), thiourea (1.5g, 20.2mmol) was added at room temperature, and the reaction Heat to 90°C and stir for 3 hours.
  • Step 3 Cuprous bromide (607.1 mg, 4.25 mmol) was dissolved in acetonitrile (5 mL), tert-butyl nitrite (583.0 mg, 5.66 mmol) was added at room temperature, and the mixture was stirred for 5 minutes and then added with 2-(2-amino) Thiazol-4-yl)piperidine-1-carboxylate benzyl ester (900 mg, 2.83 mmol), the reaction solution was stirred at room temperature for 3 hours.
  • Step 4 Benzyl 2-(2-bromothiazol-4-yl)piperidine-1-carboxylate (137.5 mg, 0.36 mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL) at room temperature 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol) under nitrogen The reaction was stirred at 100°C for 2 hours under
  • Step 1 7-Chloroisoquinolin-1-amine (1.0g, 5.60mmol) was dissolved in acetonitrile (20mL), N-bromosuccinimide (1.0g, 5.60mmol) was added under ice bath, and the reaction Stir under ice bath for 2 hours. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-5%) to obtain the target product 4-bromo-7-chloroisoquinolin-1-amine (1.3 g, yield 90.2%) as pale yellow solid.
  • ES-API: [M+H] + 257.0, 259.0.
  • Step 2 4-Bromo-7-chloroisoquinolin-1-amine (1.3g, 5.05mmol) and di-tert-butyl dicarbonate (4.41g, 20.19mmol) were suspended in dichloromethane (25mL), added at room temperature Triethylamine (2.55 g, 25.24 mmol) and 4-dimethylaminopyridine (62 mg, 0.51 mmol), and the reaction was stirred at room temperature for 18 hours. Dichloromethane (30 mL) and water (15 mL) were added to the reaction solution, the organic layer was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Add (4-bromo-7-chloroisoquinolin-1-yl) di-tert-butyl iminodicarbonate (350 mg, 0.77 mmol), bis(pinacol) diboron to a 50 mL round-bottomed flask (388 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (56 mg, 0.076 mmol), potassium acetate (225 mg, 2.29 mmol), 1,4-dioxo Hexacyclic (15 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 2 hours.
  • Step 4 tert-butyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (170 mg, 0.43 mmol), (4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-7-chloroisoquinolin-1-yl)di-tert-butyl iminodicarbonate (720 mg, crude), potassium carbonate (180 mg, 1.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol), 1,4-dioxane
  • the ring (16 mL) and water (4 mL) were replaced with nitrogen three times, and the reaction was carried out at 110°C for 2 hours.
  • Step 5 Add (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 to a 5mL microwave tube -yl)-7-chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (30 mg, 0.044 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.087 mmol), potassium carbonate (18 mg, 0.13 mmol), 2-dicyclohexyl Phosphine-2',6'-dimethoxy-biphenyl (5mg, 0.007mmol), Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl yl)(2'-a
  • reaction solution was concentrated, 7.0M ammonia methanol solution (5mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-( 1-Methyl-1H-pyrro[2,3-b]pyridin-4-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4- yl)thiazol-2-yl)isoquinolin-1-amine (Z161, 11 mg, yield 58.2%), pale yellow solid.
  • Step 1 Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (250mg, 1.06mmol), 1,5-dimethyl-1H- Pyrazole-4-boronic acid pinacol ester (553g, 2.66mmol), potassium carbonate (406mg, 2.94mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78mg, 0.11 mmol), 1,4-dioxane (15 mL) and water (3 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours.
  • Step 2 Dissolve 3-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (185mg, 0.70mmol) To N,N-dimethylformamide (6 mL) was added N-iodosuccinimide (173 mg, 0.77 mmol) under an ice bath, and the reaction was stirred at 0° C. for 15 minutes. Water was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried in vacuo.
  • Step 3 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-iodo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (120mg, 0.32 mmol) and di- tert- butyl dicarbonate (209 mg, 0.96 mmol) were suspended in dichloromethane (6 mL), triethylamine (97 mg, 0.96 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added at room temperature , the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated.
  • Step 4 Add 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1(2H to a 5mL microwave tube )-carboxylate tert-butyl ester (40mg, 0.084mmol), bis(pinacol)diboron (43mg, 0.17mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (9 mg, 0.013 mmol), potassium acetate (25 mg, 0.25 mmol), N,N-dimethylformamide (1 mL), purged with nitrogen for 1 minute, reacted at 110° C.
  • Step 5 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (50mg) to a 5mL microwave tube , 0.13mmol), 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, crude), potassium carbonate (53 mg, 0.38 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.013 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, placed in a microwave The reaction was carried out in the reactor at 110°C for 1 hour.
  • Step six 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-( 1,5-Dimethyl-1H-pyrazol-4-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (9 mg, 0.014 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride dioxane solution (5 mL, 20.0 mmol), and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 Take 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxyl tert-butyl acid (0.06g, 0.116mmol), pinacol diboronate (0.055g, 0.22mmol), potassium acetate (21mg g, 0.22mmol), [1,1'-bis(diphenylphosphine)di Ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane (5 mL) and stirred at 110°C for 2 hours.
  • Step 2 Take (1-(tert-butoxycarbonyl)-3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrrolo[4,3, 2-ij]isoquinolin-6-yl)boronic acid (38 mg, 0.08 mmol), 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N , N-dimethylmethylamine (42 mg, 0.14 mmol), potassium carbonate (22 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5 mg ) was dissolved in 1,4-dioxane/water (2.5 ml) and stirred at 110°C for 2 hours.
  • Step 3 Take 6-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-(7-fluoroimidazolium [1,2-a]pyridin-3-yl)pyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (10 mg, 0.016 mmol) was dissolved in anhydrous dichloride Methane (0.5 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was carried out at room temperature for 2 hours.
  • Step 1 2,2-Dimethoxyethane-1-amine (4.75g, 45.22mmol) was dissolved in methanol (90mL) and 3-bromo-2-methylbenzaldehyde (9.0g, 45.22mmol) was added at room temperature , the reaction was stirred at 70 °C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.71 g, 45.22 mmol) was added in portions, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated to remove the solvent, ice water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL ⁇ 2).
  • Step 2 Cool chlorosulfonic acid (28.5 mL, 433.74 mmol) to 0 °C, slowly add N-(3-bromo-2-methylbenzyl)-2,2-dimethoxyethane-1- Amine (12.5 g, 43.37 mmol) over 30 minutes. The reaction was stirred at 100°C for 2 hours, then cooled and poured into ice (250 g), filtered, and the filtrate was cooled in an ice bath and adjusted to pH 14 with 50% sodium hydroxide solution. Extracted with dichloromethane (150 mL ⁇ 2), the combined organic layers were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 7-Bromo-8-methylisoquinoline (4.8g, 21.61mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (7.90g, 38.90mmol) was added under ice bath, The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, saturated sodium bicarbonate solution (250 mL), and extracted with 10% methanol/dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 4 Phosphorus oxychloride (41.0 mL, 441.03 mmol) was cooled to 0° C., 7-bromo-8-methylisoquinoline 2-oxide (4.2 g, 17.64 mmol) was added in batches, and the reaction was carried out at room temperature. The reaction was stirred for 15 minutes and then at 105°C for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL ⁇ 3), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 7-Bromo-1-chloro-8-methylisoquinoline (1.1 g, 4.29 mmol) was suspended in carbon tetrachloride (70 mL), and N-bromosuccinimide (840 mg, 4.72 mmol) was added. ), benzoyl peroxide (277 mg, 0.86 mmol), and the reaction was refluxed for 6 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 6 (2,4-Dimethoxyphenyl)methanamine (1.50g, 8.94mmol) and potassium carbonate (0.74g, 5.37mmol) were dissolved in N,N-dimethylformamide (25mL), in A solution of 7-bromo-8-(bromomethyl)-1-chloroisoquinoline in N,N-dimethylformamide (1.5 mL) was added dropwise under an ice bath, and the reaction was stirred at 0°C for 2 hours. The reaction solution was added with water (60 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 7 3-Bromo-1-(3,4-dimethylbenzyl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (1.1 g, 2.855 mmol) was added with trifluoro Acetic acid (30 mL), and the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated, 7M ammonia methanol (30 mL) was added, and it was concentrated again. The obtained crude product was purified by flash silica gel column (methanol solution/dichloromethane: 0-7%) to obtain the target product 3-bromo-1,2-dihydropyrro[4,3,2-ij]isoquinoline (620 mg, produced rate 92.4%), light brown solid.
  • ES-API: [M+H] + 235.0, 237.0.
  • Step 8 Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (320mg, 2.86mmol), 7-fluoro-3-(4,4 to a 250mL round-bottomed flask , 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)imidazo[1,2-a]pyridine (3.2g, crude), sodium carbonate (433mg, 4.08mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.14 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, the reaction The reaction was carried out at 100°C for 4 hours.
  • Step 9 3-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinoline (175mg, 0.60mmol) Dissolved in N,N-dimethylformamide (6 mL), N-iodosuccinimide (149 mg, 0.66 mmol) was added under an ice bath, and the reaction was stirred at 0°C for 30 minutes.
  • Step 11 Add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1 to a 5mL microwave tube (2H)-tert-butyl carboxylate (100 mg, 0.19 mmol), bis(pinacol)diboron (98 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (21 mg, 0.03 mmol), potassium acetate (57 mg, 0.58 mmol), N,N-dimethylformamide (2 mL), purged with nitrogen for 1 minute, and reacted at 110° C. for 1 hour in a microwave reactor.
  • 2H 2-tert-butyl carboxylate
  • bis(pinacol)diboron 98 mg, 0.39 mmol
  • Step 12 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (120 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min , in a microwave reactor at 110 °C for 1 hour.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dry dioxane (4 mL), and bis-borate pinacol ester (505.9 mg, 1.99 mg) was added at room temperature mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol) and potassium acetate (325.4 mg, 3.32 mmol), oil bath 100°C under nitrogen protection The reaction was stirred for 18 hours.
  • ES-API: [M+H] + 207.2.
  • Step 2 (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (153.2 mg, 0.74 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 5- Bromo-1,2-dimethyl-1H-imidazole (155.4 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50.4 mg, 0.07 mmol), Potassium carbonate (204.2 mg, 1.48 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection.
  • Step 4 7-(1,2-Dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-amine (90.5mg, 0.24mmol) was dissolved in dichloromethane (2.0 mL), di-tert-butyl dicarbonate (209.3 mg, 0.96 mmol), triethylamine (121.2 mg, 1.20 mmol) and 4-dimethylaminopyridine (5.8 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature React for 2 hours.
  • Step 5 tert-butyl (7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamic acid tert-butyl ester (75.3 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and bis(pinacol borate) (66.0 mg, 0.26 mmol), [1,1'-bis(diphenylphosphine) was added at room temperature ) ferrocene] palladium dichloride (14.4 mg, 0.02 mmol), potassium acetate (25.5 mg, 0.26 mmol), nitrogen was replaced, and the reaction was stirred at 90° C.
  • Step seven ((2-(1-amino-7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinolin-4-yl)-5-(tetrahydro- 2H-Pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (35.3 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL), the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dioxane (4.0 mL) and water (1.0 mL), and (1,5-dioxane) was added at room temperature Methyl-1H-pyrazol-4-yl)boronic acid (278.6 mg, 1.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol), Potassium carbonate (458.2 mg, 3.32 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection.
  • ES-API: [M+H] + 257.2.
  • Step 3 7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (231.2 mg, 0.60 mmol) was dissolved in dichloromethane (6.0 mL), di-tert-butyl dicarbonate (523.2 mg, 2.40 mmol), triethylamine (303.0 mg, 3.00 mmol) and 4-dimethylaminopyridine (14.6 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature The reaction was carried out for 5 hours.
  • Step 4 (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl)-carbamic acid tert-butyl ester (265.7 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), bis(pinacol borate) (137.2 mg, 0.54 mmol), [1,1'-bis(diphenylene) were added at room temperature phosphine) ferrocene] palladium dichloride (36.0 mg, 0.05 mmol), potassium acetate (441.0 mg, 4.50 mmol), nitrogen was replaced, and the reaction was stirred at 90° C. in a microwave for 2 hours under nitrogen protection.
  • N,N-dimethylformamide 2.0 mL
  • bis(pinacol borate) 137.2 mg, 0.54 mmol
  • [1,1'-bis(diphenylene) were added at room temperature phosphine) ferrocen
  • Step 5 (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl))isoquinolin-1-yl)-carbamic acid tert-butyl ester (195.3 mg, 0.33 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL) ), tert-butyl((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.5 mg) was added at room temperature , 0.25mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21.6mg, 0.03mmol), potassium carbonate (69.0mg, 0.50mmol), microwave 110 under nitrogen protection The reaction was stirred for 2 hours.
  • Step six tert-butyl ((2-(1-amino-7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.6 mg, 0.17 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoromethane was added Acetic acid (2.0 mL), the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 Under nitrogen protection, (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.07 mmol), (2,3-lutidine-4-yl)boronic acid ( 22mg, 0.15mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- A mixed solution of 2-yl)palladium(II) (5 mg, 0.01 mmol) and potassium carbonate (30 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 °C
  • reaction solution was poured into ethyl acetate (10 mL), and washed with saturated brine (5 mL) and water (5 mL) in this order.
  • the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give (tert-butoxycarbonyl) (4-(4-(((tert-butoxycarbonyl) as a yellow oily liquid.
  • Step 2 Under ice bath conditions, trifluoroacetic acid (0.5 mL) was added dropwise to (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl) -5-(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(2,3-lutidine-4-yl)isoquinolin-1-yl)carbamic acid tert. A solution of butyl ester (40 mg, 53 ⁇ mol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (40.0 mg, 0.06 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (4,5- Lutidine-3-yl)boronic acid (10.5 mg, 0.07 mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (16.6 mg, 0.12 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 560.2.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), (4-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 546.2.
  • Step 2 (2-(1-Amino-7-(4-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- tert-Butyl 4-yl)methyl)(methyl)carbamate (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (5-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 546.2.
  • Step 2 ((2-(1-Amino-7-(5-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole -4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours .
  • Step 1 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (40 mg, 0.2 mmol), potassium carbonate (27 mg, 0.2 mmol), [1,1'-bis( Diphenylphosphine)ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours.
  • Step 2 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-5-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours.
  • Step 2 Take 1,3-bis(1,1-dimethylethyl)2-(7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Boran-2-yl)isoquinolinyl)iminodicarbonate (400 mg, 0.8 mmol), tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate (310 mg, 0.8 mmol), potassium carbonate (0.22 g, 1.6 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (50 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours.
  • Step 3 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)pyrazole tert-butyl (40 mg, 0.2 mmol), carbonic acid and (27 mg, 0.2 mmol), 1,1-bis(diphenyl) Phosphino)ferrocene palladium dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110° C.
  • Step 4 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours.
  • Step 1 4-Bromopyridin-3-ol (500mg, 2.874mmol), bromocyclopropane (1.151mL, 14.368mmol), potassium carbonate (1189.66mg, 8.621mmol), potassium iodide (95.40mg, 0.575mmol) were added into N-methylpyrrolidone (8mL), the microwave reaction was stirred at 180°C for 5 hours, after the reaction was completed, water (30mL), ethyl acetate (30mLx3) were added, the organic phases were combined, washed with saturated brine (30mLx1), and anhydrous sodium sulfate Dry, filter and concentrate to obtain crude product.
  • Step 2 Dissolve 4-bromo-3-(cyclopropoxy)pyridine (80mg, 0.374mmol) and pinacol biboronate (189.81mg, 0.747mmol) in 1,4-dioxane (8mL) ), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30.52 mg, 0.037 mmol) and potassium acetate (73.36 mg, 0.747 mmol) were added. Under nitrogen, stir at 90°C for 3 hours.
  • Step 3 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 3-cyclopropoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)pyridine (120 mg, crude) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), chlorine (2- Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) catalyst ( 12.55 mg, 0.017 mmol) and potassium carbonate (36.09
  • Step 4 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(3-cyclopropoxypyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (20 mg, 0.025 mmol) was dissolved in dichloromethane (2 mL) and then added Trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour.
  • the system was replaced with nitrogen three times and then protected with a nitrogen balloon.
  • the reaction was carried out at 100°C for 2 hours, the reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified with a flash silica gel column (ethyl acetate: petroleum ether).
  • Step 2 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methoxypyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), tris Fluoroacetic acid (3 mL) and dichloromethane (6 mL) were stirred at room temperature for 30 minutes.
  • Step 1 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 25mL three-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.073 mmol), 3-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (31.79mg, 0.145mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.45mg, 0.015mmol), potassium carbonate (30.08mg
  • Step 2 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methylpyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), trifluoro Acetic acid (3 mL) and 6 mL of dichloromethane (6 mL) were stirred at room temperature for 30 minutes.
  • Step 2 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(2-methylpyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.040 mmol) was dissolved in dichloromethane (2 mL) followed by the addition of trifluoro Acetic acid (1 mL), stirred at room temperature for 1 hour.
  • Step 1 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)pyrazole (38.64 mg, 0.174 mmol) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), added Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (12.55 mg, 0.017 mmol) and
  • Step 2 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinolin-1-yl)iminodicarbonate (40 mg, 0.053 mmol) was dissolved in dichloromethane (5 mL) ), then trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (300mg, 1.25mmol) and 1-methylimidazole-5-boronic acid pinacol ester (1.04g, 4.98mmol) were dissolved in 1,4- Dioxane (20 mL) and water (4 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (137 mg, 0.19 mmol), potassium carbonate (516 mg, 3.73 mmol) , nitrogen was replaced three times, and the reaction was stirred at 100 °C for 18 h.
  • Step 2 8-Fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (190mg, 0.78mmol) was dissolved in N,N-dimethylformamide (6mL) , N-iodosuccinimide (229 mg, 1.02 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 18 hours.
  • Step 3 8-Fluoro-4-iodo-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (260mg, 0.71mmol) and di-tert-butyl dicarbonate (616mg, 2.82 mmol) was suspended in dichloromethane (15 mL), triethylamine (357 mg, 4.07 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours.
  • Step 5 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (60mg) to a 5mL microwave tube , 0.15 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(1-methyl- 1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (180 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, in a microwave reactor at 110 °C The reaction was carried out for 45 minutes.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.04 mmol) was dissolved in methanol (1 mL), 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 20.0 mmol) was reacted at room temperature for 18 hours.
  • Step 1 Add 7-bromoisoquinolin-1-amine (510mg, 2.28mmol), pyridin-4-ylboronic acid (562mg, 4.57mmol), 1-bis(diphenylphosphino) to a 25mL three-necked round bottom flask ) ferrocene palladium dichloride (167 mg, 0.22 mmol), potassium carbonate (948 mg, 6.85 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted at 100°C for 2 hours.
  • Step 2 Add 7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 2.26mmol), N-iodosuccinimide (661mg, 2.94mmol) and Dimethylformamide (10 mL) was reacted at 100°C for 1 hour under nitrogen protection. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500 mg, yield: 63.7%).
  • ES-API: [M+H] + 348.0
  • Step 3 add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 1.44mmol), di-tert-butyl dicarbonate (1.26g, 5.76mmol) to a 25mL three-necked round bottom flask ), triethylamine (728 mg, 7.2 mmol), 4-dimethylaminopyridine (17.6 mg, 0.144 mmol), dichloromethane (10 mL), the system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted overnight at room temperature .
  • Step 4 Add ⁇ [4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl] ⁇ [(2-methylpropan-2-yl)oxy] to a 25mL three-necked round bottom flask Carbonyl ⁇ amino ⁇ carboxylate tert-butyl ester (150 mg, 0.274 mmol), pinacol diboronate (139.2 mg, 0.545 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30 mg, 0.04 mmol), potassium acetate (80.68 mg, 0.82 mmol), dioxane (10 mL), the system was replaced with nitrogen three times, and then reacted for 3 hours under the protection of a nitrogen balloon at 90 degrees.
  • Step 6 Add (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl) to a 5mL single-necked round-bottomed flask ) thiazol-2-yl)-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl (100 mg, 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (200 mg, 0.83 mmol) and 4-pyridineboronic acid (204 mg, 1.66 mmol) were dissolved in 1,4-dioxane (10 mL) and water ( 2.5 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.08 mmol), potassium carbonate (344 mg, 2.49 mmol), nitrogen was replaced three times, and the reaction was carried out at 100 °C Stir for 2 hours. The reaction solution was concentrated.
  • Step 4 Add (8-fluoro-4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (150mg, 0.27mmol) to a 50mL round bottom flask , bis(pinacol)diboron (135mg, 0.53mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29mg, 0.04mmol), potassium acetate (78mg, 0.80 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours.
  • Step 5 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-4- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, were reacted in a microwave reactor at 110° C.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (75 mg, 0.12 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL) was added , 20.0 mmol), the reaction was reacted at room temperature for 18 hours.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (300 mg, 1.25 mmol) and 3-pyridineboronic acid (306 mg, 2.49 mmol) were dissolved in 1,4-dioxane (12 mL) and water ( 3 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (91 mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), nitrogen was replaced three times, and the reaction was stirred at 100 °C 2 hours. The reaction solution was concentrated.
  • Step 2 8-Fluoro-7-(pyridin-3-yl)isoquinolin-1-amine (265mg, 1.11mmol) was dissolved in N,N-dimethylformamide (12mL) and N- Iodosuccinimide (324 mg, 1.44 mmol) and the reaction was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 8-fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, yield 98.9%), light brown solid.
  • ES-API: [M+H] + 356.0.
  • Step 3 8-Fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, 1.10 mmol) and di-tert-butyl dicarbonate (956 mg, 4.38 mmol) were suspended in dichloro Methane (25 mL), triethylamine (554 mg, 5.48 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours.
  • Step 5 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 70 mg, 0.18 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-3- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (13 mg, 0.018 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, reacted in a microwave reactor at 110° C.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (90 mg, 0.12 mmol) was dissolved in methanol (1 mL), and a 4.0 M solution of hydrogen chloride in dioxane was added ( 5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (1.5g, 4.45mmol) and 2-(2,5-dihydrofuran-3-yl)- 4,4,5,5-Tetramethyl-1,3,2-dioxaborane (0.96 g, 4.89 mmol) was dissolved in 2-methyltetrahydrofuran (8 mL) and water (2 mL), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.33 g, 0.45 mmol), potassium carbonate (1.84 g, 13.35 mmol), nitrogen purged three times, and the reaction was stirred at 85°C for 3 hours.
  • Step 3 Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (1.25g, 3.81mmol) was dissolved in dichloromethane (10mL), added with trichloromethane Fluoroacetic acid (10 mL), the reaction was allowed to react at room temperature for 3 hours.
  • Step 4 copper bromide (2.28g, 10.18mmol) was dissolved in acetonitrile (15mL), tert-butyl nitrite (525mg, 5.09mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5 was added dropwise - A suspension of methyl (tetrahydrofuran-3-yl)thiazole-4-carboxylate (775 mg, 3.40 mmol) in acetonitrile (20 mL), the reaction was stirred at 60°C for 2 hours.
  • Step 5 Methyl 2-bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (300 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL), and 2.0 M lithium borohydride solution in tetrahydrofuran was added dropwise under ice bath (1.0 mL, 2.0 mmol) and methanol (66 mg, 2.06 mmol), the reaction was stirred under an ice bath for 30 minutes, then at room temperature for 2 hours. The reaction solution was quenched with water (6 mL) and 1.0 M dilute hydrochloric acid (3 mL) under ice bath, and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 6 2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methanol (470mg, 1.78mmol) was dissolved in dichloromethane (25mL), Dess-Martin oxidant (906mg) was added under ice bath , 2.14 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with dichloromethane (40 mL), washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 2-Bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carbaldehyde (200 mg, 0.76 mmol) and methylamine hydrochloride (258 mg, 3.82 mmol) were suspended in 1,2-dichloromethane (12 mL) ) and methanol (4 mL), sodium triacetylborohydride (322 mg, 1.53 mmol) was added, and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was adjusted to pH 10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50 mL).
  • Step 8 1-(2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N-methylmethanamine (205mg, crude) and triethylamine (112mg, 1.11mmol) were dissolved in two Chloromethane (10 mL) was added with di-tert-butyl dicarbonate (210 mg, 0.96 mmol) under an ice bath, and the reaction was stirred at room temperature for 1 hour.
  • Step 9 Add ((2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (150 mg, 0.40 mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (450 mg, crude), potassium carbonate (165 mg, 1.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (29 mg, 0.04 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, and reacted in a microwave reactor at 110° C.
  • Step ten (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazole[ 1,2-a]Pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (130 mg, 0.17 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane was added (4 mL, 16.0 mmol) and the reaction was allowed to react for 2 hours at room temperature.
  • reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(7-fluoroimidazo[1,2-a]pyridine-3- yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)isoquinolin-1-amine (Z160, 45 mg, 54.8% yield), Pale yellow solid.
  • Step eleven 7-(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazole -2-yl)isoquinolin-1-amine (Z160, 40 mg, 0.084 mmol) was suspended in dichloromethane (5 mL), triethylamine (26 mg, 0.25 mmol) and di- tert- butyl dicarbonate (28 mg) were added at room temperature , 0.13 mmol), and the reaction was stirred at room temperature for 1 hour.
  • Step 12 (R)-(2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydrofuran -3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (12 mg, 0.02 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added ), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 2,2-Dimethoxyethane-1-amine (5.18g, 49.26mmol) was dissolved in methanol (100mL), 3-bromo-2-fluorobenzaldehyde (10g, 49.26mmol) was added at room temperature, The reaction was stirred at 70°C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.86 g, 49.26 mmol) was added portionwise, and the reaction was stirred at room temperature for 16 hours. Concentrate to remove the solvent, add ice water (300 mL), and extract with dichloromethane (100 mL ⁇ 3).
  • Step 2 Cool chlorosulfonic acid (31.8 mL, 482.63 mmol) to 0 °C, slowly add N-(3-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1-amine dropwise (14.1 g, 48.26 mmol) over 30 minutes.
  • the reactant was stirred at 100°C for 45 minutes, then cooled and poured into ice (300 g), filtered, the filtrate was cooled in an ice bath, and the pH was adjusted to 14 with 50% sodium hydroxide solution, and dichloromethane (150 mL ⁇ 2 ) extraction, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 3 7-Bromo-8-fluoroisoquinoline (5.5g, 24.33mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (9.88g, 48.66mmol) was added under ice bath, and the reaction The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, added to saturated sodium bicarbonate solution (200 mL), and extracted with 10% methanol/dichloromethane (100 mL ⁇ 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Add 7-bromo-8-fluoroisoquinolin-1-amine (1.0 g, 4.15 mmol), bis(pinacol)diboron (1.58 g, 6.22 mmol) to a 50 mL round-bottomed flask, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.30 g, 0.42 mmol), potassium acetate (1.22 g, 12.45 mmol), 1,4-dioxane (25 mL), The nitrogen was replaced three times, and the reaction was carried out at 95°C for 18 hours.
  • Step 6 Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (1.0 g, 3.82 mmol), (1-amino-8-fluoroisoquinolin-7-yl) to a 100 mL round-bottomed flask ) boric acid (2.65g, crude product), potassium carbonate (1.58g, 11.45mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (0.28g, 0.38mmol), 1,1'-bis(diphenylphosphino)ferrocene] 4-Dioxane (40 mL) and water (10 mL) were replaced with nitrogen three times, and the reaction was carried out at 100° C.
  • Step 7 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (730mg, 2.46mmol) was dissolved in N,N-dimethyl Formamide (20 mL), N-iodosuccinimide (720 mg, 3.20 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 3 hours.
  • Step 8 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (980 mg, 2.32 mmol) and di-tert-dicarbonate Butyl ester (2.03g, 9.28mmol) was suspended in dichloromethane (25mL), triethylamine (1.17g, 11.61mmol) and 4-dimethylaminopyridine (28mg, 0.23mmol) were added at room temperature, and the reaction was stirred at room temperature 18 hours.
  • Step 9 Add 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl) to a 50 mL round bottom flask ) amino) isoquinoline (150 mg, 0.24 mmol), bis(pinacol)diboron (122 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.036 mmol), potassium acetate (71 mg, 0.72 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours.
  • Step ten add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (80mg) to a 5mL microwave tube , 0.20 mmol), 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (230 mg, crude), potassium carbonate (85 mg, 0.61 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, react in microwave The reaction was carried out at 110°C for 45 minutes in a vessel.
  • Step 2 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(4-(dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4 -yl)thiazol-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (45 mg, 0.08 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride was added Dioxane solution (5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 N,N-diisopropylethylamine (6.48mL, 37.17mmol) and 50% ethyl acetate solution of 1-propylphosphoric anhydride (11.82g, 18.57mmol) were added to 3-bromo-6 -Chloro-2-picolinic acid (2.93 g, 12.39 mmol), tert-butylamine (1.56 g, 14.87 mmol) in dichloromethane (30 mL) solution, stirred at room temperature for 1 hour. After the reaction, it was quenched by adding saturated sodium carbonate solution (50 mL), and extracted with dichloromethane (30 mL ⁇ 3).
  • 1-propylphosphoric anhydride 11.82g, 18.57mmol
  • Step 2 Under nitrogen protection, 3-bromo-N-(tert-butyl)-6-chloropyridine amide (2.1 g, 7.02 mmol), (E)-1-ethoxyethylene-2-boronic acid pinacol ester (1.85g, 9.36mmol), tris(dibenzylideneacetone)dipalladium (0.33g, 0.36mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (0.30g, 0.72mmol) ) and potassium carbonate (2.99 g, 21.61 mmol) in 1,4-dioxane (30 mL) and water (7 mL) were stirred at 80°C for 1 hour.
  • Step 3 Add (E)-N-(tert-butyl)-6-chloro-3-(2-ethoxyvinyl)pyridineamide (700 mg, 2.48 mmol) to concentrated sulfuric acid (2 mL) under ice bath conditions. ), the temperature was raised to 110°C and stirred for 2 hours. Cool to room temperature and pour slowly into potassium hydroxide (4.23 g, 75.27 mmol) in ice water. Concentration gave 2-chloro-1,7-naphthyridin-8(7H)-one (450 mg, crude) as a yellow solid containing potassium sulfate.
  • ES-API: [M+H] + 181.1.
  • Step 4 Under nitrogen protection, 2-chloro-1,7-naphthyridin-8(7H)-one (450mg, 2.49mmol), 1,5-dimethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.11 g, 4.98 mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.04 mmol) and potassium carbonate (344 mg, 2.49 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100°C for 2 hours.
  • Step 5 Add phosphorus oxychloride (5 mL) to crude 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine-8(7H) under ice bath condition )-one (300 mg, 1.25 mmol), the temperature was raised to 100° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 6 Ammonia (8 mL, 122 mmol) was added to compound 8-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine (150 mg, 0.58 mmol) sulfolane (4 mL) solution, microwave reaction at 150 °C for 10 hours. After the reaction, the reaction solution was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL ⁇ 3) and washed with water (20 mL) successively.
  • Step 7 Add N-iodosuccinimide (226 mg, 1 mmol) to 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridin-8-amine (200 mg, 0.84 mmol) of a mixed solution of acetonitrile (4 mL) and N,N-dimethylformamide (0.4 mL), and stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium thiosulfate (20 mL) solution, and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 8 2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-iodo-1,7-naphthyridin-8-amine (270mg, 0.74mmol), di-tert-butyl dicarbonate A solution of ester (645 mg, 2.96 mmol), triethylamine (0.514 mL, 3.70 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight.
  • reaction solution was concentrated and purified by flash silica gel column (0-80% ethyl acetate/petroleum ether) to obtain 2-methylpropan-2-yl((2-(1,5-dimethylpyrazole-4) as a white solid -yl)-5-iodopyrido[3,4-b]pyridin-8-yl)(((2-methylprop-2-yl)oxy)carbonyl)amino)carboxylate (170 mg, yield 41%).
  • ES-API: [M+H] + 566.2.
  • Step 10 Under nitrogen protection, add (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)(methyl)carbamic acid tert-butyl ester (111mg) to the above reaction solution , 0.28 mmol), potassium carbonate (59 mg, 0.42 mmol) and water (0.4 mL), stirred at 100 °C for 2 hours. After completion of the reaction, the reaction solution was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL).
  • Step 11 Under ice bath conditions, add trifluoroacetic acid (0.5 mL) dropwise to (tert-butoxycarbonyl)(5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl )-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthalene A solution of tert-butyl pyridin-8-yl)carbamate (60 mg, 80 ⁇ mol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour.
  • Step 1 Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 4-methoxy-3-(4,4,4,5,5 to a 25mL three-necked round bottom flask) -Tetramethyl-1,3,2-boron-2-yl)pyridine (586mg, 2.49mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C.
  • Step 2 Add 8-fluoro-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (260mg crude product), N-iodosuccinimide to a 25mL single-neck round bottom flask (651 mg, 2.89 mmol) and dimethylformamide (10 mL), reacted at 100° C. for 1 hour. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (880 mg, 2-step yield: 53%) ).
  • ES-API: [M+H] + 396.0.
  • Step 3 Add 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (200mg 0.5mmol), di-tertiary dicarbonate to a 25mL three-necked round-bottomed flask Butyl ester (441 mg, 2.02 mmol), triethylamine (256 mg, 2.53 mmol), 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and then reacted overnight at room temperature under nitrogen balloon protection.
  • Step 4 Add ⁇ [8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-yl] ⁇ [tert-butoxycarbonyl ⁇ to a 25mL three-necked round-bottomed flask tert-Butyl amino ⁇ carboxylate (130 mg, 0.21 mmol), pinacol diboronate (110 mg, 0.43 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (24 mg, 0.03 mmol) , potassium acetate (64 mg, 0.65 mmol), dioxane (10 mL).
  • Step 1 Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 2-methyl-5-(4,4,5,5-tetramethyl) into a 25mL three-necked round bottom flask base-1,3,2-dioxaborol-2-yl)pyridine 818mg, 3.73mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12mmol) ), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C.
  • Step 3 add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (170mg 0.45mmol), di-tert-butyl dicarbonate (391mg, 1.79mmol) to a 25mL three-necked round bottom flask, Triethylamine (227 mg, 2.24 mmol), 4-dimethylaminopyridine (5.5 mg, 0.04 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and the reaction was carried out overnight under nitrogen balloon protection at room temperature.
  • Step 5 Add ⁇ [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-8-fluoro into a 25mL three-necked round bottom flask -7-(6-Methylpyridin-3-yl)isoquinolin-1-yl] ⁇ [(2-methylpyridin-2-yl)oxy]carbonyl ⁇ amino ⁇ carboxylic acid tert-butyl ester (300 mg, crude ), ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (50 mg, 0.153 mmol), 1, 1-Bis(diphenylphosphino)ferrocene palladium dichloride (9.4 mg, 0.01 mmol), potassium carbonate (53 mg, 0.38 mmol), dioxane (10 mL) and water (1 mL).
  • reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was used in a flash silica column.
  • Step 6 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-yl)carboxylate tert-butyl ester (90 mg, 0.12 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes.
  • Step 2 (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (340 mg, 1.65 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 4-bromo was added at room temperature -1-ethyl-5-methyl-1H-pyrazole (300 mg, 1.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (121 mg, 0.17 mmol), Potassium carbonate (684 mg, 4.95 mmol) was stirred in an oil bath at 100° C. for 5 hours under nitrogen protection.
  • Step 3 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (180 mg, 0.67 mmol) was dissolved in acetonitrile (5 mL), added N-Iodosuccinimide (180 mg, 0.80 mmol) and the reaction was allowed to react at room temperature for 2 hours.
  • Step 5 tert-butyl (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamate ( 120mg, 0.20mmol) was dissolved in N,N-dimethylformamide (2.0mL), at room temperature was added pinacol bis-boronate (77mg, 0.30mmol), [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (15 mg, 0.02 mmol), potassium acetate (59 mg, 0.60 mmol), nitrogen was replaced, and the reaction was stirred at 100° C. for 2 hours under nitrogen protection.
  • Step six (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl))isoquinolin-1-yl)carbamic acid tert-butyl ester (115 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) and water (0.5 mL), and tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate was added at room temperature (151 mg, 0.39 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl) -2-yl)palladium(II) (14 mg, 0.02
  • Step 7 ((2-(1-Amino-7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-isoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-)yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (60 mg, 0.08 mmol) was dissolved in dichloromethane (2.0 mL) and trichloromethane was added. Fluoroacetic acid (0.5 mL), and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 get 5-bromo-1-methyl-1H-pyrazole (1.6g, 10mmol), cyclopropylboronic acid (2.58g, 30mmol), 1,1-bis(diphenylphosphino)ferrocene Palladium chloride (160 mg, 0.24 mmol), potassium carbonate (4.14 g, 30 mmol) were dissolved in 1,4-dioxane (50 ml) and water (10 ml), and stirred at 110° C. for 2 hours.
  • Step 2 get 5-cyclopropyl-1-methyl-1H-pyrazole (244mg, 2mmol) and dissolve it in acetonitrile, add N-bromosuccinimide (430mg, 2.4mmol) under ice bath, react at room temperature 2 hours. After the reaction, water (10ml) was added, extracted with ethyl acetate (10mL ⁇ 3), the organic phase was washed with saturated sodium bicarbonate solution (10ml), washed with saturated brine (10ml), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure 4-Bromo-5-cyclopropyl-1-methyl-1H-pyrazole (340 mg, 85% yield) was obtained.
  • ES-API: [M+H]+ 201.1.
  • Step 3 get 4-bromo-5-cyclopropyl-1-methyl-1H-pyrazole (200mg, 1mmol), biboronic acid pinacol ester (510mg, 2mmol), 1,1-bis(diphenylphosphine) base) ferrocene palladium dichloride (24 mg, 0.036 mmol), potassium acetate (196 mg, 2 mmol) was dissolved in 1,4-dioxane (5 mL), and stirred at 110° C. for 2 hours.
  • Step five get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinoline-1-amine (85mg g, 0.3mmol) is dissolved in N,N -Dimethylformamide (1 mL), N-iodosuccinimide (68 mg g, 0.3 mmol) was added under an ice bath, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to precipitate a solid, and suction filtration to obtain 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinoline -1-amine (105 mg, 85% yield).
  • ES-API: [M+H]+ 409.0.
  • Step six get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (105mg, 0.25mmol) dissolved in Dichloromethane (5 ml), triethylamine (50 mg, 0.5 mmol), DMAP (4 mg, 0.025 mmol), di-tert-butyl dicarbonate (110 mg, 0.5 mmol) were added under ice bath, and the reaction was carried out at room temperature for 2 hours.
  • Step eight take 2-methylpropan-2-yl ⁇ [7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)isoquinolin-1-yl] ⁇ [(2-methylpropan-2-yl)oxy]carbonyl ⁇ amino ⁇ carboxylate tert-butyl ester (73 mg, 0.12 mmol), ((2-bromo-5-( Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (46 mg, 0.12 mmol), 1,1-bis(diphenylphosphino)diocene Iron palladium dichloride (8 mg g, 0.012 mmol), potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (2 ml) and water (0.5 ml), and stirred at 110° C.
  • Step 2 get (7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(4-((dimethylamino)methyl)-5-(tetrahydro Di-tert-butyl -2H-pyran-4-yl)thiazol-2-yl)-8-fluoroisoquinolin-1-yl)carbamate (40 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (0.5 mL) ), trifluoroacetic acid (0.2 mL) was added, and the mixture was reacted at room temperature for 2 hours.
  • Buffer preparation Use sterile water to prepare 1 ⁇ reaction buffer: 40 mM Tris-HCl, 20 mM MgCl 2 , 0.01% Brij35, 50 ⁇ M DTT, 0.1 mg/ml BSA, and use it on the day of the experiment.
  • 1000 ⁇ stocking drug plate preparation prepare 1000 ⁇ compound stocking plate, dilute 10 mM compound stock solution with DMSO, the initial concentration is 1 mM, 10 concentration gradients, 3.162 times dilution.
  • the compound storage plate was sealed with sealing film and stored in a -20°C refrigerator for later use.
  • Compound preparation and dosing Take out the 1000 ⁇ storage plate and thaw at room temperature in the dark. Then prepare a 5X intermediate plate with reaction buffer and mix thoroughly. Transfer 2 ⁇ L from the 5 ⁇ intermediate plate to a 384-well plate, set up negative control wells and positive control wells (add 2 ⁇ L of reaction buffer containing 0.5% DMSO), and repeat each point twice.
  • reaction solution preparation and incubation use reaction buffer to dilute HPK1 protein into 2.5 ⁇ working solution, add 4 ⁇ L of 2.5 ⁇ HPK1 protein to each well containing the test compound and the positive control well, and add 4 ⁇ L of HPK1 protein-free protein to the negative control well.
  • reaction buffer Centrifuge at 1000 rpm for 1 minute, then incubate in a 20°C incubator for 15 minutes.
  • Use reaction buffer to prepare 2.5 ⁇ MBP protein and ATP mixed working solution the concentrations are 0.5 ⁇ g/ ⁇ L and 50 ⁇ M, respectively, add 4 ⁇ L MBP and ATP mixed working solution to each well, centrifuge at 1000 rpm for 1 minute, and then incubator at 20 °C Incubate for 90 minutes.
  • ADP-Glo detection and plate reading Add 10 ⁇ L of ADP-Glo to each well of the experimental plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 20°C incubator for 60 minutes. Then transfer 10 ⁇ L of the incubation solution from the experimental plate to a new 384-well plate, add 10 ⁇ L of kinase detection reagent to each well, centrifuge at 400g for 1 minute, incubate in a 20°C incubator for 60 minutes, and read with a microplate reader Chemiluminescence signal.
  • Inhibition rate% (1-(experimental well-negative control well)/(positive control well-negative control well))*100%; negative control well: 10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+DMSO; positive Control wells: 1nM HPK1+10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+DMSO; experimental wells: 1nM HPK1+10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+compound; use Graphpad Prism 8.0.1 to analyze data, and use four-parameter method to fit drug effects Inhibition rate curves and IC50 values of the drugs were calculated.
  • the compounds of the present invention have high inhibitory activity on HPK1 kinase, and the IC50 value is less than 10 ⁇ M (for example, 0.1 nM to 10 ⁇ M); the IC50 value of some compounds is even less than 1 ⁇ M (for example, 0.1 nM to 1 ⁇ M) or less than 500 nM (for example, 0.1 nM to 1 ⁇ M). 0.1 nM to 500 nM).
  • Table 1 The experimental results of some of the compounds are shown in Table 1.

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Abstract

Disclosed are compounds as represented by formulas (A) to (D) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, the definitions of the groups in the formulas being detailed in the description. Further disclosed are pharmaceutical compositions containing the described compounds and the use thereof in the preparation of drugs for preventing and/or treating diseases or disorders associated with HPK 1 activity.

Description

氨基取代的吡啶并环类化合物及其制法和用途Amino-substituted pyridocyclic compounds and their preparation and use 技术领域technical field
本发明属于医药领域，具体涉及氨基取代的吡啶并环类化合物及其制法和用途。The invention belongs to the field of medicine, in particular to an amino-substituted pyridocyclic compound and a preparation method and application thereof.
背景技术Background technique
造血祖细胞激酶1(HPK1，又称为MAP4K1)是造血系统特异性丝氨酸/苏氨酸蛋白激酶，属于哺乳动物ste20相关蛋白激酶的MAP4K家族。HPK1主要在造血组织和细胞中表达。HPKl存在3种激活方式，即丝氨酸磷酸化、苏氨酸磷酸化或酪氨酸磷酸化。已有研究表明体外HPK1-/-T细胞具有较低的TCR激活阈值，增殖稳健，产生更多的Th1细胞因子。在小鼠实验性自身免疫性脑脊髓炎(EAE)模型中，当使用由髓鞘少突胶质细胞糖蛋白(MOG)衍生的肽免疫HPK1-/-小鼠时，会出现更严重的自身免疫性症状。此外，在产生PGE2的路易斯(Lewis)肺癌肿瘤模型中，与野生型小鼠相比，HPK1敲除小鼠的肿瘤发展显著缓慢。另外大量研究结果表明，HPKl可与许多接头蛋白结合，如SLP-76家族、CARD11、HIS、HIP-55、GRB2家族、LAT、CRK家族等相互作用，活化造血干细胞的JNK/SAPK信号途径，从而对TCR通路进行负向调节。因HPK1在免疫方面的重要作用，HPKl抑制剂在恶性实体肿瘤或者血液癌(如急性髓性白血病、膀胱上皮癌、乳腺癌、结肠癌、肺癌、胰腺癌、黑色素瘤)、自身免疫性疾病(如系统性红斑狼疮、银肩病关节炎)和炎症反应中均扮演重要的角色。目前尚无针对HPKl靶点的药物上市，为了能更好地满足巨大的临床需求，我们旨在开发出更有效的HPKl抑制剂。Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1) is a hematopoietic system-specific serine/threonine protein kinase that belongs to the MAP4K family of mammalian ste20-related protein kinases. HPK1 is mainly expressed in hematopoietic tissues and cells. There are three activation modes of HPK1, namely serine phosphorylation, threonine phosphorylation or tyrosine phosphorylation. Previous studies have shown that in vitro HPK1-/- T cells have a lower TCR activation threshold, proliferate robustly, and produce more Th1 cytokines. In a mouse model of experimental autoimmune encephalomyelitis (EAE), HPK1-/- mice develop more severe self when immunized with peptides derived from myelin oligodendrocyte glycoprotein (MOG) immune symptoms. Furthermore, in the PGE2-producing Lewis lung cancer tumor model, tumor development was significantly slower in HPK1-knockout mice compared with wild-type mice. In addition, a large number of research results show that HPK1 can interact with many adaptor proteins, such as SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, CRK family, etc., and activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby Negative regulation of the TCR pathway. Due to the important role of HPK1 in immunity, HPK1 inhibitors have been implicated in malignant solid tumors or blood cancers (such as acute myeloid leukemia, bladder epithelial cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma), autoimmune diseases ( Such as systemic lupus erythematosus, psoriasis arthritis) and inflammatory response play an important role. Currently there is no drug targeting HPK1 targets on the market, in order to better meet the huge clinical needs, we aim to develop more effective HPK1 inhibitors.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种结构新颖的高效HPKl抑制剂，其具有活性高，选择性好且毒副作用低等优点，具有良好的理化性质和成药特性。The present invention provides an efficient HPK1 inhibitor with novel structure, which has the advantages of high activity, good selectivity, low toxicity and side effects, and has good physicochemical properties and drug-forming properties.
本发明第一方面提供了式(A)或式(D)所示化合物或其药学上可接受的盐、溶剂合物或前药：The first aspect of the present invention provides a compound represented by formula (A) or formula (D) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
Figure PCTCN2022085658-appb-000001
Figure PCTCN2022085658-appb-000001
各式中，various,
Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C6-14 aryl or 5 to 20 membered heteroaryl; the 3 to 20 membered heterocyclyl, the 5 to 20 membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷 基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
Cy2环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy2 ring is C 3-20 -membered cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
R x为氢；或者 R x is hydrogen; or
R x为Cy2环上一个位置的取代基； R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000002
其中， Rx is
Figure PCTCN2022085658-appb-000002
in,
R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment; or
当R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2a为氢、氘或C 1-6烷基(例如甲基)，R 2b为氢、氘或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl), R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond; the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected from the S1 group are substituted;
或者or
R x为
Figure PCTCN2022085658-appb-000003
其中， Rx is
Figure PCTCN2022085658-appb-000003
in,
R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1; or
R 2e和R 2f各自独立地为氢或C 1-6烷基(例如甲基)； R 2e and R 2f are each independently hydrogen or C 1-6 alkyl (eg, methyl);
或者or
R x为
Figure PCTCN2022085658-appb-000004
其中， Rx is
Figure PCTCN2022085658-appb-000004
in,
R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3 -20 -cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group contains as ring atoms The 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到 20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；或者当其中两个R 2位于同一个碳原子时，这两个R 2与和它们相连的碳原子共同构成C 3-6单环环烷基或3至6元单环杂环基；所述3至6元单环杂环基含有1个或2个选自N、S或O的杂原子作为环原子；所述C 3-6单环环烷基或3至6元单环杂环基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom; or when two R 2 are located on the same carbon atom, the two R 2 together with the carbon atom to which they are attached constitute a C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocycle base; the 3- to 6-membered monocyclic heterocyclic group contains 1 or 2 heteroatoms selected from N, S or O as ring atoms; the C 3-6 monocyclic cycloalkyl or 3- to 6-membered unit The cyclic heterocyclyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
R 3为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 3 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
R 4为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 4 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
p为0、1、2或3；p is 0, 1, 2, or 3;
p1为0、1或2；p1 is 0, 1 or 2;
q为0或1；q is 0 or 1;
L 1为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 1 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
L 2为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 2 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
X为CR 8或N；其中，R 8为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； X is CR 8 or N; wherein, R 8 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy ;
Y为CR 9或N；其中，R 9为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； Y is CR 9 or N; wherein, R 9 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy ;
且当式(A)中X和Y为CH；L 1为一根键时，
Figure PCTCN2022085658-appb-000005
不为苯基或卤代苯基； And when X and Y in formula (A) are CH; L 1 is a bond,
Figure PCTCN2022085658-appb-000005
not phenyl or halophenyl;
上述各基团中，R 5、R 6各自独立地为H、氘、卤素、氰基、羟基、C 1-6烷基、氘代C 1-6烷基或C 1-6烷氧基； In each of the above groups, R 5 and R 6 are each independently H, deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, deuterated C 1-6 alkyl or C 1-6 alkoxy;
上述各基团中，R 7为H、C 1-6烷基或氘代C 1-6烷基； In the above-mentioned groups, R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl;
上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝 基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously substituted by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
在一实施方案中，其中，所述化合物如式(A1)、式(A2)、式(A3)、式(D1)、式(D2)或式(D3)所示：In one embodiment, wherein, the compound is represented by formula (A1), formula (A2), formula (A3), formula (D1), formula (D2) or formula (D3):
Figure PCTCN2022085658-appb-000006
Figure PCTCN2022085658-appb-000006
各式中，R 1、R 2、R 3、R 4、R x、L 1、L 2、Cy1环、Cy2环、m、n、p、p1、q各自定义同前。 In each formula, R 1 , R 2 , R 3 , R 4 , R x , L 1 , L 2 , Cy1 ring, Cy2 ring, m, n, p, p1, and q are as defined above.
在一实施方案中，其中，所述化合物如式(A11)、式(A21)、式(A31)、式(D11)、式(D21)或式(D31)所示：In one embodiment, wherein, the compound is represented by formula (A11), formula (A21), formula (A31), formula (D11), formula (D21) or formula (D31):
Figure PCTCN2022085658-appb-000007
Figure PCTCN2022085658-appb-000007
各式中，R 1、R 2、R 3、R 4、R x、Cy1环、Cy2环、m、n、p、p1、q各自定义同前。在一实施方案中，其中，所述化合物如式(A12)、式(A22)、式(A32)、式(D12)、式(D22)或式(D32)所示： In each formula, R 1 , R 2 , R 3 , R 4 , R x , Cy1 ring, Cy2 ring, m, n, p, p1, and q are as defined above. In one embodiment, wherein, the compound is represented by formula (A12), formula (A22), formula (A32), formula (D12), formula (D22) or formula (D32):
Figure PCTCN2022085658-appb-000008
Figure PCTCN2022085658-appb-000008
各式中，R 1、R 2、R x、L 1、L 2、Cy1环、Cy2环、m、n、q各自定义同前。 In each formula, R 1 , R 2 , R x , L 1 , L 2 , Cy1 ring, Cy2 ring, m, n, and q are as defined above.
在一实施方式中，式(A)化合物或其药学上可接受的盐、溶剂化物或前药通过包括以下步骤的方法制备：In one embodiment, a compound of formula (A) or a pharmaceutically acceptable salt, solvate or prodrug thereof is prepared by a method comprising the steps of:
Figure PCTCN2022085658-appb-000009
Figure PCTCN2022085658-appb-000009
其中，Cy1环、Cy2环、R 1、m、n、R 2、R 3、R 4、R x、p、L 1、L 2、X、Y的定义如前式(A)化合物所定义。 Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , m, n, R 2 , R 3 , R 4 , R x , p, L 1 , L 2 , X and Y are as defined in the compound of formula (A).
R m和R m’选自本领域公知可供反应的基团。 Rm and Rm' are selected from reactive groups known in the art.
优选地，R m和R m’选自卤素原子、硼酸基或硼酸酯基；条件是：R m选自卤素原子时，R m’选自硼酸基或硼酸酯基，R m’选自卤素原子时，R m选自硼酸基或硼酸酯基； Preferably, R m and R m' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R m is selected from halogen atoms, R m' is selected from boronic acid groups or boronic acid ester groups, and R m' is selected from From a halogen atom, R m is selected from a boronic acid group or a boronic acid ester group;
所述硼酸基或硼酸酯基选自
Figure PCTCN2022085658-appb-000010
或-B(OH) 2。 The boronic acid group or boronic acid ester group is selected from
Figure PCTCN2022085658-appb-000010
or -B(OH) 2 .
在一实施方式中，式(D)化合物或其药学上可接受的盐、溶剂化物或前药通过包括以下步骤的方法制备：In one embodiment, a compound of formula (D) or a pharmaceutically acceptable salt, solvate or prodrug thereof is prepared by a method comprising the steps of:
Figure PCTCN2022085658-appb-000011
Figure PCTCN2022085658-appb-000011
其中，Cy1环、Cy2环、R 1、R 2、m、n、R 3、R 4、R x、p1、q、L 1、L 2、X、Y的定义如前式(D)化合物所定义。 Wherein, Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, R 3 , R 4 , R x , p1, q, L 1 , L 2 , X, Y are as defined in the compound of formula (D) above definition.
R n和R n’选自本领域公知可供反应的基团。 Rn and Rn ' are selected from reactive groups known in the art.
优选地，R n和R n’选自卤素原子、硼酸基或硼酸酯基；条件是：R n选自卤素原子时，R n’选自硼酸基或硼酸酯基，R n’选自卤素原子时，R n选自硼酸基或硼酸酯基； Preferably, R n and R n' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R n is selected from halogen atoms, R n' is selected from boronic acid groups or boronic ester groups, and R n' is selected from From a halogen atom, R n is selected from a boronic acid group or a boronic acid ester group;
所述硼酸基或硼酸酯基选自
Figure PCTCN2022085658-appb-000012
或-B(OH) 2。 The boronic acid group or boronic acid ester group is selected from
Figure PCTCN2022085658-appb-000012
or -B(OH) 2 .
本发明第二方面提供了式(B)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：The second aspect of the present invention provides a compound represented by formula (B) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
Figure PCTCN2022085658-appb-000013
Figure PCTCN2022085658-appb-000013
式中，In the formula,
Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C6-14 aryl or 5 to 20 membered heteroaryl; the 3 to 20 membered heterocyclyl, the 5 to 20 membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
Cy2环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy2 ring is C 3-20 -membered cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
R x为氢；或者 R x is hydrogen; or
R x为Cy2环上一个位置的取代基； R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000014
其中， Rx is
Figure PCTCN2022085658-appb-000014
in,
R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment; or
当R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2a为氢、氘或C 1-6烷基(例如甲基)，R 2b为氢、氘或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl), R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond; the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected from the S1 group are substituted;
或者or
R x为
Figure PCTCN2022085658-appb-000015
其中， Rx is
Figure PCTCN2022085658-appb-000015
in,
R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1; or
R 2e和R 2f各自独立地为氢或C 1-6烷基(例如甲基)； R 2e and R 2f are each independently hydrogen or C 1-6 alkyl (eg, methyl);
或者or
R x为
Figure PCTCN2022085658-appb-000016
其中， Rx is
Figure PCTCN2022085658-appb-000016
in,
R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3 -20 -cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group contains as ring atoms The 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环 杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；或者当其中两个R 2位于同一个碳原子时，这两个R 2与和它们相连的碳原子共同构成C 3-6单环环烷基或3至6元单环杂环基；所述3至6元单环杂环基含有1个或2个选自N、S或O的杂原子作为环原子；所述C 3-6单环环烷基或3至6元单环杂环基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom; or when two R 2 are located on the same carbon atom, the two R 2 together with the carbon atom to which they are attached constitute a C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocycle base; the 3- to 6-membered monocyclic heterocyclic group contains 1 or 2 heteroatoms selected from N, S or O as ring atoms; the C 3-6 monocyclic cycloalkyl or 3- to 6-membered unit The cyclic heterocyclyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
R 3为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 3 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
R 4为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 4 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
且R 3、R 4不同时为H； and R 3 and R 4 are not H at the same time;
p为0、1、2或3；p is 0, 1, 2, or 3;
L 1为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 1 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
L 2为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 2 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
上述各基团中，R 5、R 6各自独立地为H、氘、卤素、氰基、羟基、C 1-6烷基、氘代C 1-6烷基或C 1-6烷氧基； In each of the above groups, R 5 and R 6 are each independently H, deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, deuterated C 1-6 alkyl or C 1-6 alkoxy;
上述各基团中，R 7为H、C 1-6烷基或氘代C 1-6烷基； In the above-mentioned groups, R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl;
上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单 环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously substituted by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
在一实施方式中，式(B)化合物或其药学上可接受的盐、溶剂化物或前药通过包括以下步骤的方法制备：In one embodiment, a compound of formula (B) or a pharmaceutically acceptable salt, solvate or prodrug thereof is prepared by a method comprising the steps of:
Figure PCTCN2022085658-appb-000017
Figure PCTCN2022085658-appb-000017
其中，Cy1环、Cy2环、R 1、R 2、m、n、R 3、R 4、L 1、L 2、R x、p的定义如前所定义式(B)化合物所定义。 Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, R 3 , R 4 , L 1 , L 2 , R x , and p are as defined above for the compound of formula (B).
R y和R y’选自本领域公知可供反应的基团。 Ry and Ry' are selected from reactive groups known in the art.
优选地，R y和R y’选自卤素原子、硼酸基或硼酸酯基；条件是：R y选自卤素原子时，R y’选自硼酸基或硼酸酯基，R y’选自卤素原子时，R y选自硼酸基或硼酸酯基； Preferably, R y and R y' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R y is selected from halogen atoms, R y' is selected from boronic acid groups or boronic ester groups, and R y' is selected from When from a halogen atom, R y is selected from a boronic acid group or a boronic acid ester group;
所述硼酸基或硼酸酯基选自
Figure PCTCN2022085658-appb-000018
或-B(OH) 2。 The boronic acid group or boronic acid ester group is selected from
Figure PCTCN2022085658-appb-000018
or -B(OH) 2 .
本发明第三方面提供了式(C)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：The third aspect of the present invention provides a compound represented by formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
Figure PCTCN2022085658-appb-000019
Figure PCTCN2022085658-appb-000019
式中，In the formula,
Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C6-14 aryl or 5 to 20 membered heteroaryl; the 3 to 20 membered heterocyclyl, the 5 to 20 membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
(a)Cy2环为C 6-14芳基时； (a) when Cy2 ring is C 6-14 aryl;
(a1)R x为Cy2环上一个位置的取代基； (a1) R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000020
其中，R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或 Rx is
Figure PCTCN2022085658-appb-000020
Wherein, when R 2a and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered The monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the said The 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3 or 4 selected from group S1 group substituted; or
R x为
Figure PCTCN2022085658-appb-000021
其中，R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； Rx is
Figure PCTCN2022085658-appb-000021
wherein R 2e and R 2f together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains a nitrogen atom and optionally 1 or 2 heterocyclic heteroaryl groups independently selected from N, O, S and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally Or 4 groups selected from S1 group are substituted;
R 2为Cy2环其余任意位置上的取代基；m为1或2；R 2选自下组：3到20元杂环基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-NH-C 3-20环烷基、-NH-3到20元杂环基、N-5到20元杂芳基、-NH-C 6-14芳基；其中，所述3到20元杂环基、C 3-20环烷基、5到20元杂芳基、C 6-14芳基任选地被1、2、3或4个选自S3组的基团所取代；所述3到20元杂环基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered heteroaryl, -NH-C 6- 14 Aryl; wherein, the 3- to 20-membered heterocyclic group, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optionally replaced by 1, 2, 3 or 4 substituted with a group selected from the S3 group; the 3- to 20-membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
或者or
(a2)R x为Cy2环上一个位置的取代基； (a2) R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000022
其中， Rx is
Figure PCTCN2022085658-appb-000022
in,
R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为C 1-6烷基、C 3-20环烷基或3到20元杂环基；且当R 2c为C 1-6烷基时R 2d不为3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not 3 to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is replaced by 1 , 2, 3 or 4 groups selected from group S1; or
R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氘，R 2b为氢、氘或C 1-6烷基(例如甲基)且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2a is deuterium, R 2b is hydrogen, Deuterium or C 1-6 alkyl (eg methyl) and the bond between R 2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the The 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclic groups , the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the S1 group;
或者or
R x为
Figure PCTCN2022085658-appb-000023
其中， Rx is
Figure PCTCN2022085658-appb-000023
in,
R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为C 1-6烷基、C 3-20环烷基或3到20元杂环基；且当R 2c为C 1-6烷基时R 2d不为3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 20-membered heterocyclyl; the 3- to 20-membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from the S1 group;
或者or
R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢或氘或C 1-6烷基(例如甲基)，R 2g，R 2h、R 2h’、R 2g’中至少一个为氘；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen or deuterium or C 1-6 alkyl (eg methyl), at least one of R 2g , R 2h , R 2h' and R 2g' is deuterium; The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as a ring and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3, or 4 Replaced by a group selected from group S1;
或者or
R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6 烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O ) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O) -NRaRb ,-S ( =O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from the group S1; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1 , 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
或者or
(b)Cy2环为5到20元杂芳基；所述5到20元杂芳基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；(b) Cy2 ring is a 5- to 20-membered heteroaryl group; the 5- to 20-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
(b1)R x为Cy2环上一个位置的取代基； (b1) R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000024
其中， Rx is
Figure PCTCN2022085658-appb-000024
in,
当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment;
R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1;
R 2为Cy2环其余任意位置上的取代基；m为1或2；R 2选自下组：3到20元杂环基、-O-C 3-20环烷基、-O-3到20元杂环基、O-5到20元杂芳基、-O-C 6-14芳基、-NH-C 3-20环烷基、-NH-3到20元杂环基、N-5到20元杂芳基、-NH-C 6-14芳基；其中，所述3到20元杂环基、C 3-20环烷基、5到20元杂芳基、C 6-14芳基任选地被1、2、3或4个选自S3组的基团所取代；所述3到20元杂环基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, O-5 to 20 membered heteroaryl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered Heteroaryl, -NH-C 6-14 aryl; wherein, the 3- to 20-membered heterocyclic group, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optional is substituted with 1, 2, 3 or 4 groups selected from group S3; the 3- to 20-membered heterocyclyl group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
或者or
(b2)R x为Cy2环上一个位置的取代基； (b2) R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000025
其中， Rx is
Figure PCTCN2022085658-appb-000025
in,
R 2a为氢、氘或甲基；R 2b为氢、氘或甲基；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、 O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or methyl; R 2b is hydrogen, deuterium or methyl; the bond between R 2a and carbon atom is a single bond; R 2c and R 2d are independently hydrogen, C 1-6 alkyl , C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; the 3- to 20-membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the The 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氘，R 2b为氢、氘或甲基；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2a is deuterium, R 2b is hydrogen, deuterium or methyl; and the bond between R 2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
或者or
R x为
Figure PCTCN2022085658-appb-000026
其中， Rx is
Figure PCTCN2022085658-appb-000026
in,
R 2g、R 2h、R 2h’、R 2g’各自独立地为氢、氘或甲基；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are each independently hydrogen, deuterium or methyl; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is 1, 2, 3 or 4 groups selected from group S1;
或者or
R 2g为氘；R 2h、R 2h’、R 2g’各自独立地为氢、氘或甲基；或者R 2g’为氘；R 2h、R 2h’、R 2g各自独立地为氢、氘或甲基；R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R2g is deuterium; R2h , R2h' , R2g' are each independently hydrogen, deuterium or methyl; or R2g' is deuterium; R2h , R2h' , R2g are each independently hydrogen, deuterium or methyl; R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; the 3- to 20-membered heterocyclic group The cyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2, 3 or 4 groups selected from the S1 group are substituted;
R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选 地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O ) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O) -NRaRb ,-S ( =O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from the group S1; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1 , 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
或者or
(b3)R x为Cy2环上一个位置的取代基； (b3) R x is a substituent at a position on the Cy2 ring;
R x为
Figure PCTCN2022085658-appb-000027
其中，R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氢或甲基，R 2b为氢或甲基；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代； Rx is
Figure PCTCN2022085658-appb-000027
wherein, R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, and R 2a is hydrogen or methyl, R 2b is hydrogen or methyl; and the bond between R 2a and a carbon atom is a single bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered heterocyclic group The bicyclic heteroaryl groups each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclic group, the 5 or The 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S4;
或者or
R x为
Figure PCTCN2022085658-appb-000028
其中，R 2g、R 2h、R 2h’、R 2g’各自独立地为氢或甲基；R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代； Rx is
Figure PCTCN2022085658-appb-000028
Wherein, R 2g , R 2h , R 2h' , R 2g' are each independently hydrogen or methyl; R 2c and R 2d together with the atoms connected to them constitute a 3-20-membered heterocyclic group, a 5- or 6-membered unit Cyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, The 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S4;
R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选 地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O ) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O) -NRaRb ,-S ( =O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from the group S1; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1 , 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
上述各基团中，各个S3组的基团各自独立地选自下组：C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)-NR aR b、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-3到20元杂环基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C 1-4烷基-C(＝O)-5或6元单环杂芳基、-C 1-4烷基-C(＝O)-8至10元双环杂芳基、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)O-3到20元杂环基、-C 1-4烷基-C(＝O)O-C 6-14芳基、-C 1-4烷基-C(＝O)O-5或6元单环杂芳基、-C 1-4烷基-C(＝O)O-8至10元双环杂芳基；其中，所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； In the above-mentioned groups, the groups of each S3 group are each independently selected from the following group: C 3-20 cycloalkyl, 3 to 20-membered heterocyclic group, C 6-14 aryl, 5 or 6-membered monocyclic heterocyclic group Aryl, 8- to 10-membered bicyclic heteroaryl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3 to 20-membered heterocyclyl, -C(=O)-C 6-14 Aryl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6- 14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C(=O)-NR a R b , -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl , -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-C(=O)- C 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)-C 6-14 aryl , -C 1-4 alkyl-C(=O)-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-C(=O)-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O) OC 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)OC 6-14 aryl , -C 1-4 alkyl-C(=O)O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-C(=O)O-8 to 10-membered bicyclic heteroaryl; Wherein, the C 3-20 cycloalkyl group, the 3- to 20-membered heterocyclic group, the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic group The heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, The 8- to 10-membered bicyclic heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3 到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 Substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
上述各基团中，各个S4组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、氘代C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，除了上述氘代C 1-6烷基外，任意基团中所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above-mentioned groups, the groups of each S4 group are independently selected from the following groups: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, deuterated C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heterocyclyl Aryl, 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heterocycle Aryl, -O-8 to 10 membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20 membered heterocyclyl, -C≡CC 6-14 aryl, - C≡C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, - C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1- 4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl base, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, - C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3- 20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S (=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3- to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl -C(=O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C( =O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1 -6Alkyl -C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl Aryl, -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , - C≡CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl- NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 - NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O) -NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; wherein , in addition to the above-mentioned deuterated C 1-6 alkyl, the C 1-6 alkyl, the C 1-6 alkoxy, the C 2-6 alkenyl, the C 2- 6 Alkynyl groups are each independently optionally substituted with 1, 2 or 3 groups selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20-membered Heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally surrounded by 1, 2, 3, or 4 is substituted with a group selected from Group S2; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously substituted by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
在一实施方案中，Cy1环选自下组：In one embodiment, the Cy1 ring is selected from the group consisting of:
Figure PCTCN2022085658-appb-000029
Figure PCTCN2022085658-appb-000029
Figure PCTCN2022085658-appb-000030
Figure PCTCN2022085658-appb-000030
上述各个基团上的n个氢原子可以任意地被R 1所取代；n为0、1、2或3；各个R 1各自独立地定义同前。 The n hydrogen atoms on each of the above groups can be optionally substituted by R 1 ; n is 0, 1, 2 or 3; each R 1 is independently defined as before.
在一实施方案中，
Figure PCTCN2022085658-appb-000031
选自下组： In one embodiment,
Figure PCTCN2022085658-appb-000031
Choose from the following group:
Figure PCTCN2022085658-appb-000032
Figure PCTCN2022085658-appb-000032
Figure PCTCN2022085658-appb-000033
Figure PCTCN2022085658-appb-000033
Figure PCTCN2022085658-appb-000034
Figure PCTCN2022085658-appb-000034
Figure PCTCN2022085658-appb-000035
Figure PCTCN2022085658-appb-000035
在一实施方案中，Cy2环选自下组：In one embodiment, the Cy2 ring is selected from the group consisting of:
Figure PCTCN2022085658-appb-000036
Figure PCTCN2022085658-appb-000036
在一实施方案中，
Figure PCTCN2022085658-appb-000037
中，R x为氢；Cy2环选自下组： In one embodiment,
Figure PCTCN2022085658-appb-000037
In, R x is hydrogen; Cy2 ring is selected from the following group:
Figure PCTCN2022085658-appb-000038
Figure PCTCN2022085658-appb-000038
且Cy2环可以被1或2个R 2取代；各个R 2各自独立地定义同前。 And the Cy2 ring may be substituted by 1 or 2 R 2 ; each R 2 is independently defined as before.
在一实施方案中，R x为氢；m为1或2；
Figure PCTCN2022085658-appb-000039
选自下组： In one embodiment, Rx is hydrogen; m is 1 or 2;
Figure PCTCN2022085658-appb-000039
Choose from the following group:
Figure PCTCN2022085658-appb-000040
Figure PCTCN2022085658-appb-000040
各式中，各个R 2各自独立地定义同前。 In each formula, each R 2 is independently defined as above.
在一实施方案中，
Figure PCTCN2022085658-appb-000041
选自下组：
Figure PCTCN2022085658-appb-000042
各式中，R 2、R x定义同式(C)中(a)中定义。 In one embodiment,
Figure PCTCN2022085658-appb-000041
Choose from the following group:
Figure PCTCN2022085658-appb-000042
In each formula, R 2 and R x are defined as in (a) in formula (C).
在一实施方案中，
Figure PCTCN2022085658-appb-000043
选自下组： In one embodiment,
Figure PCTCN2022085658-appb-000043
Choose from the following group:
Figure PCTCN2022085658-appb-000044
Figure PCTCN2022085658-appb-000044
各式中，R 2、R x定义同式(C)中(b)中定义。 In each formula, R 2 and R x are defined as in (b) in formula (C).
在一实施方案中，
Figure PCTCN2022085658-appb-000045
选自下组： In one embodiment,
Figure PCTCN2022085658-appb-000045
Choose from the following group:
Figure PCTCN2022085658-appb-000046
Figure PCTCN2022085658-appb-000046
各式中，各个R x、R 2各自独立地定义同前。 In each formula, each of R x and R 2 is independently defined as above.
在一实施方案中，
Figure PCTCN2022085658-appb-000047
选自下组： In one embodiment,
Figure PCTCN2022085658-appb-000047
Choose from the following group:
Figure PCTCN2022085658-appb-000048
Figure PCTCN2022085658-appb-000048
各式中，各个R x、R 2各自独立地定义同前。 In each formula, each of R x and R 2 is independently defined as above.
在一实施方案中，R x选自下组： In one embodiment, Rx is selected from the group consisting of:
Figure PCTCN2022085658-appb-000049
Figure PCTCN2022085658-appb-000049
Figure PCTCN2022085658-appb-000050
Figure PCTCN2022085658-appb-000050
上述各个基团中环上的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代；The hydrogen atoms on the ring in each of the above groups can be independently optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group;
上述各个基团中非环上的氢原子可以各自独立地任选地被1或2个选自氘和甲基的基团所取代。The acyclic hydrogen atoms in each of the above groups may each independently be optionally substituted with 1 or 2 groups selected from deuterium and methyl.
在一实施方案中，R x选自下组：
Figure PCTCN2022085658-appb-000051
各式中， 各个n1、各个n2各自独立地为0、1、2或3；上述各个基团中的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代。 In one embodiment, Rx is selected from the group consisting of:
Figure PCTCN2022085658-appb-000051
In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
在一实施方案中，R x选自下组：
Figure PCTCN2022085658-appb-000052
各式中，各个n1、各个n2各自独立地为0、1、2或3；上述各个基团中的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代。 In one embodiment, Rx is selected from the group consisting of:
Figure PCTCN2022085658-appb-000052
In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
在一实施方案中，R x为
Figure PCTCN2022085658-appb-000053
其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c、R 2d各自独立地为H、C 1-6烷基、C 3-6单环环烷基或3到6元单环杂环基。 In one embodiment, Rx is
Figure PCTCN2022085658-appb-000053
Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 Monocyclic heterocyclyl.
在一实施方案中，R x为
Figure PCTCN2022085658-appb-000054
其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c、R 2d各自独立地为H、C 1-6烷基、C 3-6单环环烷基或3到6元单环杂环基；且当R 2c为C 1-6烷基时R 2d不为3到6元单环杂环基。 In one embodiment, Rx is
Figure PCTCN2022085658-appb-000054
Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 6-membered monocyclic heterocyclyl.
在一实施方案中，R x为
Figure PCTCN2022085658-appb-000055
其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c和R 2d与和它们相连的氮原子共同构成3到6元单环杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到6元单环杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到6元单环杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代。 In one embodiment, Rx is
Figure PCTCN2022085658-appb-000055
Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d together with the nitrogen atom connected to them form a 3- to 6-membered monocyclic heterocyclic group, a 5- or 6-membered monocyclic heterocyclic group Aryl or 8- to 10-membered bicyclic heteroaryl; the 3- to 6-membered monocyclic heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain One nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 6-membered monocyclic heterocyclyl, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S4.
在一实施方案中，R 2选自下组： In one embodiment, R is selected from the group consisting of:
Figure PCTCN2022085658-appb-000056
Figure PCTCN2022085658-appb-000056
在一实施方式中，所述的式(C)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药通过包括以下步骤的方法制备：In one embodiment, the compound of formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is prepared by a method comprising the following steps:
Figure PCTCN2022085658-appb-000057
Figure PCTCN2022085658-appb-000057
其中，Cy1环、Cy2环、R 1、R 2、m、n、R x的定义如前式(C)化合物所定义。 The definitions of Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, and R x are as defined in the compound of formula (C).
R Z和R Z’选自本领域公知可供反应的基团。 R Z and R Z' are selected from reactive groups known in the art.
优选地，R Z和R Z’选自卤素原子、硼酸基或硼酸酯基；条件是：R Z选自卤素原子时，R Z’选自硼酸基或硼酸酯基，R Z’选自卤素原子时，R Z选自硼酸基或硼酸酯基； Preferably, R Z and R Z' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R Z is selected from halogen atoms, R Z' is selected from boronic acid groups or boronic ester groups, and R Z' is selected from When from a halogen atom, R Z is selected from a boronic acid group or a boronic acid ester group;
所述硼酸基或硼酸酯基选自
Figure PCTCN2022085658-appb-000058
或-B(OH) 2。 The boronic acid group or boronic acid ester group is selected from
Figure PCTCN2022085658-appb-000058
or -B(OH) 2 .
在一实施方案中，本发明化合物选自表(I)：In one embodiment, the compound of the present invention is selected from Table (I):
表(I)Table (I)
Figure PCTCN2022085658-appb-000059
Figure PCTCN2022085658-appb-000059
Figure PCTCN2022085658-appb-000060
Figure PCTCN2022085658-appb-000060
Figure PCTCN2022085658-appb-000061
Figure PCTCN2022085658-appb-000061
Figure PCTCN2022085658-appb-000062
Figure PCTCN2022085658-appb-000062
Figure PCTCN2022085658-appb-000063
Figure PCTCN2022085658-appb-000063
Figure PCTCN2022085658-appb-000064
Figure PCTCN2022085658-appb-000064
Figure PCTCN2022085658-appb-000065
Figure PCTCN2022085658-appb-000065
Figure PCTCN2022085658-appb-000066
Figure PCTCN2022085658-appb-000066
Figure PCTCN2022085658-appb-000067
Figure PCTCN2022085658-appb-000067
Figure PCTCN2022085658-appb-000068
Figure PCTCN2022085658-appb-000068
Figure PCTCN2022085658-appb-000069
Figure PCTCN2022085658-appb-000069
Figure PCTCN2022085658-appb-000070
Figure PCTCN2022085658-appb-000070
Figure PCTCN2022085658-appb-000071
Figure PCTCN2022085658-appb-000071
Figure PCTCN2022085658-appb-000072
Figure PCTCN2022085658-appb-000072
Figure PCTCN2022085658-appb-000073
Figure PCTCN2022085658-appb-000073
Figure PCTCN2022085658-appb-000074
Figure PCTCN2022085658-appb-000074
在一实施方案中，上述各个基团中，所述3到20元杂环基选自下组：3到6元单环杂环基、7至11元螺杂环基、6至10元稠杂环基、6到14元桥杂环基。In one embodiment, in each of the above groups, the 3- to 20-membered heterocyclic group is selected from the group consisting of: 3- to 6-membered monocyclic heterocyclic group, 7- to 11-membered spiro heterocyclic group, 6- to 10-membered condensed heterocyclic group Heterocyclyl, 6- to 14-membered bridged heterocyclyl.
在一实施方案中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-6单环环烷基、3到20元杂环基、苯基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-6单环环烷基、-O-3到20元杂环基、-O-苯基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-6单环环烷基、-C≡C-3到20元杂环基、-C≡C-苯基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-2烷基-羟基、-C 1-2烷基-氰基、-C 1-2烷基-C 1-4烷基、-C 1-2烷基-C 1-4烷氧基、-C 1-2烷基-C 3-6单环环烷基、-C 1-2烷基-O-C 3-6单环环烷基、-C 1-2烷基-3至20元杂环基、-C 1-2烷基-O-3至20元杂环基、-C 1-2烷基-苯基、-C 1-2烷基-O-苯基、-C 1-2烷基-5或6元单环杂芳基、-C 1-2烷基-O-5或6元单环杂芳基、-C 1-2烷基-8至10元双环杂芳基、-C 1-2烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-4烷基、-C(＝O)O-C 3-6单环环烷基、-C(＝O)-C 1-4烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-苯基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-2烷基-S(＝O) 2-C 1-4烷基、-C 1-2烷基-S(＝O) 2-C 3-6单环环烷基、-C 1-2烷基-S(＝O) 2-3至20元杂环基、-C 1-2烷基-C(＝O)O-C 1-4烷基、-C 1-2烷基-C(＝O)O-C 3-6单环环烷基、-C 1-2烷基-C(＝O)-C 1-4烷基、-C 1-2烷基-C(＝O)-C 3-6单环环烷基、-C 1-2烷基-C(＝O)-苯基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C 1-2烷基-NR a1R b1、-C 1-2烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-2烷基-C(＝O)-NR a1R b1、-C 1-2烷基-OR c1、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2、-C 1-2烷基-NR d1-C(＝O)-R c1、-C 1-2烷基-NR d1-C(＝O)-NR a1R b1、-C 1-2烷基-NR d1-S(＝O) 2-R c1、-C 1-2烷基-S(＝O) 2-NR a1R b1、-C 1-2烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-4烷基、所述C 1-4烷氧基、所述C 2-4烯基、所述C 2-4炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-6单环环烷基、所述3到20元杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子。 In one embodiment, the groups of each S1 group are each independently selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C1-4 alkyl, C2-4 Alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, 3 to 20 membered heterocyclyl, phenyl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-6 membered monocyclic cycloalkyl, -O-3 to 20 membered heterocyclyl, -O-phenyl, -O-5 or 6 membered monocyclic heteroaryl, - O-8 to 10 membered bicyclic heteroaryl, -C≡CC 3-6 monocyclic cycloalkyl, -C≡C-3 to 20 membered heterocyclyl, -C≡C-phenyl, -C≡C- 5- or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-2 alkyl-hydroxy, -C 1-2 alkyl-cyano, -C 1-2 Alkyl-C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkane base-OC 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-3 to 20-membered heterocyclyl, -C 1-2 alkyl-O-3 to 20-membered heterocyclyl, -C 1- 2 alkyl-phenyl, -C 1-2 alkyl-O-phenyl, -C 1-2 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-2 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-2 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-2 alkyl-O-8 to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-4 alkyl, -S(=O) 2 -C 3-6 monocyclic cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O)OC 1-4 alkyl, -C(=O)OC 3-6 monocyclic cycloalkyl, -C(=O)-C 1-4 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-phenyl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-2 alkyl-S(=O) 2 - C 1-4 alkyl, -C 1-2 alkyl-S(=O) 2 -C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-2 alkyl-C(=O)OC 1-4 alkyl, -C 1-2 alkyl-C(=O)OC 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C(=O)-C 1-4 alkyl, -C 1-2 alkyl-C(=O)-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl -C(=O)-phenyl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C 1-2 alkyl -NR a1 R b1 , -C 1-2 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡CC 1-2 alkyl-C (=O)-NR a1 R b1 , -C 1-2 alkyl-OR c1 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , -P(=O)-(C 1-4 alkane base) 2 , -C 1-2 alkyl-NR d1 -C(=O)-R c1 , -C 1-2 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1- 2 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-2 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-2 alkyl-NR d1 -S( =O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; wherein, the C 1-4 alkyl group, the C 1-4 alkoxy group group, the C 2-4 alkenyl group, and the C 2-4 alkynyl group are each independently optionally substituted with 1, 2 or 3 groups selected from halogen, deuterium, cyano or hydroxyl; Each of the C 3-6 monocyclic cycloalkyl group, the 3- to 20-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group independently optionally substituted with 1, 2, 3 or 4 groups selected from group S2; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 20-membered heterocyclic group The 10-membered bicyclic heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms.
在一实施方案中，各个S4组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、氘代C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-6单环环烷基、3到20元杂环基、苯基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-6单环环烷基、-O-3到20元杂环基、-O-苯基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-6单环环烷基、-C≡C-3到20元杂环基、-C≡C-苯基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-2烷基-羟基、-C 1-2烷基-氰基、-C 1-2烷基-氘代C 1-4烷基、-C 1-2烷基-C 1-4烷氧基、-C 1-2烷基-C 3-6单环环烷基、-C 1-2烷基-O-C 3-6单环环烷基、 -C 1-2烷基-3至20元杂环基、-C 1-2烷基-O-3至20元杂环基、-C 1-2烷基-苯基、-C 1-2烷基-O-苯基、-C 1-2烷基-5或6元单环杂芳基、-C 1-2烷基-O-5或6元单环杂芳基、-C 1-2烷基-8至10元双环杂芳基、-C 1-2烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-4烷基、-C(＝O)O-C 3-6单环环烷基、-C(＝O)-C 1-4烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-苯基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-2烷基-S(＝O) 2-C 1-4烷基、-C 1-2烷基-S(＝O) 2-C 3-6单环环烷基、-C 1-2烷基-S(＝O) 2-3至20元杂环基、-C 1-2烷基-C(＝O)O-C 1-4烷基、-C 1-2烷基-C(＝O)O-C 3-6单环环烷基、-C 1-2烷基-C(＝O)-C 1-4烷基、-C 1-2烷基-C(＝O)-C 3-6单环环烷基、-C 1-2烷基-C(＝O)-苯基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C 1-2烷基-NR a1R b1、-C 1-2烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-2烷基-C(＝O)-NR a1R b1、-C 1-2烷基-OR c1、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2、-C 1-2烷基-NR d1-C(＝O)-R c1、-C 1-2烷基-NR d1-C(＝O)-NR a1R b1、-C 1-2烷基-NR d1-S(＝O) 2-R c1、-C 1-2烷基-S(＝O) 2-NR a1R b1、-C 1-2烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，除了上述氘代C 1-4烷基外，任意基团中所述C 1-4烷基、所述C 1-4烷氧基、所述C 2-4烯基、所述C 2-4炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-6单环环烷基、所述3到20元杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子。 In one embodiment, the groups of each S4 group are each independently selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, deuterated C1-4 alkyl, C2 -4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, 3 to 20 membered heterocyclyl, phenyl, 5 or 6 membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-6 monocyclic cycloalkyl, -O-3 to 20-membered heterocyclyl, -O-phenyl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-6 monocyclic cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡C-phenyl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-2 alkyl-hydroxy, -C 1-2 alkyl-cyano, -C 1 -2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-3 to 20-membered heterocyclyl, -C 1-2 alkyl-O-3 to 20-membered heterocyclyl, -C 1-2 alkyl-phenyl, -C 1-2 alkyl-O-phenyl, -C 1-2 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-2 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-2 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-2 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-4 alkyl, -S(=O) 2 -C 3-6 monocyclic cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C( =O)OC 1-4 alkyl, -C(=O)OC 3-6 monocyclic cycloalkyl, -C(=O)-C 1-4 alkyl, -C(=O)-C 3- 6 monocyclic cycloalkyl, -C(=O)-phenyl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-2 alkyl-S(= O) 2 -C 1-4 alkyl, -C 1-2 alkyl-S(=O) 2 -C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-S(=O) 2 -3- to 20-membered heterocyclyl, -C 1-2 alkyl-C(=O)OC 1-4 alkyl, -C 1-2 alkyl-C(=O)OC 3-6 monocyclic cycloalkane base, -C 1-2 alkyl-C(=O)-C 1-4 alkyl, -C 1-2 alkyl-C(=O)-C 3-6 monocyclic cycloalkyl, -C 1 -2 alkyl-C(=O)-phenyl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C 1 -2 alkyl-NR a1 R b1 , -C 1-2 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡CC 1-2 Alkyl-C(=O)-NR a1 R b1 , -C 1-2 alkyl-OR c1 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , -P(=O)-(C 1- 4 alkyl) 2 , -C 1-2 alkyl-NR d1 -C(=O)-R c1 , -C 1-2 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-2 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-2 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-2 alkyl-NR d1 - S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; wherein, except for the above-mentioned deuterated C 1-4 alkyl group, any group The C 1-4 alkyl group, the C 1-4 alkoxy group, the C 2-4 alkenyl group, and the C 2-4 alkynyl group are each independently optionally replaced by 1, 2 or Substituted with 3 groups selected from halogen, deuterium, cyano or hydroxyl; the C 3-6 monocyclic cycloalkyl, the 3- to 20-membered heterocyclyl, the phenyl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom.
在一实施方案中，各个R a、各个R b、各个R a1、各个R b1各自独立地为氢、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、-C 1-2烷基-羟基、-C 1-2烷基-氰基、-C 1-2烷基-卤代C 1-4烷基、-C 1-2烷基-氘代C 1-4烷基、-C 1-2烷基-C 1-4烷氧基、-C 1-2烷基-卤代C 1-4烷氧基、-C 1-2烷基-氘代C 1-4烷氧基、C 3-6单环环烷基、-C 1-2烷基-C 3-6单环环烷基、-C 1-2烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-2烷基-3至6元单环杂环基、-C 1-2烷基-O-3至6元单环杂环基、苯基、-C 1-2烷基-苯基、5或6元单环杂芳基、-C 1-2烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-2烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-4烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2；或 In one embodiment, each R a , each R b , each R a1 , each R b1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl base, -C 1-2 alkyl-hydroxyl, -C 1-2 alkyl-cyano, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterium Substituted C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-2 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-2 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-2 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-2 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-2 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-4 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-4 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-4 alkyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy, deuterated C 1-4 alkoxy Oxy group, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , -P(=O)-(C 1-4 alkyl) 2 ; or
各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2。 Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclyl groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-4 alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, -NH 2 , -NHC 1-4 alkoxy base, -N(C 1-4 alkyl) 2 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , -P(=O)-(C 1-4 alkyl) 2 .
在一实施方案中，各个R d、各个R d1各自独立地为氢、C 1-4烷基或氘代C 1-4烷基。 In one embodiment, each R d , each R d1 is each independently hydrogen, C 1-4 alkyl, or deuterated C 1-4 alkyl.
在一实施方案中，各个R c、各个R c1各自独立地为氢、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、-C 1-2烷基-卤代C 1-4烷基、-C 1-2烷基-氘代C 1-4烷基、-C 1-2烷基-C 1-4烷氧基、-C 1-2烷基-卤代C 1-4烷氧基、-C 1-2烷基-氘代C 1-4烷氧基、C 3-6单环环烷基、-C 1-2烷基-C 3-6单环环烷基、-C 1-2烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-2烷基-3至6元单环杂 环基、-C 1-2烷基-O-3至6元单环杂环基、苯基、-C 1-2烷基-苯基、5或6元单环杂芳基、-C 1-2烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-2烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2。 In one embodiment, each R c , each R c1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy base, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterated C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-2 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-2 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-2 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-2 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-2 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy , -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , - P(=O)-(C 1-4 alkyl) 2 .
在一实施方案中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-C 1-2烷基-P(＝O)-(C 1-4烷基) 2、-P(＝O)-(C 1-4烷基) 2。 In one embodiment, the groups of each S2 group are each independently selected from the group consisting of oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C1-4 alkyl, halogenated C1-4 Alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, -NH 2 , -NHC 1-4 alkoxy base, -N(C 1-4 alkyl) 2 , -C 1-2 alkyl-P(=O)-(C 1-4 alkyl) 2 , -P(=O)-(C 1-4 alkyl) 2 .
在一实施方案中，所述-C 1-2烷基-为未取代的；或者-C 1-2烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-2烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6。 In one embodiment, the -C 1-2 alkyl- is unsubstituted; or the hydrogen atoms on the -C 1-2 alkyl- are each independently selected from halogen, cyano, hydroxyl, C 1- 4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, -CH 2 -hydroxyl group, -CH 2 -cyano group, phenyl group substituted or C 1-2 alkyl group Two hydrogen atoms of the same carbon atom are simultaneously substituted with -(CH 2 ) j - to form a cycloalkyl group, where j is 2, 3, 4, 5 or 6.
在一实施方案中，任何一个3到20元杂环基选自下组：3到6元单环杂环基、7至11元螺杂环基、6至10元稠杂环基、6到14元桥杂环基。In one embodiment, any 3 to 20 membered heterocyclyl is selected from the group consisting of: 3 to 6 membered monocyclic heterocyclyl, 7 to 11 membered spiroheterocyclyl, 6 to 10 membered fused heterocyclyl, 6 to 10 membered heterocyclyl 14-membered bridged heterocyclyl.
在一实施方案中，任何一个3到6元单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；所述3到6元单环杂环基任选地被1、2、3或4个选自S1组的基团所取代。In one embodiment, any 3 to 6 membered monocyclic heterocyclyl is selected from the group consisting of: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 3- to 6-membered monocyclic heterocyclic group is optionally replaced by 1, substituted with 2, 3 or 4 groups selected from group S1.
在一实施方案中，任何一个5或6元单环杂芳基选自下组：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪；所述5或6元单环杂芳基任选地被1、2、3或4个选自S1组的基团所取代。In one embodiment, any one 5 or 6 membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine ; The 5- or 6-membered monocyclic heteroaryl group is optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group.
如本文所述，
Figure PCTCN2022085658-appb-000075
可以被称为Cy2环。
Figure PCTCN2022085658-appb-000076
可以被称为Cy1环。 As described in this article,
Figure PCTCN2022085658-appb-000075
may be referred to as the Cy2 ring.
Figure PCTCN2022085658-appb-000076
may be referred to as the Cy1 ring.
本发明第四方面提供了一种药物组合物，所述药物组合物包括上述第一或二或三方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。A fourth aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
如本文所用，术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or subject , including water, oil, vegetable and mineral, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，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、腹膜内或静脉内给药方式。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制 成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。In embodiments of the invention, the pharmaceutical composition may be administered orally, by inhalation, rectally, nasally, bucally, topically, parenterally, such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir. Of these, oral, intraperitoneal or intravenous administration is preferred. When administered orally, the compounds of the present invention may be formulated in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and cornstarch, although lubricants such as magnesium stearate may also be added. Diluents used in capsule formulations typically include lactose and dried cornstarch. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations. When topical administration is used, especially when treating affected surfaces or organs that are easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be prepared into different topical formulations according to different affected surfaces or organs Forms, when administered topically to the eye, the compounds of the present invention may be formulated as a micronized suspension or solution in the form of an isotonic, pH, sterile, isotonic carrier, with or without the addition of a preservative such as Benzyl alkoxide chloride. For ophthalmic use, the compounds can also be formulated in the form of an ointment such as petrolatum ointment. When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions. Useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can also be employed as a solvent or suspending medium such as mono- or diglycerides.
本发明另一方面提供了上述第一或二或三方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或上述第四方面所述药物组合物在制备预防和/或治疗疾病或病症的药物中的用途；所述疾病或病症与HPK1活性相关的疾病或病症。例如所述疾病或病症为癌症。Another aspect of the present invention provides the compound of the above-mentioned first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the above-mentioned fourth aspect in the preparation of prophylaxis and/or use in a medicament for the treatment of a disease or condition; a disease or condition associated with HPK1 activity. For example, the disease or disorder is cancer.
本发明另一方面提供了上述第一或二或三方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或如上述第四方面所述药物组合物在制备HPK1抑制剂中的用途。Another aspect of the present invention provides the compound described in the first, second or third aspect above, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition described in the fourth aspect above. Use in HPK1 inhibitors.
本发明另一方面提供了一种治疗癌症的方法，其包括向有此需要的受试者施用治疗有效量的上述第一或二或三方面所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，或上述的任意组合，或施用上述第四方面所述的药物组合物的步骤。Another aspect of the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described in the first, second or third aspect or a pharmaceutically acceptable salt thereof, A stereoisomer, solvate or prodrug, or any combination of the above, or the step of administering the pharmaceutical composition of the fourth aspect above.
如本文所用，术语“受试者”是指动物，特别是哺乳动物。优选人。As used herein, the term "subject" refers to an animal, particularly a mammal. People are preferred.
如本文所用，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug depends on factors such as the particular dosing regimen, the type of disease or condition and its severity, the subject in need of treatment or the uniqueness of the host (e.g. body weight), however, the dose to be administered may be known in the art depending on the particular surrounding circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated method is routinely determined. Generally, for adult therapeutic use, the administered dose is typically in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day. The desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
如本文所用，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include: acid addition salts with inorganic acids or organic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, caproic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
如本文所用，术语“溶剂合物”和“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括乙酸等。溶剂合物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在。一般而言，溶剂化形式与非溶剂 化的形式相当，都包含在本发明的范围之内。As used herein, the terms "solvate" and "solvate" refer to substances formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid and the like. Solvates include stoichiometric amounts and non-stoichiometric amounts of solvates. Certain compounds of the present invention may exist in unsolvated as well as solvated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
如本文所用，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。且作为药物，具有优异活性的立体异构体是优选的。本发明化合物具有源于不对称碳等的光学异构体，必要时单一异构体可通过本领域已知的方法，例如结晶或手性色谱等方法进行拆分获得。As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present invention may exist in stereoisomeric forms, and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc., the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture. For example, a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof. Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation. And as a drug, a stereoisomer having excellent activity is preferable. The compounds of the present invention have optical isomers derived from asymmetric carbons and the like, and if necessary, single isomers can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.
如本文所用，术语“卤代苯基”是指只有卤素作为取代基的苯基；不包括苯基上的一个取代基为卤素，其它取代基为除卤素外的取代基。As used herein, the term "halophenyl" refers to a phenyl group having only halogen as a substituent; excluding one substituent on the phenyl group which is a halogen and the other substituents being substituents other than halogen.
如本文所用，术语“烷基”指直链或支链饱和脂肪族烃基基团。术语“C 1-20烷基”指具有1到20个碳原子的直链或支链烷基。优选是C 1-10烷基。更优选是C 1-6烷基(即具有1、2、3、4、5或6个碳原子的直链或支链烷基)。更优选是C 1-4烷基。更优选是C 1-3烷基。具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。 As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbyl group. The term "C 1-20 alkyl" refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Preferably it is a C 1-10 alkyl group. More preferred are C1-6 alkyl groups (ie straight or branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferred is C 1-4 alkyl. More preferred is C 1-3 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers, etc.
如本文所用，术语“烷氧基”指具有-O-烷基结构的基团，其中烷基的定义如上所述。术语“C 1-10烷氧基”指具有1到10个碳原子的烷氧基。优选是C 1-6烷氧基。更优选是C 1-4烷氧基。更优选是C 1-3烷氧基。具体实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、正戊氧基等。 As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, wherein alkyl is as defined above. The term "C 1-10 alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms. Preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy. More preferred is C 1-3 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.
如本文所用，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基。术语“C 2-8烯基”指具有2到8个碳原子和至少一个(例如1到2个)碳-碳双键的烯基。优选为C 2-6烯基(即具有2到6个碳原子和1到2个碳-碳双键的烯基)。更优选为C 2-4烯基(即具有2到4个碳原子和1到2个碳-碳双键的烯基)。具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。 As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain. The term "C 2-8 alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one (eg, 1 to 2) carbon-carbon double bond. Preferred is a C2-6 alkenyl group (ie an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferred is a C2-4 alkenyl group (ie an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.
如本文所用，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基。术语“C 2-8炔基”指具有2到8个碳原子和至少一个(例如1到2个)碳-碳三键的炔基。优选为C 2-6炔基(即具有2到6个碳原子和1到2个碳-碳三键的炔基)。更优选为C 2-4炔基(即具有2到4个碳原子和1到2个碳-碳三键的炔基)。具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。 As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain. The term "C 2-8 alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms and at least one (eg, 1 to 2) carbon-carbon triple bond. Preferred is a C2-6 alkynyl group (ie an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferred is a C 2-4 alkynyl group (ie an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
如本文所用，术语“卤素”指氟、氯、溴或碘。As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
如本文所用，术语“卤代”指氟代、氯代、溴代或碘代。As used herein, the term "halo" refers to fluoro, chloro, bromo or iodo.
如本文所用，术语“卤代烷基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烷基，其中烷基的定义如上所述。术语“卤代C 1-10烷基”指具有1到10个碳原子的卤代烷基。优选为卤代C 1-6烷基。更优选为卤代C 1-4烷基。更优选为卤代C 1-3烷基。具体实例包括但不限于一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙 基、二氟乙基、三氟乙基等。 As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein alkyl is as defined above. The term "haloC 1-10 alkyl" refers to a haloalkyl group having 1 to 10 carbon atoms. Preferred is halogenated C 1-6 alkyl. More preferred is a halogenated C 1-4 alkyl group. More preferred is a halogenated C 1-3 alkyl group. Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl and the like.
如本文所用，术语“卤代烷氧基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烷氧基，其中烷氧基的定义如上所述。术语“卤代C 1-10烷氧基”指具有1到10个碳原子的卤代烷氧基。优选为卤代C 1-6烷氧基。更优选为卤代C 1-4烷氧基。更优选为卤代C 1-3烷氧基。具体实例包括但不限于三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。 As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein alkoxy is as defined above. The term "haloC 1-10 alkoxy" refers to a haloalkoxy having 1 to 10 carbon atoms. Preferred is halogenated C 1-6 alkoxy. More preferred is a halogenated C 1-4 alkoxy group. More preferred is a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
如本文所用，术语“氘代”是指某基团中一个或多个氢原子被氘原子所取代。As used herein, the term "deuterated" refers to the replacement of one or more hydrogen atoms in a group with deuterium atoms.
如本文所用，术语“氘代烷基”指一个或多个(如1、2、3、4或5个)氢原子被氘原子取代的烷基，其中烷基的定义如上所述。术语“氘代C 1-10烷基”指具有1到10个碳原子的氘代烷基。优选为氘代C 1-6烷基。更优选为氘代C 1-4烷基。更优选为氘代C 1-3烷基。具体实例包括但不限于一氘甲基、二氘甲基、三氘甲基、一氘乙基、1,2-二氘乙基、三氘乙基等。 As used herein, the term "deuterated alkyl" refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by deuterium atoms, wherein alkyl is as defined above. The term "deuterated C 1-10 alkyl" refers to a deuterated alkyl group having 1 to 10 carbon atoms. Deuterated C 1-6 alkyl is preferred. More preferred is deuterated C 1-4 alkyl. More preferred is deuterated C 1-3 alkyl. Specific examples include, but are not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, monodeuteroethyl, 1,2-dideuteroethyl, trideuteroethyl, and the like.
如本文所用，术语“氘代烷氧基”指一个或多个(如1、2、3、4或5个)氢原子被氘原子取代的烷氧基，其中烷氧基的定义如上所述。术语“氘代C 1-10烷氧基”指具有1到10个碳原子的氘代烷氧基。优选为氘代C 1-6烷氧基。更优选为氘代C 1-4烷氧基。更优选为氘代C 1-3烷氧基。具体实例包括但不限于三氘甲氧基、三氘乙氧基、一氘甲氧基、一氘乙氧基、二氘甲氧基、二氘乙氧基等。 As used herein, the term "deuterated alkoxy" refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein alkoxy is as defined above . The term "deuterated C 1-10 alkoxy" refers to a deuterated alkoxy group having 1 to 10 carbon atoms. Preferred is deuterated C 1-6 alkoxy. More preferred is deuterated C 1-4 alkoxy. More preferred is deuterated C 1-3 alkoxy. Specific examples include, but are not limited to, tri-deuteriomethoxy, tri-deuteroethoxy, mono-deuteromethoxy, mono-deuteroethoxy, dideuteromethoxy, dideuteroethoxy, and the like.
如本文所用，术语“环烷基”和“环烷基环”可互换使用，指饱和单环或多环的环状烃基，例如包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。本发明中所述环烷基的环碳原子可任选地被1、2或3个氧代基取代形成环酮结构。术语“3到20元环烷基”或“C 3-20环烷基”指具有3到20个环碳原子的环烷基，包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。优选为C 3-12环烷基、C 5-20螺环烷基、C 5-20稠环烷基或C 5-20桥环烷基。更优选C 3-8单环环烷基。 As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkanes and bridged cycloalkyl groups. The ring carbon atoms of the cycloalkyl group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. The term "3 to 20 membered cycloalkyl" or "C 3-20 cycloalkyl" refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. Preferably it is C 3-12 cycloalkyl, C 5-20 spirocycloalkyl, C 5-20 fused cycloalkyl or C 5-20 bridged cycloalkyl. More preferred is C 3-8 monocyclic cycloalkyl.
术语“C 3-8单环环烷基”和“3到8元单环环烷基”指具有3到8个环碳原子的饱和单环环状烃基。优选为C 3-6单环环烷基(即3至6元单环环烷基)或C 4-6单环环烷基(即4至6元单环环烷基)。更优选为C 3、C 4、C 5或C 6单环环烷基。单环环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。 The terms "C 3-8 monocyclic cycloalkyl" and "3- to 8-membered monocyclic cycloalkyl" refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms. Preferably it is a C 3-6 monocyclic cycloalkyl group (ie, a 3- to 6-membered monocyclic cycloalkyl group) or a C 4-6 monocyclic cycloalkyl group (ie, a 4- to 6-membered monocyclic cycloalkyl group). More preferred is a C3, C4 , C5 or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
如本文所用，术语“螺环烷基”和“螺环烷基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基和多螺环烷基。术语“5到20元螺环烷基”或“C 5-20螺环烷基”指具有5到20个环碳原子的多环环状烃基，其中共用螺原子的单环为3到8元单环环烷基环。优选为6到14元(即C 6-14)螺环烷基。更优选为6到14元单螺环烷基。更优选为7到11元(即C 7-11)螺环烷基。更优选为7到11元单螺环烷基。最优选为7元(4元单环环烷基环/4元单环环烷基环)、8元(4元单环环烷基环/5元单环环烷基环)、9元(4元单环环烷基环/6元单环环烷基环，5元单环环烷基环/5元单环环烷基环)、10元(5元单环环烷基环/6元单环环烷基环)或11元(6元单环环烷基环/6元单环环烷基环)单螺环烷基。螺环烷基的具体实例包括但不限于：
Figure PCTCN2022085658-appb-000077
As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, double-spirocycloalkyl groups and poly-spirocycloalkyl groups. The term "5- to 20-membered spirocycloalkyl" or "C 5-20 spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the single ring sharing the spiro atoms is 3 to 8 membered Monocyclic cycloalkyl ring. Preferred are 6 to 14 membered (ie C6-14 ) spirocycloalkyl. More preferred is a 6- to 14-membered monospirocycloalkyl. More preferred is a 7- to 11-membered (ie C7-11 ) spirocycloalkyl. More preferred is a 7- to 11-membered monospirocycloalkyl. Most preferably 7-membered (4-membered monocyclic cycloalkyl ring/4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring/5-membered monocyclic cycloalkyl ring), 9-membered ( 4-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring/5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring/6 (6-membered monocyclic cycloalkyl ring) or 11-membered (6-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:
Figure PCTCN2022085658-appb-000077
这些螺环烷基可通过任意一个环原子与分子其余部分连接。These spirocycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
如本文所用，术语“稠环烷基”和“稠环烷基环”指两个或两个以上的单环通过共享毗邻的一对碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环稠环烷基。术语“5到20元稠环烷基”或“C 5-20稠环烷基”指具有5到20个环碳原子的多环环状烃基，其中共享毗邻碳原子对的单环为3到8元单环环烷基环。优选为6到14元(即C 6-14)稠环烷基。更优选为6到14元双稠环烷基。 更优选为7到10元(即C 7-10)稠环烷基。更优选为7到10元双稠环烷基。最优选为8元(5元单环环烷基环与5元单环环烷基环稠合)、9元(5元单环环烷基环与6元单环环烷基环稠合)或10元(6元单环环烷基环与6元单环环烷基环稠合)双稠环烷基。稠环烷基的具体实例包括但不限于： As used herein, the terms "fused cycloalkyl" and "fused cycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group in which two or more monocyclic rings are formed by sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl. The term "5 to 20 membered fused cycloalkyl" or " C5-20 fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are 3 to 20 ring carbon atoms. 8-membered monocyclic cycloalkyl ring. Preferably it is a 6- to 14-membered (ie C 6-14 ) fused cycloalkyl group. More preferred is a 6- to 14-membered di-fused cycloalkyl group. More preferred is a 7- to 10-membered (ie C 7-10 ) fused cycloalkyl group. More preferred is a 7- to 10-membered di-fused cycloalkyl group. Most preferably 8-membered (5-membered monocyclic cycloalkyl ring fused with 5-membered monocyclic cycloalkyl ring), 9-membered (5-membered monocyclic cycloalkyl ring fused with 6-membered monocyclic cycloalkyl ring) Or 10-membered (6-membered monocyclic cycloalkyl ring fused with 6-membered monocyclic cycloalkyl ring) double-fused cycloalkyl. Specific examples of fused cycloalkyl include, but are not limited to:
Figure PCTCN2022085658-appb-000078
Figure PCTCN2022085658-appb-000078
这些稠环烷基可通过任意一个环原子与分子其余部分连接。These fused cycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
如本文所用，术语“桥环烷基”和“桥环烷基环”指两个或两个以上的单环之间通过共用两个不直接连接的碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“5到20元桥环烷基”和“C 5-20桥环烷基”指具有5到20个环碳原子的多环环状烃基，其中任意两个环共用两个不直接连接的碳原子。优选为6到14元(即C 6-14)桥环烷基。更优选为7到10元(即C 7-10)桥环烷基。桥环烷基的具体实例包括但不限于： As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by sharing two non-directly attached carbon atoms between two or more monocyclic rings. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. The terms "5- to 20-membered bridged cycloalkyl" and "C 5-20 -membered bridged cycloalkyl" refer to polycyclic cyclic hydrocarbon groups having 5 to 20 ring carbon atoms in which any two rings share two non-directly connected carbon atom. Preferred is a 6- to 14-membered (ie C6-14 ) bridged cycloalkyl. More preferred is a 7- to 10-membered (ie C7-10 ) bridged cycloalkyl. Specific examples of bridged cycloalkyl groups include, but are not limited to:
Figure PCTCN2022085658-appb-000079
Figure PCTCN2022085658-appb-000079
这些桥环烷基可通过任意一个环原子与分子其余部分连接。These bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.
如本文所用，术语“卤代环烷基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的环烷基，其中环烷基的定义如上所述。As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein cycloalkyl is as defined above.
如本文所用，术语“卤代C 3-8单环环烷基”指具有3到8个环碳原子的卤代单环环烷基。优选为卤代C 3-6单环环烷基。更优选为卤代C 3、卤代C 4、卤代C 5或卤代C 6单环环烷基。具体实例包括但不限于三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。 As used herein, the term "haloC 3-8 monocyclic cycloalkyl" refers to a halogenated monocyclic cycloalkyl having 3 to 8 ring carbon atoms. Preferably it is a halogenated C 3-6 monocyclic cycloalkyl. More preferred is a haloC3 , haloC4 , haloC5 or haloC6 monocyclic cycloalkyl. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
如本文所用，术语“杂环基”和“杂环基环”可互换使用，指饱和或部分不饱和单环或多环的环状烃基，例如包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。术语“3到20元杂环基”指具有3到20个环原子的饱和或部分不饱和单环或多环的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中当环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。本发明所述的3到20元杂环基包括单环杂环基(例如3到8元单环杂环基)、5到20元螺杂环基、5到20元稠杂环基和5到20元桥杂环基。 As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclyl and bridged heterocyclyl. The ring carbon atoms of the heterocyclic group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. The term "3- to 20-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 20 ring atoms, of which one or more (preferably 1, 2, 3 or 4 ) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the rest The ring atoms are carbon. Wherein when the ring atom is a nitrogen atom, it may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein). The 3- to 20-membered heterocyclyl groups of the present invention include monocyclic heterocyclyl groups (eg, 3- to 8-membered monocyclic heterocyclyl groups), 5- to 20-membered spiro heterocyclyl groups, 5- to 20-membered fused heterocyclyl groups, and 5- to 20-membered fused heterocyclyl groups. to 20-membered bridged heterocyclyl.
如本文所用，术语“3到8元单环杂环基”和“3到8元单环杂环基环”指具有3到8个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3至6元单环杂环基。更优选为具有4到6个环原子，其中1或2个环原子为杂原子的4至6元单环杂环基。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(＝O) m'，m'是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑 烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。 As used herein, the terms "3- to 8-membered monocyclic heterocyclyl" and "3- to 8-membered monocyclic heterocyclyl ring" refer to having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are selected from A saturated or partially unsaturated monocyclic cyclic hydrocarbon radical of nitrogen, oxygen or a heteroatom of S(=O) m ' (where m' is an integer from 0 to 2). Preferred are 3- to 6-membered monocyclic heterocyclyl groups having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 4- to 6-membered monocyclic heterocyclyl group having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 5- or 6-membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (ie, S(=O) m ', where m' is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocyclyl may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclyl groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -one, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3 -Dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholine -2-keto, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydro Azetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3 -Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-2-one, 5 ,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridine-2(1H)-one Hydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro- 1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene , 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydro Pyrazine, 1,3-dihydro-2H-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H) -ketone, furan-2(5H)-one, 1,3-dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2- ketone, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H- Pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1, 3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.
如本文所用，术语“3至6元含氮杂环基”指具有3到6个环原子，其中1个环原子为氮原子，其他1个或2个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。具体实例包括但不限于氮杂丙环基、氮杂环丁烷基、氮杂戊环基(即四氢吡咯)、氮杂己环基(即六氢吡啶)、吗啉基、哌嗪基、噁唑烷。 As used herein, the term "3- to 6-membered nitrogen-containing heterocyclyl" refers to a group having 3 to 6 ring atoms, wherein 1 ring atom is a nitrogen atom and the other 1 or 2 ring atoms are selected from nitrogen, oxygen or S (=O) m ' (wherein m' is an integer from 0 to 2) is a saturated or partially unsaturated monocyclic cyclic hydrocarbon group of a heteroatom. Specific examples include, but are not limited to, aziridine, azetidinyl, azepanyl (ie, tetrahydropyrrole), azepinyl (ie, hexahydropyridine), morpholinyl, piperazinyl , oxazolidine.
如本文所用，术语“3到8元单环杂环烷基”指具有3到8个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。优选为3至6元单环杂环烷基，即具有3到6个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。杂环烷基具体实例包括但不限于氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、噁唑烷基、1,3-二氧戊环基、二氧六环基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、硫代吗啉-1,1-二氧化物基、四氢吡喃基、1,4-氧氮杂环庚烷基、1,3-氧氮杂环庚烷基、1,3-噁嗪烷基、六氢嘧啶基、1,4-二噁烷基。As used herein, the term "3 to 8 membered monocyclic heterocycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms. Preferably it is a 3- to 6-membered monocyclic heterocycloalkyl, ie a saturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, Dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-dioxanyl.
上述单环杂环基环上相连的2个环原子，包括C-C、N-C均可任选地与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂环基上相连的2个环原子优选地为C-C。The two ring atoms connected to the above-mentioned monocyclic heterocyclyl ring, including C-C and N-C, can be optionally combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring. The 2 ring atoms attached to the monocyclic heterocyclic group forming a fused ring with other rings are preferably C-C.
如本文所用，术语“螺杂环基”和“螺杂环基环”指两个或两个以上的饱和或部分不饱和单环之间共用一个碳原子(称螺原子)形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。术语“5到20元螺杂环基”指具有5到20个环原子的螺杂环基，其中共用螺原子的单环中一个单环为3到8元单环杂环基环，另一个单环为3到8元单环杂环基环或3到8元单环环烷基环。优选为具有6到14个环原子，其中1或2个环原子为杂原子的6到14元螺杂环基。更优选为具有7到11个环原子，其中1或2个环原子为杂原子的7至11元螺杂环基。最优选为7元(4元单环杂环基环/4元单环杂环基环或4元单环杂环基环/4元单环环烷基或4元单环环烷基环/4元单环杂环基环)、8元(4元单环杂环基环/5元单环杂环基环)、9元(4元单环杂环基环/6元单环杂环基环，5元单环杂环基环/5元单环杂环基环)、10元(5元单环杂环基环/6元单环杂环基环)或11元(6元单环杂环基环/6元单环杂环基环)单螺杂环基。螺杂环基的具体实例包括但不限于： As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (referred to as a spiro atom). A ring group in which one or more (eg 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer from 0 to 2) and the remaining ring atoms for carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein). Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system. Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings. The term "5- to 20-membered spiroheterocyclyl" refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocycles sharing the spiro atoms is a 3- to 8-membered monocyclic heterocyclyl ring and the other The monocycle is a 3- to 8-membered monocyclic heterocyclyl ring or a 3- to 8-membered monocyclic cycloalkyl ring. Preferred are 6- to 14-membered spiroheterocyclyl groups having 6 to 14 ring atoms, of which 1 or 2 are heteroatoms. More preferred are 7 to 11 membered spiroheterocyclyl groups having 7 to 11 ring atoms, of which 1 or 2 are heteroatoms. Most preferably 7-membered (4-membered monocyclic heterocyclyl ring/4-membered monocyclic heterocyclyl ring or 4-membered monocyclic heterocyclyl ring/4-membered monocyclic cycloalkyl or 4-membered monocyclic cycloalkyl ring/ 4-membered monocyclic heterocyclyl ring), 8-membered (4-membered monocyclic heterocyclyl ring/5-membered monocyclic heterocyclyl ring), 9-membered (4-membered monocyclic heterocyclyl ring/6-membered monocyclic heterocyclic ring) base ring, 5-membered monocyclic heterocyclyl ring/5-membered monocyclic heterocyclyl ring), 10-membered (5-membered monocyclic heterocyclyl ring/6-membered monocyclic heterocyclyl ring) or 11-membered (6-membered monocyclic heterocyclyl ring) Cycloheterocyclyl ring/6-membered monocyclic heterocyclyl ring) monospiroheterocyclyl. Specific examples of spiroheterocyclyl include, but are not limited to:
Figure PCTCN2022085658-appb-000080
Figure PCTCN2022085658-appb-000080
这些螺杂环基可通过任意一个合适的环原子与分子其余部分连接。These spiroheterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
如本文所用，术语“稠杂环基”和“稠杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共享毗邻的一对环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。共享的毗邻环原子对可以是C-C或N-C。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基。术语“5到20元稠杂环基”指具有5到20个环原子的稠杂环基，其中共享毗邻环原子对的单环为3到8元单环杂环基环。优选为具有6到14个环原子，其中1或2个环原子为杂原子的6到14元稠杂环基。更优选为具有6到10个环原子，其中1或2个环原子为杂原子的6至10元稠杂环基。更优选为具有8到10个环原子，其中1或2个环原子为杂原子的8到10元稠杂环基。最优选为8元(5元单环杂环基环与5元单环杂环基环稠合)、9元(5元单环杂环基环与6元单环杂环基环稠合)或10元(6元单环杂环基环与6元单环杂环基环稠合)双环稠杂环基。稠杂环基的具体实例包括但不限于： As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing an adjacent pair of ring atoms, wherein one or more (eg 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer from 0 to 2) and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein). Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system. Shared pairs of adjacent ring atoms can be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups. The term "5- to 20-membered fused heterocyclyl" refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein the monocycles sharing adjacent pairs of ring atoms are 3- to 8-membered monocyclic heterocyclyl rings. Preferred is a 6- to 14-membered fused heterocyclic group having 6 to 14 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 6- to 10-membered fused heterocyclic group having 6 to 10 ring atoms, of which 1 or 2 are heteroatoms. More preferred is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, of which 1 or 2 are heteroatoms. Most preferably 8-membered (5-membered monocyclic heterocyclyl ring fused with 5-membered monocyclic heterocyclyl ring), 9-membered (5-membered monocyclic heterocyclyl ring fused with 6-membered monocyclic heterocyclyl ring) Or 10-membered (6-membered monocyclic heterocyclyl ring fused with 6-membered monocyclic heterocyclyl ring) bicyclic fused heterocyclyl. Specific examples of fused heterocyclic groups include, but are not limited to:
Figure PCTCN2022085658-appb-000081
Figure PCTCN2022085658-appb-000081
这些稠杂环基可通过任意一个合适的环原子与分子其余部分连接。These fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
如本文所用，术语“桥杂环基”和“桥杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共用 两个不直接连接的环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子，其余环原子为碳。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“5到20元桥杂环基”指具有5到20个环原子的饱和或部分不饱和多环杂环基团，其中任意两个环共用两个不直接连接的环原子，每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6到14元桥杂环基。更优选为7到10元桥杂环基。桥杂环基的具体实例包括但不限于： As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to a polycyclic heterocycle formed by two or more saturated or partially unsaturated monocyclic rings by sharing two ring atoms that are not directly connected base, wherein one or more (eg 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer from 0 to 2), and the remaining ring atoms are carbon. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. The term "5- to 20-membered bridged heterocyclyl" refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected ring atoms, each monocyclic Rings can contain one or more double bonds, but no ring has a fully conjugated pi electron system. Preferred is a 6- to 14-membered bridged heterocyclyl group. More preferred is a 7- to 10-membered bridged heterocyclyl group. Specific examples of bridged heterocyclyl groups include, but are not limited to:
Figure PCTCN2022085658-appb-000082
Figure PCTCN2022085658-appb-000082
这些桥杂环基可通过任意一个合适的环原子与分子其余部分连接。These bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
在本发明中，上述各类杂环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above various types of heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
如本文所用，术语“芳基”，“芳基环”和“芳环”可互换使用，指全碳单环、全碳非稠合多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。术语“C 6-14芳基”是指具有6到14个环原子的芳基。优选为C 6-10芳基。本发明中C 6-14芳基包括单环芳基、非稠合多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，非稠合多环芳基的实例包括联苯基等。 As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic ring (rings connected to rings by covalent bonds, non-fused group) or all-carbon fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups in which at least one ring is aromatic, ie, has a conjugated pi-electron system. The term "C 6-14 aryl" refers to an aryl group having 6 to 14 ring atoms. Preferably it is a C 6-10 aryl group. The C 6-14 aryl group in the present invention includes a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group, wherein examples of the monocyclic aryl group include phenyl, and examples of the non-fused polycyclic aryl group include Biphenyl, etc.
本发明中，当C 6-14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。 In the present invention, when the C 6-14 aryl group is an aromatic condensed polycyclic ring, the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings , non-limiting examples of which include naphthyl, anthracenyl, and the like.
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.
如本文所用，术语“杂芳基”，“杂芳基环”和“杂芳环”可互换使用，指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6、10或14个π电子，基团中至少一个环是芳族的。术语“5到20元杂芳基”指具有5到20个环原子，其中1、2、3或4个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的杂芳基。优选为5到14元杂芳基。术语“5到14元杂芳基”指具有5到14个环原子，其中1、2、3或4个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的杂芳基。优选为具有5到10个环原子，其中1、2、3或4个环原子为杂原子的5到10元杂芳基。本发明中5到14元杂芳基可以为单环杂芳基、稠合双环杂芳基或稠合三环杂芳基。 As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably to refer to a monocyclic or fused ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur. A polycyclic (ie, shared adjacent pairs of ring atoms, which may be CC or NC) groups in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. The heteroaryl group has 6, 10 or 14 pi electrons shared and at least one ring in the group is aromatic. The term "5 to 20 membered heteroaryl" refers to having 5 to 20 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer 0 to 2) heteroatom heteroaryl. Preferred is a 5- to 14-membered heteroaryl group. The term "5 to 14 membered heteroaryl" refers to having 5 to 14 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen or S(=O) m ' (where m' is an integer 0 to 2) heteroatom heteroaryl. Preferred are 5 to 10 membered heteroaryl groups having 5 to 10 ring atoms of which 1, 2, 3 or 4 are heteroatoms. The 5- to 14-membered heteroaryl group in the present invention may be a monocyclic heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group.
如本文所用，术语“5或6元单环杂芳基”指具有5或6个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的单环杂芳基。单环杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。 As used herein, the term "5 or 6 membered monocyclic heteroaryl" refers to having 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O) m ' (wherein m' is a monocyclic heteroaryl group of heteroatoms of integers 0 to 2). Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole azole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
如本文所用，术语“8至10元双环杂芳基”指具有8到10个环原子，其中1、2、3、4或5个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的稠合双环杂芳基。所述稠合双环杂芳基既 可以是单芳基环(如苯基)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团(优选为9或10元双环杂芳基环)，也可以是单环杂芳基环(优选为5或6元单环杂芳基环)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团。 As used herein, the term "8 to 10 membered bicyclic heteroaryl" refers to having 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from nitrogen, oxygen or S(=O) m '(wherein m' is an integer from 0 to 2) fused bicyclic heteroaryl. The fused bicyclic heteroaryl group can be either a bicyclic group formed by condensing a single aryl ring (such as phenyl) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). is a 9- or 10-membered bicyclic heteroaryl ring), or a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic ring) ring heteroaryl ring) fused to form a bicyclic group.
上述单环杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂芳基环上相连的2个环原子优选地为C-C，非限制性地包括如下形式：The 2 ring atoms connected arbitrarily on the above-mentioned monocyclic heteroaryl ring, including C-C, N-C, N-N, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring. The 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably C-C, including without limitation the following forms:
Figure PCTCN2022085658-appb-000083
Figure PCTCN2022085658-appb-000083
上述基团中通过
Figure PCTCN2022085658-appb-000084
标记的环原子与分子其他部分连接。 through the above groups
Figure PCTCN2022085658-appb-000084
Labeled ring atoms are attached to the rest of the molecule.
8至10元双环杂芳基的非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo [1,2-b]pyridazine, etc.
双环杂芳基具体实例包括但不限于：Specific examples of bicyclic heteroaryl groups include, but are not limited to:
Figure PCTCN2022085658-appb-000085
Figure PCTCN2022085658-appb-000086
这些基团可通过任意一个合适的环原子与分子其余部分连接。与母体结构连接的环可以为单环杂芳基环或苯环。
Figure PCTCN2022085658-appb-000085
Figure PCTCN2022085658-appb-000086
These groups can be attached to the rest of the molecule through any suitable ring atom. The ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单环杂芳基环(优选为5或6元单环杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单环杂芳基环或非芳香环。所述非芳香环包括但不限于3至6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3至6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单环杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单环杂芳基环或非芳香环。In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a A polycyclic group formed by condensing multiple non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure) and the like. The polycyclic group formed by condensing the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic heteroaromatic base ring or non-aromatic ring.
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单环芳基环(优选为苯基)与一个或多个非芳香杂环稠合形成的多环基团，其中与母体结构连接的环为单环芳基环或非芳香 杂环。所述非芳香杂环包括但不限于3至6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)等。上述单环芳基环与一个或多个非芳香杂环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单环芳基环或非芳香杂环。In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic aryl ring (preferably phenyl) fused with one or more non-aromatic heterocycles The resulting polycyclic group wherein the ring attached to the parent structure is a monocyclic aryl ring or a non-aromatic heterocyclic ring. The non-aromatic heterocycle includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be 2 oxo groups are substituted to form a cyclic lactam or cyclic lactone structure), etc. The polycyclic group formed by condensing the above-mentioned monocyclic aryl ring and one or more non-aromatic heterocycles can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic aryl group Ring or non-aromatic heterocycle.
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above various types of heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
如本文所用，术语“羟基”指-OH。As used herein, the term "hydroxy" refers to -OH.
如本文所用，术语“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CH(OH)CH 3。 As used herein, the term "hydroxymethyl" refers to -CH2OH and "hydroxyethyl" refers to -CH2CH2OH or -CH(OH ) CH3 .
如本文所用，术语“氰基甲基”指-CH 2CN，“氰基乙基”指-CH 2CH 2CN或-CHCNCH 3。 As used herein, the term "cyanomethyl" refers to -CH2CN and " cyanoethyl " refers to -CH2CH2CN or -CHCNCH3 .
如本文所用，术语“氨基”指-NH 2。 As used herein, the term "amino" refers to -NH2 .
如本文所用，术语“氰基”指-CN。As used herein, the term "cyano" refers to -CN.
如本文所用，术语“硝基”指-NO 2。 As used herein, the term "nitro" refers to -NO2 .
如本文所用，术语“苄基”指-CH 2-苯。 As used herein, the term "benzyl" refers to -CH2 -benzene.
如本文所用，术语“氧代基”指＝O。As used herein, the term "oxo" refers to =O.
如本文所用，术语“羧基”指-C(O)OH。As used herein, the term "carboxy" refers to -C(O)OH.
如本文所用，术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)。As used herein, the term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).
如本文所用，术语“乙酰基”指-COCH 3。 As used herein, the term "acetyl" refers to -COCH3 .
如本文所用，术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代基(即＝O)时，意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。As used herein, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted. Oxo substitution does not occur on aryl groups. The term "optionally substituted" or "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
在任何实施方案中，化合物中存在的任何或所有氢，或化合物内的特定基团或部分中的氢可以被氘或氚代替。该化合物中存在的一个至最大数目的氢可以被氘代替。通式化合物或具体化合物中的任何基团中存在的一个至最大数目的氢可以被氘代。例如，当描述某一基团为乙基时，该乙基可以是C 2H 5或其中x个(1至5个)氢被氘代替的C 2H 5，例如C 2D xH 5-x。当描述某一基团为氘代乙基，该氘代乙基可以是x个(1至5个)氢被氘代替的C 2H 5，例如C 2D xH 5-x。 In any embodiment, any or all of the hydrogens present in the compound, or in particular groups or moieties within the compound, may be replaced by deuterium or tritium. One to the maximum number of hydrogens present in the compound can be replaced by deuterium. One to the maximum number of hydrogens present in any group in a compound of the general formula or in a specific compound may be deuterated. For example, when a group is described as an ethyl group, the ethyl group can be C2H5 or C2H5 in which x ( 1 to 5 ) hydrogens have been replaced by deuterium , such as C2DxH5- x . When a group is described as deuterated ethyl, the deuterated ethyl may be C2H5 with x (1 to 5 ) hydrogens replaced by deuterium, eg, C2DxH5 -x .
在本发明中，任意基团中，如果
Figure PCTCN2022085658-appb-000087
标记在化学键上(并非化学键本身)，则表示该基团标记的化学键与分子其他部分连接。任意基团或化合物结构式中，如果与双键连接的某个化学键被画成
Figure PCTCN2022085658-appb-000088
则表示该基团或化合物可以是顺式异构和反式异构的混合物。 In the present invention, in any group, if
Figure PCTCN2022085658-appb-000087
If the label is on a bond (not the bond itself), it means that the bond labeled by the group is attached to the rest of the molecule. In any group or compound structural formula, if a chemical bond connected to a double bond is drawn as
Figure PCTCN2022085658-appb-000088
It means that the group or compound can be a mixture of cis-isomer and trans-isomer.
具体实施方式Detailed ways
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the embodiments of the present invention.
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地 描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。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。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious. If the specific conditions are not indicated in the examples, it is carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
以下实施例中所采用的制备HPLC，若无特殊说明，可采用如下条件：The preparative HPLC adopted in the following examples, if no special instructions, can adopt the following conditions:
制备HPLC(碳酸氢铵法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:0.1％碳酸氢铵水溶液；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。Preparative HPLC (ammonium bicarbonate method): column type: Waters XBridge C18, 190*250mm, 5um; mobile phase system: A: 0.1% ammonium bicarbonate aqueous solution; B: preparative grade acetonitrile; flow rate: 15ml/min; B%= 20%-100%; column temperature: room temperature.
制备HPLC(氨水法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:0.1％氨水溶液；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。Preparative HPLC (ammonia method): column type: Waters XBridge C18, 190*250mm, 5um; mobile phase system: A: 0.1% aqueous ammonia solution; B: preparative grade acetonitrile; flow rate: 15ml/min; B%=20%-100 %; column temperature: room temperature.
制备HPLC(甲酸法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:20 0.1％甲酸；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。Preparative HPLC (formic acid method): column type: Waters XBridge C18, 190*250mm, 5um; mobile phase system: A: 20 0.1% formic acid; B: preparative grade acetonitrile; flow rate: 15ml/min; B%=20%-100 %; column temperature: room temperature.
制备HPLC(三氟乙酸法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:0.1％三氟乙酸；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。Preparative HPLC (trifluoroacetic acid method): column type: Waters XBridge C18, 190*250mm, 5um; mobile phase system: A: 0.1% trifluoroacetic acid; B: preparative grade acetonitrile; flow rate: 15ml/min; B%=20 %-100%; column temperature: room temperature.
实施例1化合物Z1的合成Example 1 Synthesis of compound Z1
Figure PCTCN2022085658-appb-000089
Figure PCTCN2022085658-appb-000089
步骤一：7-氟咪唑并[1,2-a]吡啶(950mg，6.98mmol)悬浮于乙腈(20mL)在冰浴下加入N-碘代丁二酰亚胺(1.33g，7.68mmol)，在室温下反应16h，额外的N-碘代丁二酰亚胺(242mg，1.40mmol)加入，反应继续在室温下搅拌2h。反应液加入和饱和硫代硫酸钠(25mL)，用乙酸乙酯萃取(100mL)。有机层用饱和食盐水(25mL)洗涤，用无水硫酸钠干燥并浓缩得到目标产物7-氟-3-碘咪唑并[1,2-a]吡啶(1.83g,收率100％)，灰白色固体。ES-API:[M+H] +＝263.0。 Step 1: 7-Fluoroimidazo[1,2-a]pyridine (950mg, 6.98mmol) was suspended in acetonitrile (20mL) and N-iodosuccinimide (1.33g, 7.68mmol) was added under ice bath, The reaction was carried out at room temperature for 16 h, additional N-iodosuccinimide (242 mg, 1.40 mmol) was added and the reaction continued to stir at room temperature for 2 h. The reaction solution was added with saturated sodium thiosulfate (25 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate and concentrated to give the target product 7-fluoro-3-iodoimidazo[1,2-a]pyridine (1.83 g, yield 100%), off-white solid. ES-API: [M+H] + = 263.0.
步骤二：向50mL圆底烧瓶中加入7-溴异喹啉-1-胺(500mg，2.24mmol)，双(频哪醇合)二硼(683mg，2.69mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(161mg，0.22mmol)，乙酸钾(658mg，6.72mmol)，1,4-二氧六环(15mL)，氮气置换三次，反应在95℃反应16h。将反应冷却至室温，加入二氯甲烷(25mL)溶解，用硅藻土过滤，乙酸乙酯洗涤，滤液浓缩得到淡棕色粗品异喹啉-1-胺-7-硼酸(1.2g)，该粗品无 需进一步纯化即可使用。ES-API:[M+H] +＝189.1。 Step 2: Add 7-bromoisoquinolin-1-amine (500mg, 2.24mmol), bis(pinacol)diboron (683mg, 2.69mmol), [1,1'-bis(2.69mmol) to a 50mL round-bottomed flask (diphenylphosphino)ferrocene]palladium dichloride (161 mg, 0.22 mmol), potassium acetate (658 mg, 6.72 mmol), 1,4-dioxane (15 mL), nitrogen replaced three times, the reaction was carried out at 95°C Reaction for 16h. The reaction was cooled to room temperature, and dichloromethane (25 mL) was added to dissolve, filtered through celite, washed with ethyl acetate, and the filtrate was concentrated to give a light brown crude isoquinolin-1-amine-7-boronic acid (1.2 g), the crude product Used without further purification. ES-API: [M+H] + = 189.1.
步骤三：向50mL圆底烧瓶中加入7-氟-3-碘咪唑并[1,2-a]吡啶(500mg,1.91mmol)，异喹啉-1-胺-7-硼酸(1.0g,3.82mmol),碳酸钾(791mg，5.73mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(139mg,0.19mmol)，1,4-二氧六环(20mL)和水(5mL),氮气置换三次，反应在100℃反应4小时。反应液加入水(50mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(350mg,收率66％)，淡棕色固体。ES-API:[M+H] +＝279.1。 Step 3: Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.91 mmol), isoquinolin-1-amine-7-boronic acid (1.0 g, 3.82 mmol) to a 50 mL round-bottomed flask mmol), potassium carbonate (791 mg, 5.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (139 mg, 0.19 mmol), 1,4-dioxane (20 mL ) and water (5 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours. Water (50 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to give the target product 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline- 1-amine (350 mg, 66% yield), pale brown solid. ES-API: [M+H] + = 279.1.
步骤四：7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(294mg，1.06mmol)溶于N,N-二甲基甲酰胺(8mL)在冰浴下加入N-碘代丁二酰亚胺(262mg，1.17mmol)，反应在室温下搅拌4h。反应液加入水(30mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(310mg,收率72％)，淡棕色固体。ES-API:[M+H] +＝405.0。 Step four: 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (294 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (8 mL) ) N-iodosuccinimide (262 mg, 1.17 mmol) was added in an ice bath, and the reaction was stirred at room temperature for 4 h. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to give the target product 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo Isoquinolin-1-amine (310 mg, 72% yield), pale brown solid. ES-API: [M+H] + =405.0.
步骤五：向5mL微波管里加入：7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(60mg,0.15mmol)，2-(6-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)异色满-8-基)吡咯烷-1-甲酸叔丁酯(77mg,0.18mmol),碳酸钾(62mg，0.45mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2mL)和水(0.4mL),用氮气吹1分钟，在微波反应器中100℃下反应1小时。反应液加入水(5mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-4％)得到目标产物2-(6-(1-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基]异喹啉-4-基)异色满-8-基)吡咯烷-1-羧酸叔丁酯(50mg,收率58％)，淡棕色固体。ES-API:[M+H] +＝580.3。 Step 5: Into a 5mL microwave tube, add: 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (60mg, 0.15mmol), 2 -(6-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)isochroman-8-yl)pyrrolidine-1- tert-Butyl formate (77 mg, 0.18 mmol), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1 , 4-dioxane (2mL) and water (0.4mL) were blown with nitrogen for 1 minute and reacted in a microwave reactor at 100°C for 1 hour. Water (5mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was watered Washed and dried in vacuo. The crude product was purified by flash silica gel column (7.0M ammonia in methanol/dichloromethane: 0-4%) to give the desired product 2-(6-(1-(1-amino-7-(7-fluoro). imidazo[1,2-a]pyridin-3-yl]isoquinolin-4-yl)isochroman-8-yl)pyrrolidine-1-carboxylate tert-butyl ester (50 mg, 58% yield), Light brown solid. ES-API: [M+H] + =580.3.
步骤六：2-(6-(1-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基]异喹啉-4-基)异色满-8-基)吡咯烷-1-羧酸叔丁酯(50mg,0.086mmol)溶于甲醇(1ml)，加入4M盐酸二氧六环溶液(3ml)，反应于室温下搅拌1小时。反应液浓缩，加入7.0M氨甲醇溶液(4mL)，溶剂旋干，粗品用制备HPLC纯化(碳酸氢铵法)得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(8-(吡咯烷-2基)异色满-6-基)异喹啉-1-胺(Z1，20mg,收率78％)，白色固体。 1H NMR(500MHz,CD 3OD)δ8.65(dd,J＝7.5,5.5Hz,1H),8.47(d,J＝1.5Hz,1H),7.94(d,J＝8.5Hz,1H),7.88(dd,J＝8.5,1.5Hz,1H),7.79(s,1H),7.76(s,1H),7.40(s,1H),7.34(dd,J＝9.5,2.5Hz,1H),7.17(s,1H),6.98(td,J＝7.5,2.5Hz,1H),5.02(d,J＝15.0Hz,1H),4.91(d,J＝15.0Hz,1H),4.19(t,J＝7.5Hz,1H),4.05–3.92(m,2H),3.19–3.16(m,1H),3.05–2.88(m,3H),2.32–2.23(m,1H),2.04–1.86(m,2H),1.77–1.69(m,1H).ES-API:[M+H] +＝480.2。 Step six: 2-(6-(1-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl]isoquinolin-4-yl)isochroman-8 -yl) tert-butyl pyrrolidine-1-carboxylate (50mg, 0.086mmol) was dissolved in methanol (1ml), 4M hydrochloric acid dioxane solution (3ml) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, 7.0M ammonia methanol solution (4 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4- (8-(pyrrolidin-2yl)isochroman-6-yl)isoquinolin-1-amine (Z1, 20 mg, 78% yield), white solid. 1 H NMR (500 MHz, CD 3 OD) δ8 .65(dd,J＝7.5,5.5Hz,1H),8.47(d,J＝1.5Hz,1H),7.94(d,J＝8.5Hz,1H),7.88(dd,J＝8.5,1.5Hz, 1H), 7.79(s, 1H), 7.76(s, 1H), 7.40(s, 1H), 7.34(dd, J=9.5, 2.5Hz, 1H), 7.17(s, 1H), 6.98(td, J =7.5,2.5Hz,1H),5.02(d,J=15.0Hz,1H),4.91(d,J=15.0Hz,1H),4.19(t,J=7.5Hz,1H),4.05–3.92(m ,2H),3.19–3.16(m,1H),3.05–2.88(m,3H),2.32–2.23(m,1H),2.04–1.86(m,2H),1.77–1.69(m,1H).ES -API:[M+H] + =480.2.
实施例2化合物Z2的合成The synthesis of embodiment 2 compound Z2
Figure PCTCN2022085658-appb-000090
Figure PCTCN2022085658-appb-000090
步骤一：向5mL微波管中加入1-(5-溴-2-(四氢-2H-吡喃-4-基)苯基)-N,N-二甲基甲胺(90mg,0.30mmol)，双联频那醇硼酸酯(91mg,0.36mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(22mg,0.03mmol)， 乙酸钾(88mg,0.90mmol)，1,4-二氧六环(2mL)，用氮气吹扫1分钟，反应在微波反应器中120℃下反应30分钟。反应冷却至室温，加入二氯甲烷(5mL)溶解，硅藻土过滤，乙酸乙酯洗涤，滤液浓缩得到N,N-二甲基-1-(2-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲胺(185mg,粗品)，淡棕色，无需进一步纯化即可用于下一步反应。ES-API:[M+H] +＝346.3。 Step 1: Add 1-(5-bromo-2-(tetrahydro-2H-pyran-4-yl)phenyl)-N,N-dimethylmethylamine (90mg, 0.30mmol) to a 5mL microwave tube , bispinacol borate (91mg, 0.36mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (22mg, 0.03mmol), potassium acetate (88mg, 0.90 mmol), 1,4-dioxane (2 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 120 °C for 30 min. The reaction was cooled to room temperature, dichloromethane (5 mL) was added to dissolve, filtered through celite, washed with ethyl acetate, and the filtrate was concentrated to obtain N,N-dimethyl-1-(2-(tetrahydro-2H-pyran-4). -yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)methanamine (185mg, crude), light brown, no need Further purification can be used in the next reaction. ES-API: [M+H] + =346.3.
步骤二：向5mL微波管里加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(60mg,0.15mmol)，N,N-二甲基-1-(2-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲胺(185mg,粗品)，碳酸钾(62mg,0.45mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2mL)和水(0.4mL)，用氮气吹扫1分钟，在微波反应器中100℃下反应1小时。反应液加入水(5mL)，析出固体，过滤，滤饼用水洗涤，真空干燥。粗品用制备HPLC(碳酸氢铵法)纯化得到4-(3-((二甲基氨基)甲基)-4-(四氢-2H-吡喃-4-基)苯基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(Z2,32mg,收率:43％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ8.72(t,J＝6.5Hz,1H),8.54(s,1H),7.93–7.75(m,4H),7.56(d,J＝10.0Hz,1H),7.43(d,J＝8.0Hz,1H),7.38–7.27(m,2H),7.11–6.96(m,3H),3.98(d,J＝8.0Hz,2H),3.54–3.43(m,4H),3.25(t,J＝11.5Hz,1H),2.20(s,6H),1.83–1.62(m,4H).ES-API:[M+H] +＝496.3。 Step 2: Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (60mg, 0.15mmol) to a 5mL microwave tube, N, N-Dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroyl) Alk-2-yl)phenyl)methanamine (185 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.4 mL), purged with nitrogen for 1 min, and reacted at 100 °C for 1 h in a microwave reactor. Water (5 mL) was added to the reaction solution, a solid was precipitated, filtered, and the filter cake was washed with water and dried in vacuo. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to give 4-(3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)-7-( 7-Fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (Z2, 32 mg, yield: 43%), white solid. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.72 (t, J=6.5Hz, 1H), 8.54 (s, 1H), 7.93-7.75 (m, 4H), 7.56 (d, J=10.0Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 7.38–7.27 (m, 2H), 7.11–6.96 (m, 3H), 3.98 (d, J=8.0Hz, 2H), 3.54–3.43 (m , 4H), 3.25 (t, J=11.5Hz, 1H), 2.20 (s, 6H), 1.83–1.62 (m, 4H). ES-API: [M+H] + =496.3.
实施例3化合物Z3的合成Example 3 Synthesis of compound Z3
Figure PCTCN2022085658-appb-000091
Figure PCTCN2022085658-appb-000091
步骤一：7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(160mg,0.396mmol)和二碳酸二叔丁酯(305mg,1.40mmol)悬浮于二氯甲烷(10mL)室温下加入N,N-二异丙基乙胺(206mg,1.60mmol)和4-二甲氨基吡啶(8mg,0.06mmol)，反应在室温下搅拌18h。反应液浓缩，加入水(10mL)，乙酸乙酯萃取(50mL)。有机层用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘-1-(双(叔丁基氧羰基)氨基)异喹啉(200mg,收率:83％)，淡黄色固体。ES-API:[M+H] +＝605.1。 Step 1: 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (160mg, 0.396mmol) and di-tert-butyl dicarbonate (305mg , 1.40mmol) was suspended in dichloromethane (10mL) at room temperature, added N,N-diisopropylethylamine (206mg, 1.60mmol) and 4-dimethylaminopyridine (8mg, 0.06mmol), the reaction was stirred at room temperature 18h. The reaction solution was concentrated, and water (10 mL) was added, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica column (ethyl acetate/petroleum ether: 0-60%) to give 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis (tert-butyloxycarbonyl)amino)isoquinoline (200 mg, yield: 83%), pale yellow solid. ES-API: [M+H] + =605.1.
步骤二：向50mL圆底烧瓶中加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,0.25mmol)，双联频那醇硼酸酯(126mg,0.50mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(27mg,0.038mmol)，乙酸钾(74mg,0.75mmol)，N,N-二甲基甲酰胺(4mL)，氮气置换三次，反应在90℃下反应3小时。反应液加入水(20mL)，乙酸乙酯萃取(30mL×2)。合并有机层，饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，浓缩得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼 烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(280mg,粗品)，无需进一步纯化即可用于下一步反应。ES-API:[M+H] +＝605.3。 Step 2: Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl)amino)iso to a 50mL round-bottomed flask Quinoline (150 mg, 0.25 mmol), bispinacol borate (126 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27 mg, 0.038 mmol) ), potassium acetate (74 mg, 0.75 mmol), N,N-dimethylformamide (4 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 3 hours. The reaction solution was added with water (20 mL) and extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (280 mg, crude) without further It can be used in the next reaction after purification. ES-API: [M+H] + =605.3.
步骤三：1-(6-氯-3-(四氢-2H-吡喃-4-基)吡啶-2-基)-N,N-二甲基甲胺(65mg,0.25mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(280mg,粗品)，碳酸钾(103mg,0.75mmol)，2-二环己基膦-2′,6′-二甲氧基-联苯(10mg,0.025mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(18mg,0.025mmol)，1,4-二氧六环(8mL)和水(2mL),氮气置换三次，反应在100℃下反应2小时。反应液加入乙酸乙酯(40mL)，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品用薄层制备色谱板纯化(二氯甲烷/7.0M氨甲醇溶液＝40:1)得到4-(6-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)吡啶-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(85mg,收率:48％)，淡棕色固体。ES-API:[M+H] +＝697.3。 Step 3: 1-(6-Chloro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethylamine (65mg, 0.25mmol), 7- (7-Fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (280mg, crude), potassium carbonate (103mg, 0.75mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy - Biphenyl (10 mg, 0.025 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II) (18 mg, 0.025 mmol), 1,4-dioxane (8 mL) and water (2 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 2 hours. The reaction solution was added with ethyl acetate (40 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by TLC plate (dichloromethane/7.0M ammonia in methanol = 40:1) to give 4-(6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)pyridin-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline ( 85 mg, yield: 48%), light brown solid. ES-API: [M+H] + =697.3.
步骤四：4-(6-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)吡啶-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(85mg,0.13mmol)溶于甲醇(1ml)，加入4M盐酸二氧六环溶液(5ml)，反应于室温下搅拌6小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸法)纯化得到4-(6-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)吡啶-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(Z3,25mg,收率:35.5％,甲酸盐)，白色固体。ES-API:[M+H] +＝497.2。 1H NMR(500MHz,DMSO-d 6)δ8.73(dd,J＝7.5,6.0Hz,1H),8.54(d,J＝1.5Hz,1H),8.36(d,J＝8.5Hz,1H),8.19(s,1H),8.02(s,1H),7.93–7.83(m,3H),7.59–7.53(m,2H),7.17(s,2H),7.07(td,J＝7.5,2.5Hz,1H),4.03–3.97(m,2H),3.75(s,2H),3.48(td,J＝11.5,2.5Hz,2H),3.32–3.25(m,1H),2.29(s,6H),1.80–1.67(m,4H)。 Step four: 4-(6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(7-fluoroimidazo[1 ,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (85mg, 0.13mmol) was dissolved in methanol (1ml), 4M hydrochloric acid dioxane solution was added ( 5 ml) and the reaction was stirred at room temperature for 6 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid method) to obtain 4-(6-((dimethylamino)methyl)-5-(tetrahydro-2H) -pyran-4-yl)pyridin-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (Z3, 25 mg, yield : 35.5%, formate), white solid. ES-API: [M+H] + =497.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.73 (dd, J=7.5, 6.0 Hz, 1H), 8.54 (d, J=1.5 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H) ,8.19(s,1H),8.02(s,1H),7.93-7.83(m,3H),7.59-7.53(m,2H),7.17(s,2H),7.07(td,J=7.5,2.5Hz ,1H),4.03–3.97(m,2H),3.75(s,2H),3.48(td,J=11.5,2.5Hz,2H),3.32–3.25(m,1H),2.29(s,6H), 1.80–1.67 (m, 4H).
实施例4化合物Z4的合成Example 4 Synthesis of compound Z4
Figure PCTCN2022085658-appb-000092
Figure PCTCN2022085658-appb-000092
步骤一：将4-(5-溴噻唑-2-基)哌啶-1-羧酸叔丁酯(35mg,0.1mmol)溶于二氯甲烷(0.2mL)，搅拌下，滴加三氟乙酸(0.2mL)。室温下反应2小时，反应完毕。反应液浓缩后，溶于二氯甲烷(1mL)，向体系中加入3滴甲醛水溶液。反应搅拌15分钟后，加入三乙酰基硼氢化钠(64mg,0.3mmol)，室温搅拌30分钟，反应完全转化。滴加氢氧化钠水溶液(1M)将反应液调至碱性(pH至10～11)，加入水(5mL)。乙酸乙酯萃取水相(10mLX3)。有机相合并，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，浓缩，得到5-溴-2-(1-甲基哌啶-4-基)噻唑(30mg,粗品)，不经纯化直接用于下一步反应。ES-API:[M+H] +＝261.1。 Step 1: Dissolve tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate (35 mg, 0.1 mmol) in dichloromethane (0.2 mL), add trifluoroacetic acid dropwise with stirring (0.2 mL). The reaction was completed at room temperature for 2 hours. After the reaction solution was concentrated, it was dissolved in dichloromethane (1 mL), and 3 drops of aqueous formaldehyde solution were added to the system. After the reaction was stirred for 15 minutes, sodium triacetylborohydride (64 mg, 0.3 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction was completely converted. Aqueous sodium hydroxide solution (1M) was added dropwise to adjust the reaction solution to alkaline (pH to 10-11), and water (5 mL) was added. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-bromo-2-(1-methylpiperidin-4-yl)thiazole (30 mg, crude product) Purification was used directly in the next reaction. ES-API: [M+H] + = 261.1.
步骤二：在10mL封管中，将7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(60mg,0.1mmol)，5-溴-2-(1-甲基哌啶-4-基)噻唑(30mg,粗品)溶于1,4-二氧六环(0.8mL)，依次加入碳酸钾(41mg,0.3mmol)的水溶液(0.2mL)以及[1,1'-双(二苯基膦基)二茂铁]二氯化钯(7mg,0.01mmol)。反应体系充氮气后于封管中在100℃下加热4小时，原料反 应完全。反应体系加入水(5mL)，用乙酸乙酯萃取(10mLX3)。有机相合并，依次用水(10mL)、饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，浓缩得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(2-(1-甲基哌啶-4-基)噻唑-5-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(70mg,粗品)，不经纯化直接用于下一步反应。ES-API:[M+H] +＝659.1。 Step 2: In a 10 mL sealed tube, 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (60 mg, 0.1 mmol), 5-bromo-2-(1-methylpiperidine) -4-yl)thiazole (30 mg, crude product) was dissolved in 1,4-dioxane (0.8 mL), an aqueous solution of potassium carbonate (41 mg, 0.3 mmol) (0.2 mL) and [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (7 mg, 0.01 mmol). The reaction system was filled with nitrogen and heated in a sealed tube at 100° C. for 4 hours, and the reaction of the raw materials was complete. The reaction system was added with water (5 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)- 4-(2-(1-Methylpiperidin-4-yl)thiazol-5-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (70 mg, crude) was taken directly without purification used for the next reaction. ES-API: [M+H] + =659.1.
步骤三：将7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(2-(1-甲基哌啶-4-基)噻唑-5-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(70mg,粗品)溶于二氯甲烷(1mL)，搅拌下加入三氟乙酸(0.5mL)。室温搅拌反应4小时。反应体系浓缩，加入7.0M氨/甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(氨水法)纯化得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(2-(1-甲基哌啶-4-基)噻唑-5-基)异喹啉-1-胺(Z4，9.36mg,3步收率:20％)白色固体。ES-API:[M+H] +＝459.1。 1H NMR(500MHz,DMSO-d 6)δ8.72(dd,J＝7.5,5.9Hz,1H),8.55(s,1H),8.01–7.96(m,2H),7.94(s,1H),7.87(s,1H),7.77(s,1H),7.57(dd,J＝10.0,2.5Hz,1H),7.28(s,2H),7.07(td,J＝7.5,2.6Hz,1H),3.08–2.99(m,1H),2.89(d,J＝11.3Hz,2H),2.24(s,3H),2.17–2.06(m,4H),1.80(dd,J＝24.7,15.5Hz,2H)。 Step three: 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(2-(1-methylpiperidin-4-yl)thiazol-5-yl)- 1-(Bis(tert-butyloxycarbonyl)amino)isoquinoline (70 mg, crude) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added with stirring. The reaction was stirred at room temperature for 4 hours. The reaction system was concentrated, 7.0M ammonia/methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonia method) to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl) -4-(2-(1-Methylpiperidin-4-yl)thiazol-5-yl)isoquinolin-1-amine (Z4, 9.36 mg, 3 steps yield: 20%) white solid. ES-API: [M+H] + =459.1. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.72(dd, J=7.5, 5.9Hz, 1H), 8.55(s, 1H), 8.01-7.96(m, 2H), 7.94(s, 1H), 7.87(s, 1H), 7.77(s, 1H), 7.57(dd, J=10.0, 2.5Hz, 1H), 7.28(s, 2H), 7.07(td, J=7.5, 2.6Hz, 1H), 3.08 – 2.99 (m, 1H), 2.89 (d, J=11.3 Hz, 2H), 2.24 (s, 3H), 2.17–2.06 (m, 4H), 1.80 (dd, J=24.7, 15.5 Hz, 2H).
实施例5化合物Z5的合成Example 5 Synthesis of compound Z5
Figure PCTCN2022085658-appb-000093
Figure PCTCN2022085658-appb-000093
步骤一：向250mL圆底烧瓶中加入3-溴噻吩-2-甲醛(2.0g,10.47mmol)，2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(2.86g,13.61mmol)，碳酸铯(10.20g，31.41mmol)，[1,1'-双(二苯 基膦)二茂铁]二氯化钯(382mg,0.52mmol)，四氢呋喃(60mL)，氮气置换三次，在80℃下反应16小时。反应液加入水(40mL)，乙酸乙酯萃取(100mL)。有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥并浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-甲醛(1.8g,收率88％)，黄色液体。ES-API:[M+H] +＝195.1。 Step 1: Add 3-bromothiophene-2-carbaldehyde (2.0g, 10.47mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4 to a 250mL round-bottomed flask, 5,5-Tetramethyl-1,3,2-dioxaborane (2.86 g, 13.61 mmol), cesium carbonate (10.20 g, 31.41 mmol), [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (382 mg, 0.52 mmol), tetrahydrofuran (60 mL), replaced with nitrogen three times, and reacted at 80° C. for 16 hours. Water (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to give 3-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carbaldehyde (1.8 g, yield 88%), yellow liquid. ES-API: [M+H] + = 195.1.
步骤二：3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-甲醛(1.7g,8.76mmol)和甲氨盐酸盐(2.96g,43.80mmol)悬浮于乙腈(40mL)中，加入氰基硼氢化钠(1.1g,17.52mmol)，反应在室温下反应24小时。用1M氢氧化钠溶液调反应液pH至10，旋掉大部分乙腈，用二氯甲烷萃取(40mL×2)。合并有机层，无水硫酸钠干燥，过滤，浓缩。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-10％)得到1-(3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-基)-N-甲基甲胺(1.0g,收率:54％)，黄色液体。ES-API:[M+H] +＝210.1 Step 2: 3-(3,6-Dihydro-2H-pyran-4-yl)thiophene-2-carbaldehyde (1.7g, 8.76mmol) and methylamine hydrochloride (2.96g, 43.80mmol) were suspended in acetonitrile (40 mL), sodium cyanoborohydride (1.1 g, 17.52 mmol) was added, and the reaction was allowed to react at room temperature for 24 hours. Adjust the pH of the reaction solution to 10 with 1M sodium hydroxide solution, spin off most of the acetonitrile, and extract with dichloromethane (40 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica column (7.0M ammonia in methanol/dichloromethane: 0-10%) to give 1-(3-(3,6-dihydro-2H-pyran-4-yl)thiophen-2-yl )-N-methylmethylamine (1.0 g, yield: 54%), yellow liquid. ES-API: [M+H] + = 210.1
步骤三：1-(3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-基)-N-甲基甲胺(1.0g,4.78mmol)和三乙胺(965mg,9.56mmol)溶于二氯甲烷(10mL)，冰浴下加入二碳酸二叔丁酯(1.56g,7.17mmol)，在冰浴下搅拌反应1小时。反应液浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到((3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-基)甲基)(甲基)氨基甲酸叔丁酯(1.4g,收率:88.3％)，粘稠状液体。ES-API:[M+Na] +＝332.2。 Step 3: 1-(3-(3,6-Dihydro-2H-pyran-4-yl)thiophen-2-yl)-N-methylmethylamine (1.0 g, 4.78 mmol) and triethylamine ( 965 mg, 9.56 mmol) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (1.56 g, 7.17 mmol) was added under ice bath, and the reaction was stirred under ice bath for 1 hour. The reaction solution was concentrated, and the crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain ((3-(3,6-dihydro-2H-pyran-4-yl)thiophen-2-yl) ) methyl) (methyl) tert-butyl carbamate (1.4 g, yield: 88.3%), viscous liquid. ES-API: [M+Na] + = 332.2.
步骤四：((3-(3,6-二氢-2H-吡喃-4-基)噻吩-2-基)甲基)(甲基)氨基甲酸叔丁酯(1.3g,4.20mmol)溶于甲醇(20mL)，加入10％湿钯碳(1.0g)，在氢气保护下室温搅拌反应16小时。反应液用硅藻土过滤，滤液浓缩得到甲基((3-(四氢-2H-吡喃-4-基)噻吩-2-基)氨基甲酸叔丁酯(1.3g,收率:99％)，粘稠状液体。ES-API:[M+Na] +＝334.1。 Step four: ((3-(3,6-dihydro-2H-pyran-4-yl)thiophen-2-yl)methyl)(methyl)carbamic acid tert-butyl ester (1.3g, 4.20mmol) was dissolved in In methanol (20 mL), 10% wet palladium on carbon (1.0 g) was added, and the reaction was stirred at room temperature for 16 hours under the protection of hydrogen. The reaction solution was filtered with celite, and the filtrate was concentrated to obtain tert-butyl methyl((3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)carbamate (1.3 g, yield: 99%) ), viscous liquid. ES-API: [M+Na] + =334.1.
步骤五：甲基((3-(四氢-2H-吡喃-4-基)噻吩-2-基)氨基甲酸叔丁酯(1.2g,3.86mmol)溶于乙腈(20mL)在冰浴下加入N-溴代丁二酰亚胺(687mg,3.86mmol)，反应在冰浴下搅拌1小时。反应液加入乙酸乙酯(80mL)，用饱和碳酸氢钠(30mL)、饱和食盐水(30mL)洗涤，无水硫酸钠干燥并浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物((5-溴-3-(四氢-2H-吡喃-4-基)噻吩-2-基)甲基)(甲基)氨基甲酸叔丁酯(1.3g,收率:86％)，无色液体。ES-API:[M+Na] +＝412.1,414.1。 Step 5: tert-butyl methyl((3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)carbamate (1.2 g, 3.86 mmol) was dissolved in acetonitrile (20 mL) under ice bath N-bromosuccinimide (687 mg, 3.86 mmol) was added, and the reaction was stirred under ice bath for 1 hour. Ethyl acetate (80 mL) was added to the reaction solution, and saturated sodium bicarbonate (30 mL) and saturated brine (30 mL) were added to the reaction solution. ), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product ((5-bromo-3-(tetrahydro-2H-pyran- 4-yl)thiophen-2-yl)methyl)(methyl)carbamate tert-butyl ester (1.3 g, yield: 86%), colorless liquid. ES-API: [M+Na] + =412.1, 414.1.
步骤六：((5-溴-3-(四氢-2H-吡喃-4-基)噻吩-2-基)甲基)(甲基)氨基甲酸叔丁酯(1.25g,3.20mmol)溶于甲酸(10mL)，加入37％甲醛水溶液(4mL)，在80℃搅拌反应3小时。反应液浓缩，加入饱和碳酸氢钠(60mL)，乙酸乙酯萃取(50mL×2)。有机层用无水硫酸钠干燥，过滤，浓缩。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到1-(5-溴-3-(四氢-2H-吡喃-4-基)噻吩-2-基)-N,N-二甲基甲胺(950mg,收率:97％)，黄色液体。ES-API:[M+H] +＝304.1,306.1。 Step six: ((5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)methyl)(methyl)carbamate (1.25g, 3.20mmol) was dissolved in To formic acid (10 mL), 37% aqueous formaldehyde solution (4 mL) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica column (7.0M ammonia in methanol/dichloromethane: 0-5%) to give 1-(5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl )-N,N-dimethylmethylamine (950 mg, yield: 97%), yellow liquid. ES-API: [M+H] + = 304.1, 306.1.
步骤七：向5mL微波管里加入1-(5-溴-3-(四氢-2H-吡喃-4-基)噻吩-2-基)-N,N-二甲基甲胺(61mg,0.20mmol)，双联频那醇硼酸酯(76mg,0.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(15mg,0.02mmol)，乙酸钾(59mg,0.60mmol)，N，N-二甲基甲酰胺(1.5mL)，用氮气吹扫1分钟，在微波反应器中于100℃下反应1小时。反应冷却至室温，加入乙酸乙酯(40mL)，饱和食盐水(15mL×4)洗涤，无水硫酸钠干燥并浓缩得到N,N-二甲基-1-(3-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)噻吩-2-基)甲胺(130mg,粗品)，无需进一步纯化即可用于下一步反应。ES-API:[M+H] +＝352.3。 Step 7: Add 1-(5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)-N,N-dimethylmethylamine (61mg, 0.20 mmol), bispinacol borate (76 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate ( 59 mg, 0.60 mmol), N,N-dimethylformamide (1.5 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 100 °C for 1 h. The reaction was cooled to room temperature, ethyl acetate (40 mL) was added, washed with saturated brine (15 mL×4), dried over anhydrous sodium sulfate and concentrated to obtain N,N-dimethyl-1-(3-(tetrahydro-2H-) Pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)thiophen-2-yl)methanamine (130 mg, crude product), which was used in the next reaction without further purification. ES-API: [M+H] + =352.3.
步骤八：7-氟咪唑并[1,2-a]吡啶(3.0g,22.06mmol)悬浮于乙腈(50mL)，冰浴下加入N-溴代丁二酰亚胺(4.12g,23.16mmol)，在冰浴下搅拌反应1h。反应液加入和饱和硫代硫酸钠(30mL)，饱和碳酸氢钠(30mL)和水(30mL)，二氯甲烷萃取(50mL×2)。有机层用无水硫酸钠干燥并浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/二氯甲烷：0-15％)得到目标产物3-溴-7-氟咪唑并[1,2-a]吡啶(4.0g,收率:84％)，白色固体。ES-API:[M+H] +＝215.0,217.0。 Step 8: 7-Fluoroimidazo[1,2-a]pyridine (3.0g, 22.06mmol) was suspended in acetonitrile (50mL), and N-bromosuccinimide (4.12g, 23.16mmol) was added under ice bath , and the reaction was stirred under ice bath for 1 h. The reaction solution was added with saturated sodium thiosulfate (30 mL), saturated sodium bicarbonate (30 mL) and water (30 mL), and extracted with dichloromethane (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/dichloromethane: 0-15%) to obtain the target product 3-bromo-7-fluoroimidazo[1,2-a]pyridine (4.0 g, yield: 84%) , white solid. ES-API: [M+H] + = 215.0, 217.0.
步骤九：3-溴-7-氟咪唑并[1,2-a]吡啶(3.0g,13.95mmol)和异丙醇频哪醇硼酸酯(7.78g,41.85mmol) 溶于四氢呋喃(60mL)，在氮气保护下0℃下滴加异丙基氯化镁氯化锂四氢呋喃溶液(21.50mL,27.90mmol,1.3M)，在0℃下搅拌反应2h。反应液加入水(50mL)和乙酸乙酯(100mL)，过滤，滤液用乙酸乙酯萃取(10mL×3)。合并有机层，无水硫酸钠干燥，浓缩得到7-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)咪唑并[1,2-a]吡啶(4.0g,粗品)，无需进一步纯化即可用于下一步反应。ES-API:[M+H] +＝263.1。 Step 9: 3-Bromo-7-fluoroimidazo[1,2-a]pyridine (3.0 g, 13.95 mmol) and isopropanol pinacol boronate (7.78 g, 41.85 mmol) were dissolved in tetrahydrofuran (60 mL) , isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (21.50mL, 27.90mmol, 1.3M) was added dropwise at 0°C under nitrogen protection, and the reaction was stirred at 0°C for 2h. The reaction solution was added with water (50 mL) and ethyl acetate (100 mL), filtered, and the filtrate was extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)imidazo[ 1,2-a]pyridine (4.0 g, crude) was used in the next reaction without further purification. ES-API: [M+H] + = 263.1.
步骤十：向250mL圆底烧瓶中加入3-溴-1,6-萘啶(700mg,3.13mmol)，7-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)咪唑并[1,2-a]吡啶(4.0g,粗品)，碳酸钠(1.33g,12.52mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(227mg,0.31mmol)，1,4-二氧六环(50mL)和水(10mL)，氮气置换三次，在100℃下反应4小时。反应液加入水(80mL)，旋蒸掉二氧六环，析出固体，过滤，滤饼真空干燥，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-12％)得到3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,6-萘啶-5-胺(710mg,收率:81％)，淡棕色固体。ES-API:[M+H] +＝280.1。 Step ten: add 3-bromo-1,6-naphthyridine (700mg, 3.13mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaboran-2-yl)imidazo[1,2-a]pyridine (4.0 g, crude), sodium carbonate (1.33 g, 12.52 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (227 mg, 0.31 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, and reacted at 100° C. for 4 hours. Water (80 mL) was added to the reaction solution, dioxane was evaporated by rotary evaporation, the solid was precipitated, filtered, and the filter cake was vacuum-dried. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-12%) to obtain 3-(7- Fluorimidazo[1,2-a]pyridin-3-yl)-1,6-naphthyridin-5-amine (710 mg, yield: 81%), pale brown solid. ES-API: [M+H] + = 280.1.
步骤十一：3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,6-萘啶-5-胺(685mg,2.45mmol)溶于N,N-二甲基甲酰胺(20mL)在冰浴下加入N-碘代丁二酰亚胺606mg,2.70mmol)，反应在室温下搅拌24小时。反应液加入水(80mL)，析出固体，过滤，滤饼用水洗涤，真空干燥，粗品用(甲醇/二氯甲烷＝10:1)打浆得到3-(7-氟咪唑并[1,2-a]吡啶-3-基)-8-碘-1,6-萘啶-5-胺(890mg,收率:89％)，淡棕色固体。ES-API:[M+H] +＝406.0。 Step eleven: 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,6-naphthyridin-5-amine (685 mg, 2.45 mmol) was dissolved in N,N-dimethyl N-iodosuccinimide (606 mg, 2.70 mmol) was added to N-iodosuccinimide (20 mL) in an ice bath, and the reaction was stirred at room temperature for 24 hours. The reaction solution was added with water (80 mL), the solid was precipitated, filtered, the filter cake was washed with water, dried in vacuo, the crude product was slurried with (methanol/dichloromethane=10:1) to obtain 3-(7-fluoroimidazo[1,2-a] ]pyridin-3-yl)-8-iodo-1,6-naphthyridin-5-amine (890 mg, yield: 89%), pale brown solid. ES-API: [M+H] + =406.0.
步骤十二：向5mL微波管里加入3-(7-氟咪唑并[1,2-a]吡啶-3-基)-8-碘-1,6-萘啶-5-胺(40mg,0.10mmol)，N,N-二甲基-1-(3-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)噻吩-2-基)甲胺(130mg,粗品)，碳酸钾(41mg,0.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(7mg,0.01mmol)，1,4-二氧六环(1.5mL)和水(0.3mL),用氮气吹扫1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(5mL)，乙酸乙酯萃取(40mL)。有机层用饱和食盐水(15mL)洗涤，无水硫酸钠干燥并浓缩。粗品用制备HPLC(碳酸氢铵法)纯化得到8-(5-((二甲氨基)甲基)-4-(四氢-2H-吡喃-4-基)噻吩-2-基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,6-萘啶-5-胺(Z5,13mg,收率:26％)，黄色固体。ES-API:[M+H] +＝503.1。 1H NMR(500MHz,DMSO-d 6)δ9.34(s,1H),8.93(s,1H),8.86(dd,J＝7.0,6.0Hz,1H),8.55(s,1H),8.02(s,1H),7.67–7.54(m,2H),7.39(s,2H),7.10(td,J＝7.0,3.0Hz,1H),3.94(dd,J＝10.0,2.5Hz,2H),3.58(s,2H),3.45(dd,J＝12.0,11.0Hz,2H),2.97(t,J＝12.0Hz,1H),2.22(s,6H),1.88–1.74(m,2H),1.62(d,J＝12.4Hz,2H)。 Step 12: add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-8-iodo-1,6-naphthyridin-5-amine (40 mg, 0.10 mmol), N,N-dimethyl-1-(3-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)thiophen-2-yl)methanamine (130 mg, crude), potassium carbonate (41 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (7 mg, 0.01 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C. for 45 min. Water (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to give 8-(5-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)-3 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-1,6-naphthyridin-5-amine (Z5, 13 mg, yield: 26%), yellow solid. ES-API: [M+H] + =503.1. 1 H NMR (500MHz, DMSO-d 6 )δ9.34(s,1H),8.93(s,1H),8.86(dd,J=7.0,6.0Hz,1H),8.55(s,1H),8.02( s, 1H), 7.67–7.54 (m, 2H), 7.39 (s, 2H), 7.10 (td, J=7.0, 3.0Hz, 1H), 3.94 (dd, J=10.0, 2.5Hz, 2H), 3.58 (s,2H),3.45(dd,J=12.0,11.0Hz,2H),2.97(t,J=12.0Hz,1H),2.22(s,6H),1.88–1.74(m,2H),1.62( d, J=12.4 Hz, 2H).
实施例6化合物Z6的合成Example 6 Synthesis of compound Z6
Figure PCTCN2022085658-appb-000094
Figure PCTCN2022085658-appb-000094
步骤一：1-(叔丁基)2-甲基吡咯烷-1,2-二羧酸酯(10.0g,43.6mmol)溶于无水四氢呋喃(10mL)，加入氯碘甲烷(16mL,218mmol)，室温下搅拌2分钟，降温至-78℃，搅拌10分钟，逐滴加入二异丙基 氨基锂四氢呋喃溶液(109mL,218mmol,2M)，滴完在-78℃反应1小时，加入混合溶液(醋酸/四氢呋喃＝1/2,60mL)，在-78℃下搅拌10分钟，升至室温，反应液倒入水中(20mL)，乙酸乙酯(200mL×2)萃取，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(四氢呋喃/石油醚＝20％-50％)纯化得到2-(2-氯乙酰基)吡咯烷-1-羧酸叔丁酯(10g,纯度:12％,收率:11.2％)，褐色油状。ES-API:[M+H] +＝248.2,250.2。 Step 1: 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (10.0 g, 43.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and chloroiodomethane (16 mL, 218 mmol) was added , stirred at room temperature for 2 minutes, cooled to -78 ° C, stirred for 10 minutes, added dropwise a lithium diisopropylamide tetrahydrofuran solution (109 mL, 218 mmol, 2 M), and reacted at -78 ° C for 1 hour after dropping, and added a mixed solution ( Acetic acid/tetrahydrofuran=1/2, 60mL), stirred at -78°C for 10 minutes, warmed to room temperature, poured the reaction solution into water (20mL), extracted with ethyl acetate (200mL×2), dried over anhydrous sodium sulfate, filtered , concentrated, and the crude product was purified by column chromatography (tetrahydrofuran/petroleum ether=20%-50%) to obtain tert-butyl 2-(2-chloroacetyl)pyrrolidine-1-carboxylate (10 g, purity: 12%, yield). rate: 11.2%), brown oil. ES-API: [M+H] + = 248.2, 250.2.
步骤二：2-(2-氯乙酰基)吡咯烷-1-羧酸叔丁酯(10g,40.4mmol)溶于乙醇(200mL)在室温下加入硫脲(3.07g,40.4mmol)，加热至90℃搅拌反应3小时。LC-MS检测反应完全，反应液旋干，加入水(40mL)，乙酸乙酯萃取(100mL×2)，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(二氯甲烷：甲醇＝3％-6％)纯化得到2-(2-氨基噻唑-4-基)吡咯烷-1-羧酸叔丁酯(250mg,收率:19％)，淡黄色油状。ES-API:[M+H] +＝270.1。 Step 2: Dissolve 2-(2-chloroacetyl)pyrrolidine-1-carboxylate tert-butyl ester (10g, 40.4mmol) in ethanol (200mL), add thiourea (3.07g, 40.4mmol) at room temperature, heat to The reaction was stirred at 90°C for 3 hours. LC-MS detected that the reaction was complete, the reaction solution was spin-dried, added with water (40 mL), extracted with ethyl acetate (100 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography (dichloromethane: methanol = 3%-6%) to obtain tert-butyl 2-(2-aminothiazol-4-yl)pyrrolidine-1-carboxylate (250 mg, yield: 19%) as pale yellow oil. ES-API: [M+H] + =270.1.
步骤三：溴化亚铜(199.3mg,1.39mmol)溶于乙腈(5mL)，室温下加入亚硝酸叔丁酯(152.6mg,1.86mmol)，混合物搅拌5分钟，加入2-(2-氨基噻唑-4-基)吡咯烷-1-羧酸叔丁酯(250mg,0.93mmol)，反应液在室温下搅拌3小时。LC-MS检测反应完全，冰浴下加入水(20mL)，乙酸乙酯萃取(50mL×2)，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(四氢呋喃：石油醚＝10％-30％)纯化得到2-(2-溴噻唑-4-基)吡咯烷-1-羧酸叔丁酯(210mg,收率:68.2％)，灰色固体。ES-API:[M+H] +＝333.2,335.2。 Step 3: Cuprous bromide (199.3 mg, 1.39 mmol) was dissolved in acetonitrile (5 mL), tert-butyl nitrite (152.6 mg, 1.86 mmol) was added at room temperature, the mixture was stirred for 5 minutes, and 2-(2-aminothiazole was added) -4-yl)pyrrolidine-1-carboxylate tert-butyl ester (250 mg, 0.93 mmol), the reaction solution was stirred at room temperature for 3 hours. LC-MS detected that the reaction was complete, water (20 mL) was added under an ice bath, extracted with ethyl acetate (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography (tetrahydrofuran: petroleum ether=10%- 30%) was purified to give tert-butyl 2-(2-bromothiazol-4-yl)pyrrolidine-1-carboxylate (210 mg, yield: 68.2%) as a grey solid. ES-API: [M+H] + = 333.2, 335.2.
步骤四：2-(2-溴噻唑-4-基)吡咯烷-1-羧酸叔丁酯(66.2mg,0.20mmol)溶于二氧六环(10mL)和水(2mL)中，室温下加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,粗品)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(14.4mg,0.02mmol)，磷酸钾(127.2mg,0.60mmol)，氮气保护下100℃下搅拌反应2小时。反应液加入二氯甲烷(40mL)，依次用水(10mL)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(四氢呋喃：石油醚＝40％-60％)纯化得到2-(2-(1-(双(叔丁基氧羰基)氨基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(90mg,收率:62％)。ES-API:[M+H] +＝731.2。 Step 4: Dissolve tert-butyl 2-(2-bromothiazol-4-yl)pyrrolidine-1-carboxylate (66.2 mg, 0.20 mmol) in dioxane (10 mL) and water (2 mL) at room temperature Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), under nitrogen The reaction was stirred at 100°C for 2 hours. The reaction solution was added with dichloromethane (40 mL), washed successively with water (10 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography (tetrahydrofuran: petroleum ether=40%-60%) ) was purified to give 2-(2-(1-(bis(tert-butyloxycarbonyl)amino)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline-4- yl)thiazol-4-yl)pyrrolidine-1-carboxylate tert-butyl ester (90 mg, yield: 62%). ES-API: [M+H] + =731.2.
步骤五：2-(2-(1-(双(叔丁基氧羰基)氨基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(90mg,0.12mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(1mL)，在室温下反应1小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(三氟乙酸法)纯化得到7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(吡咯烷-2-基)噻唑-2-基)异喹啉-1-胺(Z6,32mg,收率:62％)，灰色固体。ES-API:[M+H] +＝431.2。 1H NMR(500MHz,DMSO-d 6)δ9.75–9.65(m,1H),9.10–9.00(m,1H),8.98(d,J＝8.8Hz,1H),8.87–8.83(m,2H),8.30(s,1H),8.22(d,J＝8.8Hz,1H),8.11(s,1H),7.96(s,1H),7.78–7.70(m,1H),7.30–7.23(m,1H),4.95–4.88(m,1H),3.40–3.35(m,2H),2.30–2.03(m,4H)。 Step 5: 2-(2-(1-(bis(tert-butyloxycarbonyl)amino)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline-4- tert-butyl)thiazol-4-yl)pyrrolidine-1-carboxylate (90 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (trifluoroacetic acid method) to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl )-4-(4-(pyrrolidin-2-yl)thiazol-2-yl)isoquinolin-1-amine (Z6, 32 mg, yield: 62%), grey solid. ES-API: [M+H] + =431.2. 1 H NMR (500MHz, DMSO-d 6 )δ9.75-9.65(m,1H),9.10-9.00(m,1H),8.98(d,J=8.8Hz,1H),8.87-8.83(m,2H) ), 8.30(s, 1H), 8.22(d, J=8.8Hz, 1H), 8.11(s, 1H), 7.96(s, 1H), 7.78–7.70(m, 1H), 7.30–7.23(m, 1H), 4.95–4.88 (m, 1H), 3.40–3.35 (m, 2H), 2.30–2.03 (m, 4H).
实施例7化合物Z7的合成Example 7 Synthesis of compound Z7
Figure PCTCN2022085658-appb-000095
Figure PCTCN2022085658-appb-000095
步骤一：溴化铜(637.1mg,2.85mmol)溶于无水乙腈(5mL)，加入亚硝酸叔丁酯(392.4mg,3.81mmol)，室温下搅拌2分钟，加入2-氨基-6,7-二氢苯并[d]噻唑-4(5H)-酮(400mg,2.38mmol)，反应液室温搅拌2小时，LC-MS检测反应完全，反应液倒入20mL水中，用乙酸乙酯(200mL×2)萃取，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(四氢呋喃：石油醚＝10％-20％)纯化得到2-溴-6,7-二氢-苯并[d]噻唑-4(5H)-酮(320mg，收率：58％)灰色固体。ES-API:[M+H] +＝232.2,234.2。 Step 1: Dissolve copper bromide (637.1 mg, 2.85 mmol) in anhydrous acetonitrile (5 mL), add tert-butyl nitrite (392.4 mg, 3.81 mmol), stir at room temperature for 2 minutes, add 2-amino-6,7 -dihydrobenzo[d]thiazol-4(5H)-one (400 mg, 2.38 mmol), the reaction solution was stirred at room temperature for 2 hours, LC-MS detected that the reaction was complete, the reaction solution was poured into 20 mL of water, washed with ethyl acetate (200 mL ×2) extraction, drying over anhydrous sodium sulfate, filtration, concentration, and the crude product was purified by column chromatography (tetrahydrofuran: petroleum ether=10%-20%) to obtain 2-bromo-6,7-dihydro-benzo[d] Thiazol-4(5H)-one (320 mg, yield: 58%) grey solid. ES-API: [M+H] + = 232.2, 234.2.
步骤二：2-溴-6,7-二氢-苯并[d]噻唑-4(5H)-酮(320mg,1.38mmol)溶于二氯甲烷(10mL)，室温下加入甲胺盐酸盐(138.7mg,2.07mmol)，N,N-二异丙基乙胺(3mL)，搅拌20分钟，加入醋酸(5mL)，室温搅拌16小时后，冰浴下分批加入氰基硼氢化钠(260.8mg,4.14mmol)。LC-MS检测反应完全，冰浴下加入水(40mL)，用(二氯甲烷:甲醇＝10：1)混合溶液萃取(100mL×2)，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(二氯甲烷：甲醇＝3％-6％)纯化得到2-溴-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(215.1mg,收率:63％)，淡黄色油状。ES-API:[M+H] +＝247.1,249.2。 Step 2: 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL), and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), stirred for 20 minutes, added acetic acid (5 mL), stirred at room temperature for 16 hours, and added sodium cyanoborohydride ( 260.8 mg, 4.14 mmol). LC-MS detected that the reaction was complete, added water (40 mL) under ice bath, extracted with (dichloromethane: methanol = 10: 1) mixed solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was passed through a column Purification by chromatography (dichloromethane:methanol=3%-6%) gave 2-bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (215.1 mg, Yield: 63%), pale yellow oil. ES-API: [M+H] + = 247.1, 249.2.
步骤三：2-溴-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(49.4mg,0.20mmol)溶于二氧六环(10mL)和水(2mL)，室温下加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,粗品)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(14.4mg,0.02mmol)，磷酸钾(127.2mg,0.60mmol)，氮气保护下100℃搅拌反应2小时。反应液加入二氯甲烷(40mL)，依次用水(10mL)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(二氯甲烷：甲醇＝4％-6％)纯化得到2-(1-(双(叔丁基氧羰基)氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(56mg,收率：43％)。ES-API:[M+H] +＝645.2。 Step 3: 2-Bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (49.4 mg, 0.20 mmol) was dissolved in dioxane (10 mL) and water (2 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-di Methoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), the reaction was stirred at 100 °C for 2 hours under nitrogen protection. Dichloromethane (40 mL) was added to the reaction solution, washed with water (10 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography (dichloromethane: methanol=4%-6 %) was purified to give 2-(1-(bis(tert-butyloxycarbonyl)amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)- N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (56 mg, yield: 43%). ES-API: [M+H] + =645.2.
步骤四：2-(1-(双(叔丁基氧羰基)氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(56mg,0.09mmol)溶于二氯甲烷(4mL)加入三氟乙酸(2mL)，室温下反应1小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(三氟乙酸法)纯化得到2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z7,4.2mg,收率：10％)，灰色固体。ES-API:[M+H] +＝445.2。 Step 4: 2-(1-(bis(tert-butyloxycarbonyl)amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (56mg, 0.09mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (2mL) was added, and the reaction was carried out at room temperature for 1 The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (trifluoroacetic acid method) to obtain 2-(1-amino-7-(7-fluoroimidazo[1, 2-a]pyridin-3-yl)isoquinolin-4-yl)-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z7, 4.2 mg, Yield: 10%), grey solid. ES-API: [M+H] + =445.2.
步骤五：2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4- 胺(Z7,4.2mg)经手性拆分(柱型：Daicel 
Figure PCTCN2022085658-appb-000096
 IA 250*4.6mm,5μm，10mm，5um；流动相体系：(A：正己烷+2％DEA(V/V)；B：乙醇+2％DEA(V/V))；流速：1mL/min；等度洗脱程序：流动相A：流动相B＝50:50(V/V)；柱温：30℃)得到两个异构体化合物。一个异构体化合物任意指定为(R)-2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z7-1,1.4mg,收率：33％,保留时间：6.530)，为白色固体。ES-API:[M+H] +＝445.2。另一个异构体化合物任意指定为(S)-2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z7-2,2.1mg,收率:50％,保留时间：7.728)，为白色固体。ES-API:[M+H] +＝445.2。 Step 5: 2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N-methyl-4,5,6 ,7-Tetrahydrobenzo[d]thiazol-4-amine (Z7, 4.2 mg) was chiral resolved (column: Daicel
Figure PCTCN2022085658-appb-000096
IA 250*4.6mm, 5μm, 10mm, 5um; mobile phase system: (A: n-hexane + 2% DEA (V/V); B: ethanol + 2% DEA (V/V)); flow rate: 1mL/min ; isocratic elution procedure: mobile phase A: mobile phase B=50:50 (V/V); column temperature: 30° C.) to obtain two isomer compounds. An isomeric compound is arbitrarily designated as (R)-2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z7-1, 1.4 mg, yield: 33%, retention time: 6.530) as a white solid. ES-API: [M+H] + =445.2. Another isomeric compound arbitrarily designated as (S)-2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)- N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z7-2, 2.1 mg, yield: 50%, retention time: 7.728) as a white solid. ES-API: [M+H] + =445.2.
实施例8化合物Z8的合成Example 8 Synthesis of compound Z8
Figure PCTCN2022085658-appb-000097
Figure PCTCN2022085658-appb-000097
步骤一：2-((叔丁氧羰基)氨基)-5-(四氢-2H-吡喃-4-基)噻唑-4-羧酸甲酯(900mg,2.63mmol)溶于二氯甲烷(5mL)，加入三氟乙酸(3mL)，室温下反应4小时。反应液浓缩，用饱和碳酸氢钠(30mL)调pH至8，析出固体，过滤，滤饼用水(10mL)洗涤，真空干燥得到2-氨基-5-(四氢-2H-吡喃-4-基)噻唑-4-羧酸甲酯(395mg,收率:62％)，白色固体。ES-API:[M+H] +＝243.1。 Step 1: Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (900mg, 2.63mmol) was dissolved in dichloromethane ( 5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated, adjusted to pH 8 with saturated sodium bicarbonate (30 mL), a solid was precipitated, filtered, the filter cake was washed with water (10 mL), and dried in vacuo to obtain 2-amino-5-(tetrahydro-2H-pyran-4- (395 mg, yield: 62%), white solid. ES-API: [M+H] + = 243.1.
步骤二：溴化铜(950mg,4.26mmol)溶于乙腈(6mL)，室温下滴加亚硝酸叔丁酯(219mg,2.13mmol)，反应加热到60℃，滴加2-氨基-5-(四氢-2H-吡喃-4-基)噻唑-4-羧酸甲酯(345mg,1.42mmol)的乙腈悬浮液(7mL)，在60℃搅拌反应2小时。反应液倒入1M氢氧化钠水溶液(20mL)，乙酸乙酯萃取(30mL×2)。合并有机层，1M氯化铵溶液洗涤(10mL)，无水硫酸钠干燥，过滤，浓缩得到2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-羧酸甲酯(135mg,收率:31％)，白色固体。ES-API:[M+H] +＝306.0.308.0。 Step 2: copper bromide (950mg, 4.26mmol) was dissolved in acetonitrile (6mL), tert-butyl nitrite (219mg, 2.13mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5-( A suspension (7 mL) of methyl tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (345 mg, 1.42 mmol) in acetonitrile was stirred at 60°C for 2 hours. The reaction solution was poured into 1M aqueous sodium hydroxide solution (20 mL), and extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with 1M ammonium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate Ester (135 mg, yield: 31%), white solid. ES-API: [M+H] + =306.0.308.0.
步骤三：2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-羧酸甲酯(285mg,0.93mmol)溶于四氢呋喃(5mL)，冰浴下滴加硼氢化锂四氢呋喃溶液(0.93mL,1.86mmol,2.0M)，反应在冰浴下搅拌30分钟，室温下再搅 拌2小时。冰浴下用水(8mL)和1.0M稀盐酸(4mL)淬灭反应，乙酸乙酯萃取(30mL×2)。有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲醇(258mg,收率:100％)，白色固体。ES-API:[M+H] +＝278.0,280.0。 Step 3: Methyl 2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (285 mg, 0.93 mmol) was dissolved in tetrahydrofuran (5 mL), and hydroboration was added dropwise under ice bath A solution of lithium in tetrahydrofuran (0.93 mL, 1.86 mmol, 2.0 M), the reaction was stirred under an ice bath for 30 minutes and at room temperature for an additional 2 hours. The reaction was quenched with water (8 mL) and 1.0 M dilute hydrochloric acid (4 mL) under ice bath, and extracted with ethyl acetate (30 mL×2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (258 mg) , yield: 100%), white solid. ES-API: [M+H] + =278.0, 280.0.
步骤四：(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲醇(230mg,0.83mmol)和三乙胺(210mg,2.08mmol)溶于二氯甲烷(10mL)，冰浴下滴加甲磺酰氯(142mg,1.24mmol)，在冰浴下搅拌反应2小时。反应液加入二氯甲烷(40mL)，依次用水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基甲磺酸甲酯(295mg,收率:100％)，无需进一步纯化即可使用。ES-API:[M+H] +＝356.1,358.1。 Step 4: (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (230 mg, 0.83 mmol) and triethylamine (210 mg, 2.08 mmol) were dissolved in dichloro Methane (10 mL) was added dropwise with methanesulfonyl chloride (142 mg, 1.24 mmol) under an ice bath, and the reaction was stirred under an ice bath for 2 hours. The reaction solution was added with dichloromethane (40 mL), washed successively with water (10 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (2-bromo-5-(tetrahydro-2H-pyran-) Methyl 4-yl)thiazol-4-yl)methylmethanesulfonate (295 mg, yield: 100%) was used without further purification. ES-API: [M+H] + =356.1, 358.1.
步骤五：(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基甲磺酸甲酯(295mg，0.83mmol)溶于四氢呋喃(5mL)，室温下加入2.0M二甲胺四氢呋喃溶液(10mL,20.0mmol)，在室温下搅拌反应2小时。反应液加入水(10mL)，乙酸乙酯(40mL)萃取。有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N,N-二甲基甲胺(210mg,收率:83％)，粉色固体。ES-API:[M+H] +＝305.0,307.0。 Step 5: Methyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylmethanesulfonate (295 mg, 0.83 mmol) was dissolved in tetrahydrofuran (5 mL), room temperature A 2.0M solution of dimethylaminetetrahydrofuran (10 mL, 20.0 mmol) was added under it, and the reaction was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica column (7.0M ammonia in methanol/dichloromethane: 0-5%) to give 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl )-N,N-dimethylmethylamine (210 mg, yield: 83%), pink solid. ES-API: [M+H] + =305.0, 307.0.
步骤六：向5mL微波管里加入1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N,N-二甲基甲胺(45mg,0.15mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(200mg,粗品)，碳酸钾(62mg，0.45mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2mL)和水(0.5mL)，用氮气吹扫1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(5mL)，乙酸乙酯(30mL)萃取。有机层用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤浓缩。粗品用薄层制备色谱板纯化(二氯甲烷/7.0M氨甲醇溶液＝30:1)得到目标产物4-(4-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(35mg,收率:34％)，淡棕色固体。ES-API:[M+H] +＝703.3。 Step 6: Add 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N,N-dimethylmethanamine (45mg, 0.15mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (200 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, at 110 °C in a microwave reactor The reaction was carried out for 45 minutes. Water (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by thin-layer preparative chromatography (dichloromethane/7.0M ammonia methanol solution=30:1) to obtain the target product 4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyridine) Furan-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline phenoline (35 mg, yield: 34%), light brown solid. ES-API: [M+H] + =703.3.
步骤七：4-(4-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(35mg,0.05mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(1mL)，在室温下反应1小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸法)纯化得到4-(4-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(Z8,21mg,收率:84％,甲酸盐)，淡黄色固体。ES-API:[M+H] +＝503.2。 1H NMR(500MHz,DMSO-d 6)δ9.02(d,J＝9.0Hz,1H),8.74(dd,J＝7.5,6.0Hz,1H),8.58(d,J＝1.5Hz,1H),8.31(s,1H),8.01(dd,J＝9.0,1.5Hz,1H),7.90(s,1H),7.62–7.48(m,3H),7.08(td,J＝7.5,2.5Hz,1H),4.25(s,2H),3.97(dd,J＝11.0,3.5Hz,2H),3.53–3.39(m,3H),2.71(s,6H),1.89(dd,J＝12.5,1.5Hz,2H),1.70–1.60(m,2H)。 Step 7: 4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1 ,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (35 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added , at room temperature for 1 hour. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid method) to obtain 4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H) -pyran-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (Z8, 21 mg, yield : 84%, formate), pale yellow solid. ES-API: [M+H] + =503.2. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.02 (d, J=9.0 Hz, 1H), 8.74 (dd, J=7.5, 6.0 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H) ,8.31(s,1H),8.01(dd,J=9.0,1.5Hz,1H),7.90(s,1H),7.62–7.48(m,3H),7.08(td,J=7.5,2.5Hz,1H) ), 4.25(s, 2H), 3.97(dd, J=11.0, 3.5Hz, 2H), 3.53–3.39(m, 3H), 2.71(s, 6H), 1.89(dd, J=12.5, 1.5Hz, 2H), 1.70–1.60 (m, 2H).
实施例9化合物Z70、Z70-1、Z70-2的合成Example 9 Synthesis of compounds Z70, Z70-1 and Z70-2
Figure PCTCN2022085658-appb-000098
Figure PCTCN2022085658-appb-000098
步骤一：溴化铜(637.1mg,2.85mmol)溶于无水乙腈(5mL)，加入亚硝酸叔丁酯(392.4mg,3.81mmol)，在室温下搅拌2分钟后加入2-氨基-6,7-二氢苯并[d]噻唑-4(5H)-酮(400mg,2.38mmol)，反应液室温搅拌2小时。LC-MS检测反应结束，反应液倒入水(20mL)中，用乙酸乙酯(200mL×2)萃取，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(四氢呋喃：石油醚＝10％-20％)得到产物2-溴-6,7-二氢-苯并[d]噻唑-4(5H)-酮(320mg,纯度：100％,收率：58％)，灰色固体。ES-API:[M+H] +＝232.2,234.2。 Step 1: copper bromide (637.1 mg, 2.85 mmol) was dissolved in anhydrous acetonitrile (5 mL), tert-butyl nitrite (392.4 mg, 3.81 mmol) was added, 2-amino-6 was added after stirring at room temperature for 2 minutes, 7-Dihydrobenzo[d]thiazol-4(5H)-one (400 mg, 2.38 mmol), the reaction solution was stirred at room temperature for 2 hours. LC-MS detected the end of the reaction, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (200 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether=10 %-20%) to give the product 2-bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, purity: 100%, yield: 58%) as a grey solid. ES-API: [M+H] + = 232.2, 234.2.
步骤二：2-溴-6,7-二氢-苯并[d]噻唑-4(5H)-酮(320mg，1.38mmol)溶于二氯甲烷(10mL)在室温下加入甲胺盐酸盐(138.7mg,2.07mmol)，N,N-二异丙基乙胺(3mL)，搅拌20分钟后加入醋酸(5mL)，室温搅拌16小时后，冰浴下分批加入氰基硼氢化钠(260.8mg,4.14mmol)。LC-MS检测反应完全，冰浴下加入水(40mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,100mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-6％)得到产物2-溴-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(215.1mg,收率：63％)，淡黄色油状。ES-API:[M+H] +＝247.1,249.2。 Step 2: 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL) and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), after stirring for 20 minutes, acetic acid (5 mL) was added, and after stirring at room temperature for 16 hours, sodium cyanoborohydride ( 260.8 mg, 4.14 mmol). LC-MS detected that the reaction was complete, added water (40 mL) under ice bath, extracted with dichloromethane/methanol mixed solution (10:1, 100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography ( Dichloromethane: methanol=3%-6%) to obtain the product 2-bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (215.1 mg, yield: 63%), pale yellow oil. ES-API: [M+H] + = 247.1, 249.2.
步骤三：2-溴-N-甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(215.1mg,0.87mmol)溶于甲醇(5.0mL)，在室温下加入37％的甲醛水溶液(2.0mL)，搅拌18小时后，冰浴0℃下加入氰基硼氢化钠(107.9mg,1.74mmol)，搅拌10分钟后，升至室温下搅拌0.5小时。LC-MS检测反应完全，冰浴下加入水(10mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,50mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-6％)得到产物2-溴-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(209.3mg,收率：92％)，淡黄色油状。ES-API:[M+H] +＝261.2,262.2。 Step 3: 2-Bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (215.1 mg, 0.87 mmol) was dissolved in methanol (5.0 mL) at room temperature A 37% aqueous formaldehyde solution (2.0 mL) was added, and after stirring for 18 hours, sodium cyanoborohydride (107.9 mg, 1.74 mmol) was added at 0°C in an ice bath, and after stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 0.5 hours. LC-MS detected that the reaction was complete, water (10 mL) was added under ice bath, extracted with dichloromethane/methanol mixed solution (10:1, 50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (dichloromethane: methanol=3%-6%) to obtain the product 2-bromo-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (209.3 mg , yield: 92%), pale yellow oil. ES-API: [M+H] + = 261.2, 262.2.
步骤四：2-溴-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(52.2mg,0.20mmol)溶于二氧六环(10.0mL)和水(2.0mL)，在室温下加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,粗品)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(14.4mg,0.02mmol)，磷酸钾(127.2mg,0.60mmol)，在氮气保护下100℃搅拌反应2小时。反应液加入二氯甲烷(40.0mL)，依次加水(10.0mL)，饱和食盐水(20.0mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝4％-6％)得到粗品，用制备HPLC纯化(三氟醋酸)得到2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z70,26.3mg,收率:29％)。ES-API:[M+H] +＝459.2。 Step 4: 2-Bromo-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (52.2mg, 0.20mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2 ',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), phosphoric acid Potassium (127.2 mg, 0.60 mmol), and the reaction was stirred at 100 °C for 2 hours under nitrogen protection. The reaction solution was added with dichloromethane (40.0 mL), followed by adding water (10.0 mL), washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane: methanol=4 %-6%) to give crude product, which was purified by preparative HPLC (trifluoroacetic acid) to give 2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline- 4-yl)-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z70, 26.3 mg, yield: 29%). ES-API: [M+H] + =459.2.
步骤五：2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z70,26.3mg)用手性拆分(柱型：Daicel
Figure PCTCN2022085658-appb-000099
IA 250*4.6mm,5μm，10mm，5um； 流动相体系：(A：乙腈(0.2％DEA)；B：异丙醇(0.2％DEA)；流速：1mL/min；等度洗脱程序：流动相A：流动相B＝60:40(V/V)；柱温：30℃；)得到两个异构体化合物。一个结构任意指定为(R)-2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z70-1,12.1mg,收率:13％,保留时间：6.820)，白色固体。ES-API:[M+H] +＝459.2。另一个结构任意指定为(S)-2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-N,N-二甲基-4,5,6,7-四氢苯并[d]噻唑-4-胺(Z70-2,12.6mg,收率:14％,保留时间：7.928)，白色固体。ES-API:[M+H] +＝459.2。 Step 5: 2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N,N-dimethyl-4, Chiral resolution of 5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z70, 26.3 mg) (column: Daicel
Figure PCTCN2022085658-appb-000099
IA 250*4.6mm, 5μm, 10mm, 5um; Mobile phase system: (A: acetonitrile (0.2% DEA); B: isopropanol (0.2% DEA); flow rate: 1 mL/min; isocratic elution procedure: flow Phase A: mobile phase B = 60:40 (V/V); column temperature: 30°C;) to give two isomeric compounds. A structure arbitrarily designated as (R)-2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N,N- Dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z70-1, 12.1 mg, yield: 13%, retention time: 6.820), white solid. ES-API: [M+H] + =459.2. Another structure arbitrarily designated as (S)-2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N,N -Dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (Z70-2, 12.6 mg, yield: 14%, retention time: 7.928), white solid. ES-API: [M+H] + =459.2.
实施例10化合物Z73的合成Example 10 Synthesis of compound Z73
Figure PCTCN2022085658-appb-000100
Figure PCTCN2022085658-appb-000100
步骤一：(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲醇(300mg,1.08mmol)溶于二氯甲烷(25mL)，在冰浴下加入戴斯-马丁氧化剂(572mg,1.35mmol)，反应在室温下搅拌3小时。反应液加入二氯甲烷(25mL)，依次用饱和碳酸氢钠溶液(25mL)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到目标产物2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-甲醛(255mg,收率85.6％)，白色固体。ES-API:[M+H] +＝276.0,278.0。 Step 1: (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (300 mg, 1.08 mmol) was dissolved in dichloromethane (25 mL), added under ice bath Dess-Martin oxidizer (572 mg, 1.35 mmol) and the reaction was stirred at room temperature for 3 hours. Dichloromethane (25 mL) was added to the reaction solution, washed with saturated sodium bicarbonate solution (25 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-40%) to obtain the target product 2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carbaldehyde (255mg, yield 85.6%), white solid. ES-API: [M+H] + =276.0, 278.0.
步骤二：2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-甲醛(255mg,0.92mmol)和甲氨盐酸盐(312mg,4.62mmol)悬浮于1,2-二氯甲烷(12mL)和甲醇(4mL)，加入三乙酰基硼氢化钠(390mg,1.85mmol)，反应在室温下反应18小时。反应液用1M氢氧化钠溶液调pH至10，用二氯甲烷萃取(50mL)。有机层用无水硫酸钠干燥，过滤浓缩得到目标产物1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N-甲基甲胺(268mg,收率99.7％)，白色固体。ES-API:[M+H] +＝291.1,293.1。 Step 2: 2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carbaldehyde (255mg, 0.92mmol) and methylamine hydrochloride (312mg, 4.62mmol) were suspended in 1,2 - Dichloromethane (12 mL) and methanol (4 mL), sodium triacetylborohydride (390 mg, 1.85 mmol) was added, and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was adjusted to pH 10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N-methylmethanamine ( 268 mg, yield 99.7%), white solid. ES-API: [M+H] + = 291.1, 293.1.
步骤三：1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N-甲基甲胺(268mg,0.92mmol))，和三乙胺(140mg,1.38mmol)溶于二氯甲烷(10mL)，在冰浴下加入 二碳酸二叔丁酯(261mg,0.20mmol)，反应在室温下搅拌1小时。反应液浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(290mg,收率80.6％)，白色固体。ES-API:[M+H] +＝391.1,393.1。 Step 3: 1-(2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N-methylmethylamine (268 mg, 0.92 mmol)), and triethylamine (140 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (261 mg, 0.20 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate tert-butyl ester (290 mg, 80.6% yield), white solid. ES-API: [M+H] + = 391.1, 393.1.
步骤四：向5mL微波管里加入：((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(55mg,0.14mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(147mg,粗品)，碳酸钾(58mg,0.42mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(10mg,0.014mmol)，1,4-二氧六环(1.5mL)和水(0.3mL)，用氮气吹1分钟，在微波反应器中110℃ 下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用薄层制备色谱板纯化(二氯甲烷/甲醇＝25:1)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(27mg,收率24.3％)，淡黄色固体。ES-API:[M+H] +＝789.3。 Step 4: Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 55mg, 0.14mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (147 mg, crude), potassium carbonate (58 mg, 0.42 mmol), [1,1'-bis(bis(bis)) Phenylphosphine)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor for 110 The reaction was carried out at ℃ for 45 minutes. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by thin-layer preparative chromatography (dichloromethane/methanol=25:1) to obtain the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrakis) Hydro-2H-pyran-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminobis Di-tert-butyl carbonate (27 mg, yield 24.3%), pale yellow solid. ES-API: [M+H] + =789.3.
步骤五：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(27mg,0.034mmol)溶于甲醇(1mL)加入4.0M氯化氢二氧六环溶液(4mL,16.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，得到粗品用制备HPLC(甲酸)纯化得到目标产物7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z73,甲酸盐,14mg,收率77.0％)，淡黄色固体。ES-API:[M+H] +＝489.2。 1H NMR(500MHz,DMSO-d 6)δ9.08(d,J＝9.0Hz,1H),8.78–8.72(m,1H),8.56(d,J＝1.0Hz,1H),8.33–8.26(m,2H),8.01(dd,J＝9.0,1.5Hz,1H),7.90(s,1H),7.60–7.47(m,3H),7.07(td,J＝7.5,2.5Hz,1H),4.07(s,2H),3.95(dd,J＝11.0,3.5Hz,2H),3.48(t,J＝11.0Hz,2H),3.41–3.34(m,1H),2.53(s,3H),1.89(d,J＝12.0Hz,2H),1.71–1.55(m,2H). Step five: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7- Di-tert-butyl (7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (27 mg, 0.034 mmol) was dissolved in methanol (1 mL) and 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 16.0 mmol) was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl )-4-(4-(methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z73, formate , 14 mg, yield 77.0%), pale yellow solid. ES-API: [M+H] + =489.2. 1 H NMR (500MHz, DMSO-d 6 )δ9.08(d,J=9.0Hz,1H),8.78-8.72(m,1H),8.56(d,J=1.0Hz,1H),8.33-8.26( m, 2H), 8.01 (dd, J=9.0, 1.5Hz, 1H), 7.90 (s, 1H), 7.60–7.47 (m, 3H), 7.07 (td, J=7.5, 2.5Hz, 1H), 4.07 (s,2H),3.95(dd,J=11.0,3.5Hz,2H),3.48(t,J=11.0Hz,2H),3.41–3.34(m,1H),2.53(s,3H),1.89( d, J=12.0Hz, 2H), 1.71–1.55 (m, 2H).
实施例11化合物Z165的合成Example 11 Synthesis of compound Z165
Figure PCTCN2022085658-appb-000101
Figure PCTCN2022085658-appb-000101
步骤一：(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)甲醇(230mg,0.87mmol)和三乙胺(220mg,2.18mmol)溶于二氯甲烷(10mL)在冰浴下滴加甲磺酰氯(150mg,1.31mmol)，反应在冰浴下搅拌2小时，然后加入 2.0M二甲胺四氢呋喃溶液(4mL,8.0mmol)，反应在室温下搅拌1小时。反应液加入二氯甲烷(25mL)，依次用水(15mL)，饱和食盐水(15mL)洗涤，无水硫酸钠干燥并浓缩。得到粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物1-(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)-N,N-二甲基甲胺(200mg,收率78.9％)，粉色固体。ES-API:[M+H] +＝291.1,293.1。 Step 1: (2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methanol (230 mg, 0.87 mmol) and triethylamine (220 mg, 2.18 mmol) were dissolved in dichloromethane (10 mL) on ice Methanesulfonyl chloride (150 mg, 1.31 mmol) was added dropwise under the bath, the reaction was stirred under an ice bath for 2 hours, then 2.0M dimethylaminetetrahydrofuran solution (4 mL, 8.0 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Dichloromethane (25 mL) was added to the reaction solution, washed successively with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to obtain the target product 1-(2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N , N-dimethylmethylamine (200 mg, yield 78.9%), pink solid. ES-API: [M+H] + = 291.1, 293.1.
步骤二：向5mL微波管里加入：1-(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)-N,N-二甲基甲胺(50mg,0.17mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基) 氨基)异喹啉(128mg,粗品)，碳酸钾(71mg,0.51mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(13mg,0.017mmol)，1,4-二氧六环(1.5mL)和水(0.3mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(5mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(10mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用薄层制备色谱板纯化(二氯甲烷/7.0M氨甲醇溶液＝25:1)得到目标产物4-(4-((二甲氨基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(37mg,收率31.3％)，淡黄色固体。ES-API:[M+H] +＝689.2。 Step 2: Into a 5mL microwave tube, add: 1-(2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N,N-dimethylmethanamine (50mg, 0.17mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (128 mg, crude), potassium carbonate (71 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (13 mg, 0.017 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C. for 45 min. Water (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by thin-layer preparative chromatography (dichloromethane/7.0M ammonia methanol solution=25:1) to obtain the target product 4-(4-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl) )thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (37 mg, received rate 31.3%), pale yellow solid. ES-API: [M+H] + =689.2.
步骤三：4-(4-((二甲氨基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(37mg,0.05mmol)溶于甲醇(1mL)加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，得到粗品用制备HPLC(甲酸)纯化得到目标产物4-(4-(二甲氨基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(Z165,甲酸盐,15mg,收率52.0％)，淡黄色固体。ES-API:[M+H] +＝489.1。 1H NMR(500MHz,DMSO-d 6)δ9.05(d,J＝9.0Hz,1H),8.77(dd,J＝7.5,6.0Hz,1H),8.55(d,J＝1.5Hz,1H),8.26(s,1H),8.21(s,1H),8.03(dd,J＝9.0,1.5Hz,1H),7.90(s,1H),7.56(dd,J＝10.0,2.5Hz,1H),7.49(s,2H),7.06(td,J＝7.5,2.5Hz,1H),4.05–3.95(m,3H),3.84–3.81(m,1H),3.70–3.62(m,2H),3.58(dd,J＝8.0,6.5Hz,1H),2.48–2.39(m,1H),2.27(s,6H),1.94–1.84(m,1H). Step 3: 4-(4-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridine -3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (37 mg, 0.05 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added, The reaction was carried out at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, and the solvent was spin-dried to obtain a crude product which was purified by preparative HPLC (formic acid) to obtain the target product 4-(4-(dimethylamino)methyl)-5-(tetrahydrofuran-3). -yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (Z165, formate, 15mg, yield 52.0 %), pale yellow solid. ES-API: [M+H] + =489.1. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.05 (d, J=9.0 Hz, 1H), 8.77 (dd, J=7.5, 6.0 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H) ,8.26(s,1H),8.21(s,1H),8.03(dd,J=9.0,1.5Hz,1H),7.90(s,1H),7.56(dd,J=10.0,2.5Hz,1H), 7.49(s, 2H), 7.06(td, J=7.5, 2.5Hz, 1H), 4.05-3.95(m, 3H), 3.84-3.81(m, 1H), 3.70-3.62(m, 2H), 3.58( dd, J=8.0, 6.5Hz, 1H), 2.48–2.39 (m, 1H), 2.27 (s, 6H), 1.94–1.84 (m, 1H).
实施例12化合物Z78的合成Example 12 Synthesis of compound Z78
Figure PCTCN2022085658-appb-000102
Figure PCTCN2022085658-appb-000102
步骤一：2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-甲醛(500mg,1.81mmol)和(S)-2-甲基丙烷-2-亚磺酰胺 (439mg,3.62mmol)溶于二氯甲烷(25mL)，加入四乙氧基钛(1.03g,4.53mmol)，反应在室温下搅拌18小时。反应液加入饱和食盐水(50mL)，用乙酸乙酯萃取(50mL×2)。合并有机相用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到目标产物(S,E)-N-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)亚甲基)-2-甲基丙烷-2-磺酰胺(650mg,收率94.6％)，无色液体。ES-API:[M+H] +＝379.0,381.1。 Step 1: 2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carbaldehyde (500mg, 1.81mmol) and (S)-2-methylpropane-2-sulfinamide ( 439 mg, 3.62 mmol) was dissolved in dichloromethane (25 mL), titanium tetraethoxide (1.03 g, 4.53 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Saturated brine (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL×2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-40%) to give the target product (S,E)-N-(2-bromo-5-(tetrahydro-2H-pyran-4-yl) Thiazol-4-yl)methylene)-2-methylpropane-2-sulfonamide (650 mg, yield 94.6%), colorless liquid. ES-API: [M+H] + =379.0, 381.1.
步骤二：(S,E)-N-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)亚甲基)-2-甲基丙烷-2-磺酰胺(570mg,1.50mmol)溶于四氢呋喃(15mL)，在氮气保护下-78℃滴加0.5M(2-(1,3-二噁烷-2-基)乙基)溴化镁四氢呋喃溶液(1.05mL,0.53mmol)，反应在-78℃搅拌30分钟。饱和氯化铵溶液淬灭(15mL)，加入水(15mL)，用乙酸乙酯萃取(60mL)。合并有机相用饱和食盐水洗涤(25mL)，无水硫酸钠干燥，过滤浓缩得到目标产物(S)-N-((S)-1-1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-3-(1,3-二氧六环-2-基)丙基)-2-甲基丙烷-2-亚砜酰胺(1.05g,粗品)，白色固体。ES-API:[M+H] +＝495.0,497.0。 Step 2: (S,E)-N-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylene)-2-methylpropane-2- Sulfonamide (570 mg, 1.50 mmol) was dissolved in tetrahydrofuran (15 mL), and 0.5 M (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide tetrahydrofuran solution was added dropwise at -78°C under nitrogen protection (1.05 mL, 0.53 mmol) and the reaction was stirred at -78 °C for 30 minutes. Quench with saturated ammonium chloride solution (15 mL), add water (15 mL) and extract with ethyl acetate (60 mL). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product (S)-N-((S)-1-1-(2-bromo-5-(tetrahydro-2H) -pyran-4-yl)thiazol-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfoxide amide (1.05g, crude product), white solid. ES-API: [M+H] + =495.0, 497.0.
步骤三：三氟乙酸(10mL)和水(1mL)，冷却到0℃，(S)-N-((S)-1-1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-3-(1,3-二氧六环-2-基)丙基)-2-甲基丙烷-2-亚砜酰胺(1.05g,粗品)分批加入，反应在室温下搅拌45分钟，加入三乙基硅烷(1.74g,14.96mmol)，反应在室温下搅拌16小时。反应液浓缩得到目标产物(S)--2-溴-4-(吡咯烷-2-基)-5-(四氢-2H-吡喃-4-基)噻唑三氟乙酸盐(2.5g,粗品)，无需进一步纯化用于直接下一步。ES-API:[M+H] +＝317.1,319.1(游离碱)。 Step 3: Trifluoroacetic acid (10 mL) and water (1 mL), cooled to 0°C, (S)-N-((S)-1-1-(2-bromo-5-(tetrahydro-2H-pyran) -4-yl)thiazol-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfoxide amide (1.05g, crude) fraction Added in batches, the reaction was stirred at room temperature for 45 minutes, triethylsilane (1.74 g, 14.96 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain the target product (S)--2-bromo-4-(pyrrolidin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole trifluoroacetate (2.5g , crude), was used directly in the next step without further purification. ES-API: [M+H] + = 317.1, 319.1 (free base).
步骤四：(S)--2-溴-4-(吡咯烷-2-基)-5-(四氢-2H-吡喃-4-基)噻唑三氟乙酸盐(2.5g,粗品)溶于二氯甲烷(15mL)，在0℃下加入三乙胺(800mg,7.91mmol)和 二碳酸二叔丁酯(650mg,7.91mmol)，反应在室温下搅拌1小时。反应液加入二氯甲烷(25mL)，依次用水(10mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-30％)得到目标产物(S)-2-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(250mg,3步收率40％)，紫色液体。ES-API:[M+H] +＝359.0,361.0。 Step 4: (S)--2-Bromo-4-(pyrrolidin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole trifluoroacetate (2.5g, crude product) Dissolved in dichloromethane (15 mL), triethylamine (800 mg, 7.91 mmol) and di-tert-butyl dicarbonate (650 mg, 7.91 mmol) were added at 0°C, and the reaction was stirred at room temperature for 1 hour. Dichloromethane (25 mL) was added to the reaction solution, washed successively with water (10 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to give the target product (S)-2-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl) tert-butyl pyrrolidine-1-carboxylate (250 mg, 40% yield over 3 steps), purple liquid. ES-API: [M+H] + =359.0, 361.0.
步骤五：向5mL微波管里加入(S)-2-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(60mg,0.14mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(130mg,粗品),碳酸钾(60mg,0.43mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg，0.014mmol)，1,4-二氧六环(1.5mL)和水(0.3mL),用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(8mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用薄层制备色谱板纯化(二氯甲烷/7.0M氨甲醇溶液＝25:1)得到目标产物(S)-2-(2-(1-((二叔丁氧羰基)氨基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(40mg,收率34.1％)，淡黄色固体。ES-API:[M+H] +＝815.2。 Step 5: Add (S)-2-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)pyrrolidine-1-carboxylic acid tert-butyl into a 5mL microwave tube Ester (60 mg, 0.14 mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (130 mg, crude), potassium carbonate (60 mg, 0.43 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor The reaction was carried out at 110 °C for 45 minutes. Water (8 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by TLC plate (dichloromethane/7.0M ammonia methanol solution=25:1) to obtain the target product (S)-2-(2-(1-((di-tert-butoxycarbonyl)amino)-7 -(7-Fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl) Pyrrolidine-1-carboxylate tert-butyl ester (40 mg, yield 34.1%), pale yellow solid. ES-API: [M+H] + =815.2.
步骤六：(S)-2-(2-(1-((二叔丁氧羰基)氨基)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)吡咯烷-1-羧酸叔丁酯(40mg,0.05mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物(S)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(吡咯烷-2-基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z78,甲酸盐,12mg,收率43.7％)，淡黄色固体。ES-API:[M+H] +＝515.2。 1H NMR(500MHz,DMSO-d 6)δ9.01(d,J＝9.0Hz,1H),8.76(dd,J＝7.5,6.0Hz,1H),8.55(d,J＝1.0Hz,1H),8.26(s,1H),8.03(dd,J＝9.0,1.5Hz,1H),7.90(s,1H),7.57(dd,J＝10.0,2.5Hz,1H),7.48(s,2H),7.07(td,J＝7.5,2.5Hz,1H),4.29(t,J＝7.0Hz,1H),3.99–3.86(m,2H),3.55–3.37(m,3H),3.20–3.12(m,1H),2.90–2.82(m,1H),2.14–2.04(m,1H),2.02–1.77(m,5H),1.70–1.57(m, 2H). Step 6: (S)-2-(2-(1-((di-tert-butoxycarbonyl)amino)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline -4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)pyrrolidine-1-carboxylate tert-butyl ester (40 mg, 0.05 mmol) was dissolved in methanol (1 mL), A 4.0M solution of hydrogen chloride in dioxane (5 mL, 20.0 mmol) was added and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product (S)-7-(7-fluoroimidazo[1,2-a]pyridine- 3-yl)-4-(4-(pyrrolidin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z78, formate, 12 mg, 43.7% yield), pale yellow solid. ES-API: [M+H] + =515.2. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.01 (d, J=9.0 Hz, 1H), 8.76 (dd, J=7.5, 6.0 Hz, 1H), 8.55 (d, J=1.0 Hz, 1H) ,8.26(s,1H),8.03(dd,J=9.0,1.5Hz,1H),7.90(s,1H),7.57(dd,J=10.0,2.5Hz,1H),7.48(s,2H), 7.07 (td, J=7.5, 2.5Hz, 1H), 4.29 (t, J=7.0Hz, 1H), 3.99–3.86 (m, 2H), 3.55–3.37 (m, 3H), 3.20–3.12 (m, 1H), 2.90–2.82 (m, 1H), 2.14–2.04 (m, 1H), 2.02–1.77 (m, 5H), 1.70–1.57 (m, 2H).
实施例13化合物Z69的合成Example 13 Synthesis of compound Z69
Figure PCTCN2022085658-appb-000103
Figure PCTCN2022085658-appb-000103
步骤一：1-苄基2-甲基哌啶-1,2-二羧酸酯(5.0g,18.1mmol)溶于无水四氢呋喃(100mL)，加入氯碘甲烷(15.9g,90.5mmol)，在室温下搅拌2分钟,降温至-78℃搅拌10分钟，1.5小时内缓慢滴加二异丙基氨基锂溶液(45.3mL,2M,90.5mmol)，期间保持温度-70℃以下，滴完在-78℃温度下反应1小时，再加入醋酸/四氢呋喃混合溶液(1：3,80mL)，在-78℃温度下搅拌10分钟，升至室温，反应液倒入水(50mL)中，用乙酸乙酯(200mL×2)萃取，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(四氢呋喃：石油醚＝20％-50％)得到产物粗品2-(2-氯乙酰基)哌啶-1-羧酸苄酯(3.0g,纯度：56％,产率：31％)褐色油状，不经纯化直接用于下一步反应。ES-API:[M+H] +＝296.2。 Step 1: 1-benzyl 2-methylpiperidine-1,2-dicarboxylate (5.0 g, 18.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), chloroiodomethane (15.9 g, 90.5 mmol) was added, Stir at room temperature for 2 minutes, cool down to -78 ° C and stir for 10 minutes, slowly add lithium diisopropylamide solution (45.3 mL, 2 M, 90.5 mmol) dropwise within 1.5 hours, keep the temperature below -70 ° C during the period, and drop after dropping in React at -78°C for 1 hour, then add acetic acid/tetrahydrofuran mixed solution (1:3, 80mL), stir at -78°C for 10 minutes, warm to room temperature, pour the reaction solution into water (50mL), add acetic acid Extracted with ethyl ester (200 mL×2), dried over anhydrous sodium sulfate, concentrated by filtration and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether=20%-50%) to obtain crude product 2-(2-chloroacetyl)piperidine - Benzyl 1-carboxylate (3.0 g, purity: 56%, yield: 31%) as a brown oil, was used in the next reaction without purification. ES-API: [M+H] + =296.2.
步骤二：2-(2-氯乙酰基)哌啶-1-羧酸苄酯(3.0g,10.1mmol)溶于乙醇(50mL)，在室温下加入硫脲(1.5g,20.2mmol)，反应加热至90℃搅拌3小时。LC-MS检测反应完全，将反应液旋干之后加入水(40mL)，用乙酸乙酯萃取(100mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-6％)得到产物2-(2-氨基噻唑-4-基)哌啶-1-羧酸苄酯(900mg,收率：50％)，淡黄色油状。ES-API:[M+H] +＝318.2。 Step 2: Benzyl 2-(2-chloroacetyl)piperidine-1-carboxylate (3.0g, 10.1mmol) was dissolved in ethanol (50mL), thiourea (1.5g, 20.2mmol) was added at room temperature, and the reaction Heat to 90°C and stir for 3 hours. LC-MS detected that the reaction was complete, the reaction solution was spin-dried and then added with water (40 mL), extracted with ethyl acetate (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (dichloromethane: Methanol=3%-6%) to obtain the product benzyl 2-(2-aminothiazol-4-yl)piperidine-1-carboxylate (900 mg, yield: 50%) as pale yellow oil. ES-API: [M+H] + =318.2.
步骤三：溴化亚铜(607.1mg,4.25mmol)溶于乙腈(5mL)，在室温下加入亚硝酸叔丁酯(583.0mg,5.66mmol)，混合物搅拌5分钟后加入2-(2-氨基噻唑-4-基)哌啶-1-羧酸苄酯(900mg,2.83mmol)，反应液在室温下搅拌3小时。LC-MS检测反应完成后，冰浴下加入水(20mL)，用乙酸乙酯萃取(50mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析出纯化(四氢呋喃：石油醚＝10％-30％)得到产物2-(2-溴噻唑-4-基)哌啶-1-羧酸苄酯(320mg,收率：29％)，灰色固体。ES-API:[M+H] +＝382.2,384.2。 Step 3: Cuprous bromide (607.1 mg, 4.25 mmol) was dissolved in acetonitrile (5 mL), tert-butyl nitrite (583.0 mg, 5.66 mmol) was added at room temperature, and the mixture was stirred for 5 minutes and then added with 2-(2-amino) Thiazol-4-yl)piperidine-1-carboxylate benzyl ester (900 mg, 2.83 mmol), the reaction solution was stirred at room temperature for 3 hours. After LC-MS detection of the completion of the reaction, water (20 mL) was added under an ice bath, extracted with ethyl acetate (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether= 10%-30%) to give the product benzyl 2-(2-bromothiazol-4-yl)piperidine-1-carboxylate (320 mg, yield: 29%) as a grey solid. ES-API: [M+H] + = 382.2, 384.2.
步骤四：2-(2-溴噻唑-4-基)哌啶-1-羧酸苄酯(137.5mg,0.36mmol)溶于二氧六环(10.0mL)和水(2.0mL)，在室温下加入7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,粗品)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(14.4mg,0.02mmol)，磷酸钾(127.2mg,0.60mmol)，在氮气保护下100℃搅拌反应2小时。反应液加入二氯甲烷(40mL)，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(甲醇：二氯甲烷＝2％-5％)得到产物2-(2-(1-氨基-7-(7-氟咪唑[1,2-a]吡啶-3-基)异喹啉-4-基)噻唑-4-基)哌啶-1-羧酸苄酯(90.1mg,收率：52％)。ES-API:[M+H] +＝578.2。 Step 4: Benzyl 2-(2-bromothiazol-4-yl)piperidine-1-carboxylate (137.5 mg, 0.36 mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL) at room temperature 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol) under nitrogen The reaction was stirred at 100°C for 2 hours under protection. The reaction solution was added with dichloromethane (40 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (methanol: dichloromethane=2%-5 %) to give the product 2-(2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)thiazol-4-yl)piperidine - Benzyl 1-carboxylate (90.1 mg, yield: 52%). ES-API: [M+H] + =578.2.
步骤五：2-(2-(1-氨基-7-(7-氟咪唑[1,2-a]吡啶-3-基)异喹啉-4-基)噻唑-4-基)哌啶-1-羧酸苄酯(90.1mg, 0.16mmol)溶于三氟乙酸(2.0mL)，反应在100℃反应3小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，粗品用制备HPLC纯化(甲酸)得到目标产物7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(哌啶-2-基)噻唑-2-基)异喹啉-1-胺(Z69,15.6mg,收率：22％,甲酸盐)，灰色固体。ES-API:[M+H] +＝445.2。 Step Five: 2-(2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)thiazol-4-yl)piperidine- Benzyl 1-carboxylate (90.1 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (2.0 mL), and the reaction was carried out at 100° C. for 3 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl )-4-(4-(piperidin-2-yl)thiazol-2-yl)isoquinolin-1-amine (Z69, 15.6 mg, yield: 22%, formate), grey solid. ES-API: [M+H] + =445.2.
实施例14化合物Z161的合成Example 14 Synthesis of compound Z161
Figure PCTCN2022085658-appb-000104
Figure PCTCN2022085658-appb-000104
步骤一：7-氯异喹啉-1-胺(1.0g,5.60mmol)溶于乙腈(20mL)，在冰浴下加入 N-溴代丁二酰亚胺(1.0g,5.60mmol)，反应在冰浴下搅拌2小时。反应液加入水(30mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-5％)得到目标产物4-溴-7-氯异喹啉-1-胺(1.3g,收率90.2％)，淡黄色固体。ES-API:[M+H] +＝257.0,259.0。 Step 1: 7-Chloroisoquinolin-1-amine (1.0g, 5.60mmol) was dissolved in acetonitrile (20mL), N-bromosuccinimide (1.0g, 5.60mmol) was added under ice bath, and the reaction Stir under ice bath for 2 hours. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-5%) to obtain the target product 4-bromo-7-chloroisoquinolin-1-amine (1.3 g, yield 90.2%) as pale yellow solid. ES-API: [M+H] + =257.0, 259.0.
步骤二：4-溴-7-氯异喹啉-1-胺(1.3g,5.05mmol)和 二碳酸二叔丁酯(4.41g,20.19mmol)悬浮于二氯甲烷(25mL)，室温下加入三乙胺(2.55g,25.24mmol)和4-二甲氨基吡啶(62mg,0.51mmol)，反应在室温下搅拌18小时。反应液加入二氯甲烷(30mL)和水(15mL)，有机层分离，用饱和食盐水(25mL)洗涤，用无水硫酸钠干燥并浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-10％)得到目标产物(4-溴-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(1.2g,收率51.9％)，淡黄色固体。ES-API:[M+H] +＝457.0,459.0。 Step 2: 4-Bromo-7-chloroisoquinolin-1-amine (1.3g, 5.05mmol) and di-tert-butyl dicarbonate (4.41g, 20.19mmol) were suspended in dichloromethane (25mL), added at room temperature Triethylamine (2.55 g, 25.24 mmol) and 4-dimethylaminopyridine (62 mg, 0.51 mmol), and the reaction was stirred at room temperature for 18 hours. Dichloromethane (30 mL) and water (15 mL) were added to the reaction solution, the organic layer was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-10%) to obtain the target product (4-bromo-7-chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (1.2 g, yield 51.9%), pale yellow solid. ES-API: [M+H] + =457.0, 459.0.
步骤三：向50mL圆底烧瓶中加入(4-溴-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(350mg,0.77mmol)，双(频哪醇合)二硼(388mg,1.53mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(56mg,0.076mmol)，乙酸钾(225mg,2.29mmol)，1,4-二氧六环(15mL)，氮气置换三次，反应在100℃反应2小时。将反应冷却至室温，加入乙酸乙酯和水，分离的有机层用饱和食盐水(25mL)洗涤，用无水硫酸钠干燥并浓缩得到目标产物(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(720mg,粗品)，该粗品无需进一步纯化即可使用。ES-API:[M+H] +＝505.3. Step 3: Add (4-bromo-7-chloroisoquinolin-1-yl) di-tert-butyl iminodicarbonate (350 mg, 0.77 mmol), bis(pinacol) diboron to a 50 mL round-bottomed flask (388 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (56 mg, 0.076 mmol), potassium acetate (225 mg, 2.29 mmol), 1,4-dioxo Hexacyclic (15 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 2 hours. The reaction was cooled to room temperature, ethyl acetate and water were added, the separated organic layer was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate and concentrated to give the target product (4-(4,4,5,5-tetrakis). Di-tert-butyl methyl-1,3,2-dioxaboran-2-yl)-7-chloroisoquinolin-1-yl)iminodicarbonate (720 mg, crude) without further purification ready to use. ES-API: [M+H] + = 505.3.
步骤四：(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(170mg,0.43mmol)，(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(720mg,粗品)，碳酸钾(180mg,1.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(32mg,0.043mmol)，1,4-二氧六环(16mL)和水(4mL)，氮气置换三次，反应在110℃反应2小时。反应液加入水(15mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7- 氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(135mg,收率45.1％)，白色固体。ES-API:[M+H] +＝689.2。 Step 4: tert-butyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (170 mg, 0.43 mmol), (4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-7-chloroisoquinolin-1-yl)di-tert-butyl iminodicarbonate (720 mg, crude), potassium carbonate (180 mg, 1.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol), 1,4-dioxane The ring (16 mL) and water (4 mL) were replaced with nitrogen three times, and the reaction was carried out at 110°C for 2 hours. Water (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro) -2H-pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (135 mg, 45.1% yield), white solid. ES-API: [M+H] + =689.2.
步骤五：向5mL微波管里加入(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(30mg,0.044mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(23mg,0.087mmol)，碳酸钾(18mg,0.13mmol)，2-二环己基膦-2′,6′-二甲氧基-联苯(5mg,0.007mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(3mg,0.007mmol)，1,4-二氧六环(1mL)和水(0.2mL)。用氮气吹1分钟，在微波反应器中110℃下反应2小时。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用薄层色谱制备板纯化(二氯甲烷/甲醇＝20：1)得到目标产物(((2-(1-氨基-7-(1-甲基-1H-吡咯[2,3-b]吡啶-4-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(23mg,收率90.4％)，淡黄色固体。ES-API:[M+H] +＝585.3。 Step 5: Add (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 to a 5mL microwave tube -yl)-7-chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (30 mg, 0.044 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.087 mmol), potassium carbonate (18 mg, 0.13 mmol), 2-dicyclohexyl Phosphine-2',6'-dimethoxy-biphenyl (5mg, 0.007mmol), Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl yl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg, 0.007 mmol), 1,4-dioxane (1 mL) and water (0.2 mL). Blow with nitrogen for 1 minute and react in a microwave reactor at 110°C for 2 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane/methanol=20:1) to obtain the target product (((2-(1-amino-7-(1-methyl-1H-pyrrole[2,3-b]) Pyridin-4-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (23mg) , yield 90.4%), pale yellow solid. ES-API: [M+H] + =585.3.
步骤六：(((2-(1-氨基-7-(1-甲基-1H-吡咯[2,3-b]吡啶-4-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(23mg,0.04mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物7-(1-甲基-1H-吡咯[2,3-b]吡啶-4-基)-4-(4-((甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z161,11mg,收率58.2％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ9.06(d,J＝9.0Hz,1H),8.66(d,J＝1.5Hz,1H),8.40(d,J＝5.0Hz,1H),8.27(s,1H),8.17(dd,J＝9.0,1.5Hz,1H),7.64(d,J＝3.5Hz,1H),7.50(s,2H),7.41(d,J＝5.0Hz,1H),6.73(d,J＝3.5Hz,1H),3.94(dd,J＝11.0,3.5Hz,2H),3.89(s,2H),3.84(s,2H),3.52–3.46(t,J＝12.0,2H),2.39(s,3H),1.88(d,J＝13.5Hz,2H),1.70–1.53(m,2H).ES-API:[M+H] +＝485.2。 Step six: (((2-(1-amino-7-(1-methyl-1H-pyrrole[2,3-b]pyridin-4-yl)isoquinolin-4-yl)-5-(tetra Hydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (23 mg, 0.04 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride dioxane was added The solution (5mL, 20.0mmol) was reacted at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-( 1-Methyl-1H-pyrro[2,3-b]pyridin-4-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4- yl)thiazol-2-yl)isoquinolin-1-amine (Z161, 11 mg, yield 58.2%), pale yellow solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.06 (d, J=9.0 Hz, 1H), 8.66(d, J＝1.5Hz, 1H), 8.40(d, J＝5.0Hz, 1H), 8.27(s, 1H), 8.17(dd, J＝9.0, 1.5Hz, 1H), 7.64(d,J＝3.5Hz,1H),7.50(s,2H),7.41(d,J＝5.0Hz,1H),6.73(d,J＝3.5Hz,1H),3.94(dd,J＝11.0 ,3.5Hz,2H),3.89(s,2H),3.84(s,2H),3.52–3.46(t,J=12.0,2H),2.39(s,3H),1.88(d,J=13.5Hz, 2H), 1.70-1.53 (m, 2H). ES-API: [M+H] + =485.2.
实施例15化合物Z166的合成Example 15 Synthesis of compound Z166
Figure PCTCN2022085658-appb-000105
Figure PCTCN2022085658-appb-000105
步骤一：向50mL圆底烧瓶中加入3-溴-1,2-二氢吡咯[4,3,2-ij]异喹啉(250mg,1.06mmol)，1,5-二甲基-1H-吡唑-4-硼酸频哪醇酯(553g,2.66mmol)，碳酸钾(406mg,2.94mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(78mg,0.11mmol)，1,4-二氧六环(15mL)和水(3mL)，氮气置换三次，反应在100℃反应4小时。反应液加入水(25mL)，乙酸乙酯萃取(60mL)。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(7M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物3-(1,5-二甲 基-1H-吡唑-4-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(185mg,收率69.5％)，淡棕色固体。ES-API:[M+H] +＝251.2。 Step 1: Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (250mg, 1.06mmol), 1,5-dimethyl-1H- Pyrazole-4-boronic acid pinacol ester (553g, 2.66mmol), potassium carbonate (406mg, 2.94mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78mg, 0.11 mmol), 1,4-dioxane (15 mL) and water (3 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours. Water (25 mL) was added to the reaction solution, followed by extraction with ethyl acetate (60 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (7M ammonia methanol solution/dichloromethane: 0-5%) to obtain the target product 3-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2-di Hydropyrrole[4,3,2-ij]isoquinoline (185 mg, yield 69.5%), pale brown solid. ES-API: [M+H] + =251.2.
步骤二：3-(1,5-二甲基-1H-吡唑-4-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(185mg,0.70mmol)溶于N,N-二甲基甲酰胺(6mL)在冰浴下加入 N-碘代丁二酰亚胺(173mg,0.77mmol)，反应在0℃下搅拌15分钟。反应液加入水，析出的固体过滤，滤饼用水洗涤，真空干燥。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-5％)得到目标产物3-(1,5-二甲基-1H-吡唑-4-基)-6-碘-1,2-二氢吡咯[4,3,2-ij]异喹啉(120mg,收率43.2％)，淡棕色固体。ES-API:[M+H] +＝377.0。 Step 2: Dissolve 3-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (185mg, 0.70mmol) To N,N-dimethylformamide (6 mL) was added N-iodosuccinimide (173 mg, 0.77 mmol) under an ice bath, and the reaction was stirred at 0° C. for 15 minutes. Water was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried in vacuo. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-5%) to give the target product 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-iodo-1,2- Dihydropyrrole[4,3,2-ij]isoquinoline (120 mg, yield 43.2%), pale brown solid. ES-API: [M+H] + =377.0.
步骤三：3-(1,5-二甲基-1H-吡唑-4-基)-6-碘-1,2-二氢吡咯[4,3,2-ij]异喹啉(120mg,0.32mmol)和 二 碳酸二叔丁酯(209mg,0.96mmol)悬浮于二氯甲烷(6mL)，室温下加入三乙胺(97mg,0.96mmol)和4-二甲氨基吡啶(4mg,0.03mmol)，反应在室温下搅拌18小时。反应液浓缩。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-3％)得到目标产物3-(1,5-二甲基-1H-吡唑-4-基)-6-碘吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(110mg,收率72.40％)，淡棕色固体。ES-API:[M+H] +＝477.1。 Step 3: 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-iodo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (120mg, 0.32 mmol) and di- tert- butyl dicarbonate (209 mg, 0.96 mmol) were suspended in dichloromethane (6 mL), triethylamine (97 mg, 0.96 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added at room temperature , the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-3%) to obtain the target product 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-iodopyrro[4,3] ,2-ij]isoquinoline-1(2H)-carboxylic acid tert-butyl ester (110 mg, yield 72.40%), light brown solid. ES-API: [M+H] + =477.1.
步骤四：向5mL微波管里加入3-(1,5-二甲基-1H-吡唑-4-基)-6-碘吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(40mg,0.084mmol)，双(频哪醇合)二硼(43mg,0.17mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(9mg,0.013mmol)，乙酸钾(25mg,0.25mmol)，N,N-二甲基甲酰胺(1mL)，用氮气吹1分钟，在微波反应器中110℃下反应1小时。反应液加入水(10mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥得到目标产物3-(1,5-二甲基-1H-吡唑-4-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(60mg,粗品)，无需进一步纯化直接用于下一步反应。ES-API:[M-82+H] +＝395.3。 Step 4: Add 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1(2H to a 5mL microwave tube )-carboxylate tert-butyl ester (40mg, 0.084mmol), bis(pinacol)diboron (43mg, 0.17mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (9 mg, 0.013 mmol), potassium acetate (25 mg, 0.25 mmol), N,N-dimethylformamide (1 mL), purged with nitrogen for 1 minute, reacted at 110° C. for 1 hour in a microwave reactor. The reaction solution was added with water (10 mL), the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4, 4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, crude), which was used in the next reaction without further purification. ES-API: [M-82+H] + =395.3.
步骤五：向5mL微波管里加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(50mg,0.13mmol)，3-(1,5-二甲基-1H-吡唑-4-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(60mg,粗品)，碳酸钾(53mg,0.38mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(9mg,0.013mmol)，1,4-二氧六环(2mL)和水(0.5mL)，用氮气吹1分钟，在微波反应器中110℃下反应1小时。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(甲醇/二氯甲烷:0-3％)得到目标产物6-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(1,5-二甲基-1H-吡唑-4-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(9mg,收率10.7％)，淡黄色固体。ES-API:[M+H] +＝661.3。 Step 5: Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (50mg) to a 5mL microwave tube , 0.13mmol), 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, crude), potassium carbonate (53 mg, 0.38 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.013 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, placed in a microwave The reaction was carried out in the reactor at 110°C for 1 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-3%) to obtain the target product 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H -pyran-4-yl)thiazol-2-yl)-3-(1,5-dimethyl-1H-pyrazol-4-yl)pyrro[4,3,2-ij]isoquinoline-1 (2H)-Carboxylic acid tert-butyl ester (9 mg, yield 10.7%), pale yellow solid. ES-API: [M+H] + = 661.3.
步骤六：6-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(1,5-二甲基-1H-吡唑-4-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(9mg,0.014mmol)溶于甲醇(1mL)加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物1-(2-(3-(1,5-二甲基-1H-吡唑-4-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉-6-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N-甲基甲胺(Z166,甲酸盐,5mg,收率70.5％)，淡黄色固体。ES-API:[M+H] +＝461.1。 1H NMR(400MHz,DMSO-d 6)δ8.68–8.50(m,2H),8.31(s,1H),8.26(s,1H),7.75(s,1H),7.71(d,J＝8.4Hz,1H),4.92(s,2H),3.98–3.92(m,4H),3.82(s,3H),3.48(t,J＝11.2Hz,2H),3.40–3.30(m,1H),2.38(s,3H),1.86(d,J＝11.6Hz,2H),1.67–1.58(m,2H). Step six: 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-( 1,5-Dimethyl-1H-pyrazol-4-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (9 mg, 0.014 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride dioxane solution (5 mL, 20.0 mmol), and the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 1-(2-(3-(1,5-dimethyl-1H-pyrazole) -4-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinolin-6-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4- yl)-N-methylmethylamine (Z166, formate, 5 mg, yield 70.5%), pale yellow solid. ES-API: [M+H] + =461.1. 1 H NMR (400MHz, DMSO-d 6 )δ8.68-8.50(m, 2H), 8.31(s, 1H), 8.26(s, 1H), 7.75(s, 1H), 7.71(d, J=8.4 Hz, 1H), 4.92(s, 2H), 3.98–3.92(m, 4H), 3.82(s, 3H), 3.48(t, J=11.2Hz, 2H), 3.40–3.30(m, 1H), 2.38 (s, 3H), 1.86 (d, J=11.6Hz, 2H), 1.67–1.58 (m, 2H).
实施例16化合物Z167的合成Example 16 Synthesis of compound Z167
Figure PCTCN2022085658-appb-000106
Figure PCTCN2022085658-appb-000106
步骤一:取3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-碘吡咯并[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(0.06g,0.116mmol)，联硼酸频那醇酯(0.055g,0.22mmol)，醋酸钾(21mg g,0.22mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(10mg)溶于1,4-二氧六环(5mL)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙酯＝50/50)纯化，得到(1-(叔丁氧基羰基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯并[4,3,2-ij]异喹啉-6-基)硼酸(38mg,产率72％)。ES-API:[M+H] +＝435。 Step 1: Take 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxyl tert-butyl acid (0.06g, 0.116mmol), pinacol diboronate (0.055g, 0.22mmol), potassium acetate (21mg g, 0.22mmol), [1,1'-bis(diphenylphosphine)di Ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane (5 mL) and stirred at 110°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to obtain (1-(tert-butoxycarbonyl)-3-(7-fluoroimidazo[ 1,2-a]pyridin-3-yl)-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)boronic acid (38 mg, 72% yield). ES-API: [M+H] + =435.
步骤二:取(1-(叔丁氧基羰基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯并[4,3,2-ij]异喹啉-6-基)硼酸(38mg,0.08mmol)、1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N,N-二甲基甲胺(42mg,0.14mmol)，碳酸钾(22mg,0.16mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(5mg)溶于1,4-二氧六环/水(2.5ml)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙酯＝30/70)纯化，得到6-(4-((二甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)吡咯并[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(10mg,产率22％)。ES-API:[M+H] +＝615。 Step 2: Take (1-(tert-butoxycarbonyl)-3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrrolo[4,3, 2-ij]isoquinolin-6-yl)boronic acid (38 mg, 0.08 mmol), 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N , N-dimethylmethylamine (42 mg, 0.14 mmol), potassium carbonate (22 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5 mg ) was dissolved in 1,4-dioxane/water (2.5 ml) and stirred at 110°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/70) to obtain 6-(4-((dimethylamino)methyl)-5-(tetramethylene) Hydro-2H-pyran-4-yl)thiazol-2-yl)-3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrrolo[4,3,2-ij] Isoquinoline-1(2H)-carboxylate tert-butyl ester (10 mg, 22% yield). ES-API: [M+H] + =615.
步骤三:取6-(4-((二甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)吡咯并[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(10mg,0.016mmol)溶于无水二氯甲烷(0.5mL)，加入三氟乙酸(0.2mL)，室温反应2小时。LC-MS监测反应完全，反应液减压浓缩至干，加入氨甲醇溶液(1mL)中和后，再次浓缩，经制备HPLC(甲酸)纯化得到1-(2-(3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯并[4,3,2-ij]异喹啉-6-基)-5-(四氢吡喃-4-基)噻唑-4-基)-N,N-二甲基甲胺(Z167,1.58mg,产率34％,甲酸盐)。ES-API:[M+H] +＝515.0。 1H NMR(500MHz,DMSO-d 6)δ8.74–8.69(m,1H),8.63–8.59(m,1H),8.32–8.31(m,2H),8.05(d,J＝7.5Hz,1H),8.00(s,1H),7.60(dd,J＝9.5,3.0Hz,1H),7.04–7.02(m,1H),4.96(s,2H),3.95(d,J＝7.5Hz,2H),3.60(s,2H),3.50–3.45(m,1H),2.64(s,1H),2.37(s,1H),2.26(s,6H),1.89–1.87(m,2H),1.65–1.63(m,2H). Step 3: Take 6-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-(7-fluoroimidazolium [1,2-a]pyridin-3-yl)pyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (10 mg, 0.016 mmol) was dissolved in anhydrous dichloride Methane (0.5 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was carried out at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, neutralized by adding ammonia methanol solution (1 mL), concentrated again, and purified by preparative HPLC (formic acid) to obtain 1-(2-(3-(7-fluoroimidazole) [1,2-a]pyridin-3-yl)-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-(tetrahydropyran-4 -yl)thiazol-4-yl)-N,N-dimethylmethanamine (Z167, 1.58 mg, 34% yield, formate salt). ES-API: [M+H] + =515.0. 1 H NMR (500MHz, DMSO-d 6 )δ8.74-8.69(m,1H),8.63-8.59(m,1H),8.32-8.31(m,2H),8.05(d,J=7.5Hz,1H ), 8.00(s, 1H), 7.60(dd, J=9.5, 3.0Hz, 1H), 7.04–7.02(m, 1H), 4.96(s, 2H), 3.95(d, J=7.5Hz, 2H) ,3.60(s,2H),3.50–3.45(m,1H),2.64(s,1H),2.37(s,1H),2.26(s,6H),1.89–1.87(m,2H),1.65–1.63 (m,2H).
实施例17化合物Z158的合成Example 17 Synthesis of compound Z158
Figure PCTCN2022085658-appb-000107
Figure PCTCN2022085658-appb-000107
步骤一：2,2-二甲氧基乙烷-1-胺(4.75g,45.22mmol)溶于甲醇(90mL)室温下加入3-溴-2-甲基苯甲醛(9.0g,45.22mmol)，反应在70℃下搅拌反应2小时。反应冷却至0℃，硼氢化钠(1.71g,45.22mmol)分批加入，反应在室温下搅拌16小时。反应液浓缩去除溶剂，加入冰水(200mL)，用二氯甲烷(100mL×2)萃取。合并有机层用饱和食盐水(80mL)洗涤，无水硫酸钠干燥并浓缩得到目标产物N-(3-溴-2-甲基苄基)-2,2-二甲氧基乙烷-1-胺(12.5g,收率95.9％)，无色液体。ES-API:[M+H] +＝288.1,290.0。 Step 1: 2,2-Dimethoxyethane-1-amine (4.75g, 45.22mmol) was dissolved in methanol (90mL) and 3-bromo-2-methylbenzaldehyde (9.0g, 45.22mmol) was added at room temperature , the reaction was stirred at 70 °C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.71 g, 45.22 mmol) was added in portions, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated to remove the solvent, ice water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL×2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated to obtain the target product N-(3-bromo-2-methylbenzyl)-2,2-dimethoxyethane-1- Amine (12.5 g, 95.9% yield), colorless liquid. ES-API: [M+H] + = 288.1, 290.0.
步骤二：将氯磺酸(28.5mL,433.74mmol)冷却至0℃，缓慢滴加N-(3-溴-2-甲基苄基)-2,2-二甲氧基乙烷-1-胺(12.5g,43.37mmol)超过30分钟。反应物在100℃搅拌反应2小时，然后冷却并倒入冰中(250g)，过滤，滤液在冰浴中冷却，并用50％氢氧化钠溶液调pH至14。用二氯甲烷(150mL×2)萃取，合并有机层用无水硫酸钠干燥并浓缩。得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到目标产物7-溴-8-甲基异喹啉(4.8g,产率49.8％)，淡黄色固体。ES-API:[M+H] +＝222.1,224.1。 Step 2: Cool chlorosulfonic acid (28.5 mL, 433.74 mmol) to 0 °C, slowly add N-(3-bromo-2-methylbenzyl)-2,2-dimethoxyethane-1- Amine (12.5 g, 43.37 mmol) over 30 minutes. The reaction was stirred at 100°C for 2 hours, then cooled and poured into ice (250 g), filtered, and the filtrate was cooled in an ice bath and adjusted to pH 14 with 50% sodium hydroxide solution. Extracted with dichloromethane (150 mL×2), the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-50%) to obtain the target product 7-bromo-8-methylisoquinoline (4.8 g, yield 49.8%) as pale yellow solid. ES-API: [M+H] + = 222.1, 224.1.
步骤三：7-溴-8-甲基异喹啉(4.8g,21.61mmol)溶于二氯甲烷(150mL)，冰浴下加入85％间氯过氧苯甲酸(7.90g,38.90mmol)，反应在室温下搅拌反应18小时。反应冷却至0℃，饱和碳酸氢钠溶液(250mL)，用10％甲醇/二氯甲烷(100mL×3)萃取。合并有机层用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥并浓缩。得到粗品用石油醚打浆得到目标产物7-溴-8-甲基异喹啉2-氧化物(4.95g,收率96.2％)，橙 色固体。ES-API:[M+H] +＝238.0,240.0。 Step 3: 7-Bromo-8-methylisoquinoline (4.8g, 21.61mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (7.90g, 38.90mmol) was added under ice bath, The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, saturated sodium bicarbonate solution (250 mL), and extracted with 10% methanol/dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was slurried with petroleum ether to obtain the target product 7-bromo-8-methylisoquinoline 2-oxide (4.95 g, yield 96.2%) as an orange solid. ES-API: [M+H] + =238.0, 240.0.
步骤四：将三氯氧磷(41.0mL,441.03mmol)冷却至0℃，分批加入7-溴-8-甲基异喹啉2-氧化物(4.2g,17.64mmol)，反应在室温下搅拌反应15分钟，然后在105℃反应4小时。反应液浓缩，加入二氯甲烷(100mL)稀释，用1M氢氧化钠溶液(30mL×3)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(二氯甲烷/石油醚：0-70％)得到目标产物7-溴-1-氯-8-甲基异喹啉(2.0g,产率44.2％)，淡橙色固体。ES-API:[M+H] +＝256.0,258.0。 Step 4: Phosphorus oxychloride (41.0 mL, 441.03 mmol) was cooled to 0° C., 7-bromo-8-methylisoquinoline 2-oxide (4.2 g, 17.64 mmol) was added in batches, and the reaction was carried out at room temperature. The reaction was stirred for 15 minutes and then at 105°C for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL×3), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (dichloromethane/petroleum ether: 0-70%) to obtain the target product 7-bromo-1-chloro-8-methylisoquinoline (2.0 g, yield 44.2%), pale orange solid. ES-API: [M+H] + =256.0, 258.0.
步骤五：7-溴-1-氯-8-甲基异喹啉(1.1g,4.29mmol)悬浮于四氯化碳(70mL)，加入N-溴代丁二酰亚胺(840mg,4.72mmol)，过氧化苯甲酰(277mg,0.86mmol)，反应回流6小时。将反应冷却至室温，加入二氯甲烷(100mL)稀释，用1M氢氧化钠溶液(30mL)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：10-20％)得到目标产物7-溴-8-(溴甲基)-1-氯异喹啉(1.2g,产率83.4％)，淡橙色固体。ES-API:[M+H] +＝333.9,336.0,338.0。 Step 5: 7-Bromo-1-chloro-8-methylisoquinoline (1.1 g, 4.29 mmol) was suspended in carbon tetrachloride (70 mL), and N-bromosuccinimide (840 mg, 4.72 mmol) was added. ), benzoyl peroxide (277 mg, 0.86 mmol), and the reaction was refluxed for 6 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 10-20%) to obtain the target product 7-bromo-8-(bromomethyl)-1-chloroisoquinoline (1.2 g, yield 83.4%) , a pale orange solid. ES-API: [M+H] + =333.9, 336.0, 338.0.
步骤六：(2,4-二甲氧基苯基)甲胺(1.50g,8.94mmol)和碳酸钾(0.74g,5.37mmol)溶于N,N-二甲基甲酰胺(25mL)，在冰浴下滴加7-溴-8-(溴甲基)-1-氯异喹啉的N,N-二甲基甲酰胺溶液(1.5mL)，反应在0℃搅拌2小时。反应液加入水(60mL)，乙酸乙酯萃取(50mL×2)。合并有机层用饱和食盐水(40mL×3)洗涤，无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(7M氨甲醇溶液/二氯甲烷：0-2％)得到目标产物3-溴-1-(3,4-二甲基苄基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(1.2g,产率87.1％)，淡棕色固体。ES-API:[M+H] +＝385.1,387.1。 Step 6: (2,4-Dimethoxyphenyl)methanamine (1.50g, 8.94mmol) and potassium carbonate (0.74g, 5.37mmol) were dissolved in N,N-dimethylformamide (25mL), in A solution of 7-bromo-8-(bromomethyl)-1-chloroisoquinoline in N,N-dimethylformamide (1.5 mL) was added dropwise under an ice bath, and the reaction was stirred at 0°C for 2 hours. The reaction solution was added with water (60 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (7M ammonia methanol solution/dichloromethane: 0-2%) to obtain the target product 3-bromo-1-(3,4-dimethylbenzyl)-1,2-dihydropyrrole [4,3,2-ij]isoquinoline (1.2 g, 87.1% yield), pale brown solid. ES-API: [M+H] + = 385.1, 387.1.
步骤七：3-溴-1-(3,4-二甲基苄基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(1.1g,2.855mmol)加入三氟乙酸(30mL)，反应液在80℃搅拌3小时。反应液浓缩，加入7M氨甲醇(30mL)，再次浓缩。得到粗品用快速硅胶柱纯化(甲醇溶液/二氯甲烷：0-7％)得到目标产物3-溴-1,2-二氢吡咯[4,3,2-ij]异喹啉(620mg,产率92.4％)，淡棕色固体。ES-API:[M+H] +＝235.0,237.0。 Step 7: 3-Bromo-1-(3,4-dimethylbenzyl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (1.1 g, 2.855 mmol) was added with trifluoro Acetic acid (30 mL), and the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated, 7M ammonia methanol (30 mL) was added, and it was concentrated again. The obtained crude product was purified by flash silica gel column (methanol solution/dichloromethane: 0-7%) to obtain the target product 3-bromo-1,2-dihydropyrro[4,3,2-ij]isoquinoline (620 mg, produced rate 92.4%), light brown solid. ES-API: [M+H] + =235.0, 237.0.
步骤八：向250mL圆底烧瓶中加入3-溴-1,2-二氢吡咯[4,3,2-ij]异喹啉(320mg,2.86mmol)，7-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)咪唑并[1,2-a]吡啶(3.2g,粗品),碳酸钠(433mg，4.08mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(100mg,0.14mmol)，1,4-二氧六环(50mL)和水(10mL)，氮气置换三次，反应在100℃反应4小时。反应液加入水(50mL)，乙酸乙酯萃取(80mL×2)。合并有机层用无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(300mg,收率75.9％)，淡棕色固体。ES-API:[M+H] +＝291.1。 Step 8: Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (320mg, 2.86mmol), 7-fluoro-3-(4,4 to a 250mL round-bottomed flask , 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)imidazo[1,2-a]pyridine (3.2g, crude), sodium carbonate (433mg, 4.08mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.14 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, the reaction The reaction was carried out at 100°C for 4 hours. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (80 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (M ammonia methanol solution/dichloromethane: 0-5%) to obtain the target product 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,2- Dihydropyrrole[4,3,2-ij]isoquinoline (300 mg, yield 75.9%), pale brown solid. ES-API: [M+H] + = 291.1.
步骤九：3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉(175mg,0.60mmol)溶于N,N-二甲基甲酰胺(6mL)在冰浴下加入 N-碘代丁二酰亚胺(149mg,0.66mmol)，反应在0℃下搅拌30分钟。反应液加入水，析出的固体过滤，滤饼用水洗涤，真空干燥得到目标产物3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-碘代-1,2-二氢吡咯[4,3,2-ij]异喹啉(210mg,收率83.7％)，淡棕色固体。ES-API:[M+H] +＝417.0。 Step 9: 3-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinoline (175mg, 0.60mmol) Dissolved in N,N-dimethylformamide (6 mL), N-iodosuccinimide (149 mg, 0.66 mmol) was added under an ice bath, and the reaction was stirred at 0°C for 30 minutes. Water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodo-1,2 - Dihydropyrrole[4,3,2-ij]isoquinoline (210 mg, yield 83.7%), pale brown solid. ES-API: [M+H] + =417.0.
步骤十：3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-碘代-1,2-二氢吡咯[4,3,2-ij]异喹啉(210mg,0.50mmol)和 二碳酸二叔丁酯(330mg,1.51mmol)悬浮于二氯甲烷(10mL)室温下加入三乙胺(204mg,2.02mmol)，和4-二甲氨基吡啶(6mg,0.05mmol)，反应在室温下搅拌4小时。反应液浓缩，得到粗品用快速硅胶柱纯化((甲醇/乙酸乙酯＝10:1)/石油醚：0-70％)得到目标产物3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-碘吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(185mg,收率71.01％)，淡棕色固体。ES-API:[M+H] +＝517.0。 Step ten: 3-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline ( 210 mg, 0.50 mmol) and di-tert-butyl dicarbonate (330 mg, 1.51 mmol) were suspended in dichloromethane (10 mL). Triethylamine (204 mg, 2.02 mmol), and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added at room temperature. mmol) and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column ((methanol/ethyl acetate=10:1)/petroleum ether: 0-70%) to obtain the target product 3-(7-fluoroimidazo[1,2-a]) Pyridin-3-yl)-6-iodopyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (185 mg, yield 71.01%), pale brown solid. ES-API: [M+H] + =517.0.
步骤十一：向5mL微波管里加入3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-碘吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(100mg,0.19mmol)，双(频哪醇合)二硼(98mg,0.39mmol)，[1,1'-双(二苯基膦)二茂铁]二 氯化钯(21mg,0.03mmol)，乙酸钾(57mg,0.58mmol)，N,N-二甲基甲酰胺(2mL)，用氮气吹1分钟，在微波反应器中110℃下反应1小时。反应液加入水(10mL)，析出的固体过滤，滤饼用水洗涤，真空干燥得到目标产物3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(120mg,粗品)，无需进一步纯化即可用于下一步反应。ES-API:[M-82+H] +＝435.2。 Step 11: Add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1 to a 5mL microwave tube (2H)-tert-butyl carboxylate (100 mg, 0.19 mmol), bis(pinacol)diboron (98 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (21 mg, 0.03 mmol), potassium acetate (57 mg, 0.58 mmol), N,N-dimethylformamide (2 mL), purged with nitrogen for 1 minute, and reacted at 110° C. for 1 hour in a microwave reactor. The reaction solution was added with water (10 mL), the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-(4, 4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (120 mg, crude), which was used in the next reaction without further purification. ES-API: [M-82+H] + =435.2.
步骤十二：向5mL微波管里加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(60mg,0.15mmol)，3-(7-氟咪唑并[1,2-a]吡啶-3-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(120mg,粗品)，碳酸钾(64mg,0.46mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应1小时。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(7M氨甲醇溶液/二氯甲烷:0-3％)得到目标产物6-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(60mg,收率56.0％)，淡黄色固体。ES-API:[M+H] +＝701.2。 Step 12: Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (120 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min , in a microwave reactor at 110 °C for 1 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (7M ammonia methanol solution/dichloromethane: 0-3%) to obtain the target product 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-( Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrrole[4,3,2-ij] Isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, yield 56.0%), pale yellow solid. ES-API: [M+H] + =701.2.
步骤十三：6-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-3-(7-氟咪唑并[1,2-a]吡啶-3-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(60mg,0.09mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物1-(2-(3-(7-氟咪唑并[1,2-a]吡啶-3-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉-6-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N-甲基甲胺(Z158,甲酸盐,15mg,收率31.9％)，白色固体。ES-API:[M+H] +＝501.2。 1H NMR(500MHz,DMSO-d 6)δ8.87–8.65(m,2H),8.57–8.52(m,1H),8.35(s,1H),8.28(s,1H),8.04–7.96(m,2H),7.59(dd,J＝10.0,2.5Hz,1H),7.07–7.00(m,1H),4.95(s,2H),4.01(s,2H),3.95(dd,J＝11.0,4.0Hz,2H),3.48(t,J＝12.0Hz,2H),3.38–3.34(m,1H),1.87(dd,J＝13.0,2.0Hz,2H),1.68–1.57(m,2H). Step Thirteen: 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3- (7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrrole[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, 0.09 mmol) in In methanol (1 mL), 4.0 M hydrogen chloride dioxane solution (5 mL, 20.0 mmol) was added, and the reaction was carried out at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 1-(2-(3-(7-fluoroimidazo[1,2-a]) Pyridin-3-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinolin-6-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4 -yl)-N-methylmethylamine (Z158, formate, 15 mg, 31.9% yield), white solid. ES-API: [M+H] + =501.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.87-8.65(m, 2H), 8.57-8.52(m, 1H), 8.35(s, 1H), 8.28(s, 1H), 8.04-7.96(m) ,2H),7.59(dd,J=10.0,2.5Hz,1H),7.07–7.00(m,1H),4.95(s,2H),4.01(s,2H),3.95(dd,J=11.0,4.0 Hz, 2H), 3.48 (t, J=12.0Hz, 2H), 3.38–3.34 (m, 1H), 1.87 (dd, J=13.0, 2.0Hz, 2H), 1.68–1.57 (m, 2H).
实施例18化合物Z168的合成Example 18 Synthesis of compound Z168
Figure PCTCN2022085658-appb-000108
Figure PCTCN2022085658-appb-000108
步骤一：7-溴-8-氟异喹啉-1-胺(400mg,1.66mmol)溶于干燥二氧六环(4mL)，在室温下加入双联硼酸频那醇酯(505.9mg,1.99mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(122.4mg,0.17mmol)和醋酸钾(325.4mg,3.32mmol)，在氮气保护下油浴100℃搅拌反应18小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到粗品经硅胶柱层析纯化(二氯甲烷：甲醇＝1％-4％)得到产物(1-氨基-8-氟异喹啉-7-基)硼酸(153.2mg,收率：45％)。ES-API:[M+H] +＝207.2。 Step 1: 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dry dioxane (4 mL), and bis-borate pinacol ester (505.9 mg, 1.99 mg) was added at room temperature mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol) and potassium acetate (325.4 mg, 3.32 mmol), oil bath 100°C under nitrogen protection The reaction was stirred for 18 hours. The reaction solution was added with a mixed solution of dichloromethane/methanol (10:1, 10 mL) for extraction, followed by adding water (10 mL), washing with saturated brine (20 mL), drying over anhydrous sodium sulfate, filtration and concentration to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=1%-4%) to give the product (1-amino-8-fluoroisoquinolin-7-yl)boronic acid (153.2 mg, yield: 45%). ES-API: [M+H] + = 207.2.
步骤二：(1-氨基-8-氟异喹啉-7-基)硼酸(153.2mg,0.74mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入5-溴-1,2-二甲基-1H-咪唑(155.4mg,0.89mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(50.4mg,0.07mmol)，碳酸钾(204.2mg,1.48mmol)，在氮气保护下油浴100℃搅拌反应18小时。反应液加入二氯甲烷：甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到粗品通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-4％)得到产物7-(1,2-二甲基-1H-咪唑-5-基)-8-氟异喹啉-1-胺(154.3mg,收率：81％)。ES-API:[M+H] +＝257.2。 Step 2: (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (153.2 mg, 0.74 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 5- Bromo-1,2-dimethyl-1H-imidazole (155.4 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50.4 mg, 0.07 mmol), Potassium carbonate (204.2 mg, 1.48 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection. The reaction solution was added with dichloromethane:methanol mixed solution (10:1, 10 mL) for extraction, successively added water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product and purified by silica gel column chromatography (dichloromethane: methanol=1%-4%) to obtain the product 7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinolin-1-amine (154.3 mg, yield rate: 81%). ES-API: [M+H] + = 257.2.
步骤三：7-(1,2-二甲基-1H-咪唑-5-基)-8-氟异喹啉-1-胺(154.3mg,0.60mmol)溶于N,N-二甲基甲酰胺(2.0mL)，加入N-碘代丁二酰亚胺(148.5mg,0.66mmol)，反应在室温下反应1小时。LC-MS检测反应完全，加入水(10mL)，用二氯甲烷：甲醇混合溶液萃取(10：1,30mL×2)，无水硫酸钠干燥，过滤浓缩，得到粗品通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-碘-异喹啉-1-胺(90.5mg,收率：39％)，白色固体。ES-API:[M+H] +＝383.2 Step 3: 7-(1,2-Dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinolin-1-amine (154.3mg, 0.60mmol) was dissolved in N,N-dimethylmethane Amide (2.0 mL), N-iodosuccinimide (148.5 mg, 0.66 mmol) was added, and the reaction was allowed to react at room temperature for 1 hour. LC-MS detected that the reaction was complete, added water (10 mL), extracted with dichloromethane: methanol mixed solution (10:1, 30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product and purified by silica gel column chromatography ( Dichloromethane: methanol = 1%-3%) to give the product 7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-amine ( 90.5 mg, yield: 39%), white solid. ES-API: [M+H] + = 383.2
步骤四：7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-碘-异喹啉-1-胺(90.5mg,0.24mmol)溶于二氯甲烷(2.0mL)，加入二叔丁基二碳酸酯(209.3mg,0.96mmol)，三乙胺(121.2mg,1.20mmol)和4-二甲氨基吡啶(5.8 mg,0.12mmol)，反应在室温下反应2小时。LC-MS检测反应完全，加入水(10mL)，用乙酸乙酯萃取(30mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物(7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-碘-异喹啉-1-基)氨基二甲酸叔丁酯(75.3mg,收率：54％)，白色固体。ES-API:[M+H] +＝583.2。 Step 4: 7-(1,2-Dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-amine (90.5mg, 0.24mmol) was dissolved in dichloromethane (2.0 mL), di-tert-butyl dicarbonate (209.3 mg, 0.96 mmol), triethylamine (121.2 mg, 1.20 mmol) and 4-dimethylaminopyridine (5.8 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature React for 2 hours. LC-MS detected the completion of the reaction, added water (10 mL), extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (dichloromethane: methanol=1%-3 %) to give the product (tert-butyl 7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamate (75.3 mg , yield: 54%), white solid. ES-API: [M+H] + =583.2.
步骤五：(7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-碘-异喹啉-1-基)氨基二甲酸叔丁酯(75.3mg,0.13mmol)溶于N,N-二甲基甲酰胺(2.0mL)，在室温下加入双联硼酸频那醇酯(66.0mg,0.26mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(14.4mg,0.02mmol)，醋酸钾(25.5mg,0.26mmol)，置换氮气，氮气保护下微波90℃搅拌反应2小时。LC-MS检测反应完全，加入水(10mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,50mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-6％)得到产物(7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)氨基二甲酸叔丁酯(63.4mg,收率：84％)。ES-API:[M+H] +＝583.2。 Step 5: tert-butyl (7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamic acid tert-butyl ester (75.3 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and bis(pinacol borate) (66.0 mg, 0.26 mmol), [1,1'-bis(diphenylphosphine) was added at room temperature ) ferrocene] palladium dichloride (14.4 mg, 0.02 mmol), potassium acetate (25.5 mg, 0.26 mmol), nitrogen was replaced, and the reaction was stirred at 90° C. for 2 hours by microwave under nitrogen protection. LC-MS detected that the reaction was complete, added water (10 mL), extracted with dichloromethane/methanol mixed solution (10:1, 50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane). Methane: methanol = 3%-6%) to give the product (7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-(4,4,5,5-tetramethyl) (63.4 mg, yield: 84%). ES-API: [M+H] + =583.2.
步骤六：(7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)氨基二甲酸叔丁酯(63.4mg,0.11mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(51.5mg,0.13mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(14.4mg,0.02mmol)，碳酸钾(30.4mg,0.22mmol)，在氮气保护下微波110℃搅拌反应2小时。反应液加入二氯甲烷：甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物((2-(1-氨基-7-(1,2-二甲基-1H-咪唑-5-基)-8-氟异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.3mg,收率：57％)。ES-API:[M+H] +＝567.2。 Step 6: (7-(1,2-Dimethyl-1H-imidazol-5-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-di tert-butyl oxaborol-2-yl))isoquinolin-1-yl)carbamate (63.4 mg, 0.11 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), ((2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (51.5 mg, 0.13 mmol) was added at room temperature , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14.4 mg, 0.02 mmol), potassium carbonate (30.4 mg, 0.22 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 Hour. The reaction solution was added with dichloromethane:methanol mixed solution (10:1, 10 mL) for extraction, successively added with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol = 3%-7%) to give the product ((2-(1-amino-7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinoline-4 -yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (35.3 mg, yield: 57%). ES-API: [M+H] + =567.2.
步骤七：((2-(1-氨基-7-(1,2-二甲基-1H-咪唑-5-基)-8-氟异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.3mg,0.06mmol)溶于二氯甲烷(4.0mL)，加入三氟乙酸(1.0mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，粗品用制备HPLC纯化(三氟醋酸)得到目标产物7-(1,2-二甲基-1H-咪唑-5-基)-8-氟-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z168,2.80mg,收率：10％)。ES-API:[M+H] +＝467.2。 Step seven: ((2-(1-amino-7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinolin-4-yl)-5-(tetrahydro- 2H-Pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (35.3 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL), the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (trifluoroacetic acid) to obtain the target product 7-(1,2-dimethyl-1H-imidazol-5-yl) )-8-Fluoro-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine ( Z168, 2.80 mg, yield: 10%). ES-API: [M+H] + =467.2.
实施例19化合物Z169的合成Example 19 Synthesis of compound Z169
Figure PCTCN2022085658-appb-000109
Figure PCTCN2022085658-appb-000109
步骤一：7-溴-8-氟异喹啉-1-胺(400mg,1.66mmol)溶于二氧六环(4.0mL)和水(1.0mL)，在室温下加入(1,5-二甲基-1H-吡唑-4-基)硼酸(278.6mg,1.99mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(122.4mg,0.17mmol)，碳酸钾(458.2mg,3.32mmol)，在氮气保护下油浴100℃搅拌反应18小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-4％)得到产物7-(1,5-二甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(226.3mg,收率：53％)。ES-API:[M+H] +＝257.2。 Step 1: 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dioxane (4.0 mL) and water (1.0 mL), and (1,5-dioxane) was added at room temperature Methyl-1H-pyrazol-4-yl)boronic acid (278.6 mg, 1.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol), Potassium carbonate (458.2 mg, 3.32 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection. The reaction solution was extracted with a mixed solution of dichloromethane/methanol (10:1, 10 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol=1%-4%) to obtain the product 7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (226.3 mg, yield : 53%). ES-API: [M+H] + = 257.2.
步骤二：7-(1,5-二甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(226.3mg,0.88mmol)溶于N,N-二甲基甲酰胺(4.0mL)，加入N-碘代丁二酰亚胺(258.8mg,1.15mmol)，反应在室温下反应2小时。LC-MS检测反应完全，加入水(10mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,30mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(231.2mg,收率：95％)，白色固体。ES-API:[M+H] +＝383.2。 Step 2: 7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (226.3mg, 0.88mmol) was dissolved in N,N-dimethyl Formamide (4.0 mL), N-iodosuccinimide (258.8 mg, 1.15 mmol) was added, and the reaction was allowed to react at room temperature for 2 hours. LC-MS detected that the reaction was complete, added water (10 mL), extracted with a dichloromethane/methanol mixed solution (10:1, 30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane). Methane: methanol=1%-3%) to give the product 7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (231.2 mg , yield: 95%), white solid. ES-API: [M+H] + =383.2.
步骤三：7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(231.2mg,0.60mmol)溶于二氯甲烷(6.0mL)，加入二叔丁基二碳酸酯(523.2mg,2.40mmol)，三乙胺(303.0mg,3.00mmol)和4-二甲氨基吡啶(14.6mg,0.12mmol)，反应在室温下反应5小时。LC-MS检测反应完全，加入水(10mL)，用乙酸乙酯萃取(30mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物(7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-碘代异喹啉-1-基)-氨基二甲酸叔丁酯(265.7mg,收率：76％)，白色固体。ES-API:[M+H] +＝583。 Step 3: 7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (231.2 mg, 0.60 mmol) was dissolved in dichloromethane (6.0 mL), di-tert-butyl dicarbonate (523.2 mg, 2.40 mmol), triethylamine (303.0 mg, 3.00 mmol) and 4-dimethylaminopyridine (14.6 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature The reaction was carried out for 5 hours. LC-MS detected the completion of the reaction, added water (10 mL), extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (dichloromethane: methanol=1%-3 %) to give the product (7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl)-carbamic acid tert-butyl ester ( 265.7 mg, yield: 76%), white solid. ES-API: [M+H] + =583.
步骤四：(7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-碘代异喹啉-1-基)-氨基二甲酸叔丁酯(265.7mg,0.45mmol)溶于N,N-二甲基甲酰胺(2.0mL)，在室温下加入双联硼酸频那醇酯(137.2mg,0.54mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(36.0mg,0.05mmol)，醋酸钾(441.0mg,4.50mmol)，置换氮气，氮气保护下微波90℃搅拌反应2小时。LC-MS检测反应完全，加入水(10mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,50mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-6％)得到产物(7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)-氨基二甲酸叔丁酯(195.3mg,收率：74％)。ES-API:[M+H] +＝583.2。 Step 4: (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl)-carbamic acid tert-butyl ester (265.7 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), bis(pinacol borate) (137.2 mg, 0.54 mmol), [1,1'-bis(diphenylene) were added at room temperature phosphine) ferrocene] palladium dichloride (36.0 mg, 0.05 mmol), potassium acetate (441.0 mg, 4.50 mmol), nitrogen was replaced, and the reaction was stirred at 90° C. in a microwave for 2 hours under nitrogen protection. LC-MS detected that the reaction was complete, added water (10 mL), extracted with dichloromethane/methanol mixed solution (10:1, 50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane). Methane: methanol = 3%-6%) to give the product (7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetrakis) Methyl-1,3,2-dioxaborol-2-yl))isoquinolin-1-yl)-carbamic acid tert-butyl ester (195.3 mg, yield: 74%). ES-API: [M+H] + =583.2.
步骤五：(7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)-氨基二甲酸叔丁酯(195.3mg,0.33mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入叔丁基((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸酯(97.5mg,0.25mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(21.6mg,0.03mmol)，碳酸钾(69.0mg,0.50mmol)，在氮气保护下微波110℃搅拌反应2小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物叔丁基((2-(1-氨基-7-(1,5-二甲基-1H-吡唑-4-基)-8-氟异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸酯(97.6mg,收率：69％)。ES-API:[M+H] +＝567.2。 Step 5: (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl))isoquinolin-1-yl)-carbamic acid tert-butyl ester (195.3 mg, 0.33 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL) ), tert-butyl((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.5 mg) was added at room temperature , 0.25mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21.6mg, 0.03mmol), potassium carbonate (69.0mg, 0.50mmol), microwave 110 under nitrogen protection The reaction was stirred for 2 hours. The reaction solution was extracted with a mixed solution of dichloromethane/methanol (10:1, 10 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol = 3%-7%) to give the product tert-butyl((2-(1-amino-7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoroiso Quinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.6 mg, yield: 69%) . ES-API: [M+H] + =567.2.
步骤六：叔丁基((2-(1-氨基-7-(1,5-二甲基-1H-吡唑-4-基)-8-氟异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸酯(97.6mg,0.17mmol)溶于二氯甲烷(4.0mL)，加入三氟乙酸(2.0mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物7-(1,5-二甲基-1H-吡唑-4-基)-8-氟-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z169,39.4mg,收率：49％)。ES-API:[M+H] +＝467.2。 1H NMR(500MHz,DMSO-d 6)δ8.74(d,J＝8.8Hz,1H),8.23(s,1H),7.71(t,J＝8.3Hz,1H),7.59(s,1H),7.26(s,2H),3.97–3.90(m,2H),3.86-3.80(m,5H),3.48(t,J＝11.4Hz,2H),2.37(s,3H),2.33(s,3H),1.90–1.84(m,2H),1.68–1.58(m,2H). Step six: tert-butyl ((2-(1-amino-7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.6 mg, 0.17 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoromethane was added Acetic acid (2.0 mL), the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(1,5-dimethyl-1H-pyrazole-4- yl)-8-fluoro-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z169, 39.4 mg, yield: 49%). ES-API: [M+H] + =467.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.74(d, J=8.8Hz, 1H), 8.23(s, 1H), 7.71(t, J=8.3Hz, 1H), 7.59(s, 1H) ,7.26(s,2H),3.97-3.90(m,2H),3.86-3.80(m,5H),3.48(t,J＝11.4Hz,2H),2.37(s,3H),2.33(s,3H ),1.90–1.84(m,2H),1.68–1.58(m,2H).
实施例20化合物Z170的合成Example 20 Synthesis of compound Z170
Figure PCTCN2022085658-appb-000110
Figure PCTCN2022085658-appb-000110
步骤一：氮气保护下，(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸叔丁酯(50mg,0.07mmol)，(2,3-二甲基吡啶-4-基)硼酸(22mg,0.15mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(5mg,0.01mmol)和碳酸钾(30mg,0.22mmol)的1,4-二氧六环(2mL)和水(0.4mL)的混合溶液在110℃搅拌2小时。反应液倒入乙酸乙酯(10mL)，依次用饱和食盐水(5mL)和水(5mL)洗涤。有机相用无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(0-100％乙酸乙酯/石油醚)纯化，得到黄色油状液体(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(2,3-二甲基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(40mg收率73％)。ES-API:[M+H-Boc] +＝760.3。 Step 1: Under nitrogen protection, (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.07 mmol), (2,3-lutidine-4-yl)boronic acid ( 22mg, 0.15mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- A mixed solution of 2-yl)palladium(II) (5 mg, 0.01 mmol) and potassium carbonate (30 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 °C for 2 hours . The reaction solution was poured into ethyl acetate (10 mL), and washed with saturated brine (5 mL) and water (5 mL) in this order. The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give (tert-butoxycarbonyl) (4-(4-(((tert-butoxycarbonyl) as a yellow oily liquid. Butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(2,3-lutidine-4 -yl)isoquinolin-1-yl)carbamate tert-butyl ester (40 mg yield 73%). ES-API: [M+H-Boc] + =760.3.
步骤二：冰浴条件下，将三氟乙酸(0.5mL)滴加到(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(2,3-二甲基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(40mg,53μmol)的二氯甲烷(1mL)溶液中，室温搅拌1小时。反应液浓缩，用7M胺甲醇(5mL)中和，随后浓缩并用制备HPLC(碳酸氢铵)纯化得到白色固体7-(2,3-二甲基吡啶-4-基)-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(8.6mg，纯度100％，收率35％)。ES-API:[M+H] +＝460.2。 1H NMR(400MHz,DMSO-d 6)δ8.98(d,J＝8.4Hz,1H),8.36(d,J＝4.8Hz,1H),8.31(d,J＝1.2Hz,1H),8.26(s,1H),7.74(dd,J＝8.8,1.6Hz,1H),7.40(s,2H),7.19(d,J＝5.2Hz,1H),3.94(dd,J＝11.2,3.6Hz,2H),3.81(s,2H),3.49(t,J＝11.6Hz,2H),3.39–3.34(m,1H),2.55(s,3H),2.37(s,3H),2.22(s,3H),1.88(d,J＝12.8Hz,2H),1.73–1.56(m,2H). Step 2: Under ice bath conditions, trifluoroacetic acid (0.5 mL) was added dropwise to (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl) -5-(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(2,3-lutidine-4-yl)isoquinolin-1-yl)carbamic acid tert. A solution of butyl ester (40 mg, 53 μmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The reaction was concentrated, neutralized with 7M amine methanol (5 mL), then concentrated and purified by preparative HPLC (ammonium bicarbonate) to give 7-(2,3-lutidine-4-yl)-4-(4- ((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (8.6 mg, 100% purity, 35% yield ). ES-API: [M+H] + =460.2. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.98 (d, J=8.4Hz, 1H), 8.36 (d, J=4.8Hz, 1H), 8.31 (d, J=1.2Hz, 1H), 8.26 (s,1H),7.74(dd,J=8.8,1.6Hz,1H),7.40(s,2H),7.19(d,J=5.2Hz,1H),3.94(dd,J=11.2,3.6Hz, 2H), 3.81(s, 2H), 3.49(t, J=11.6Hz, 2H), 3.39–3.34(m, 1H), 2.55(s, 3H), 2.37(s, 3H), 2.22(s, 3H) ), 1.88(d, J=12.8Hz, 2H), 1.73–1.56(m, 2H).
实施例21化合物Z171的合成Example 21 Synthesis of compound Z171
Figure PCTCN2022085658-appb-000111
Figure PCTCN2022085658-appb-000111
步骤一：((2-(1-((叔丁氧基羰基)氨基)-7-氯异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基二甲酸叔丁酯(40.0mg,0.06mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入(4,5-二甲基吡啶-3-基)硼酸(10.5mg,0.07mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(7.2mg,0.01mmol)，碳酸钾(16.6mg,0.12mmol)，在氮气保护下微波110℃搅拌反应2小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物((2-(1-氨基-7-(4,5-二甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(32.1mg,收率：95％)。ES-API:[M+H] +＝560.2。 Step 1: ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (40.0 mg, 0.06 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (4,5- Lutidine-3-yl)boronic acid (10.5 mg, 0.07 mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (16.6 mg, 0.12 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours. The reaction solution was extracted with a mixed solution of dichloromethane/methanol (10:1, 10 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol = 3%-7%) to give the product ((2-(1-amino-7-(4,5-lutidine-3-yl)isoquinolin-4-yl)-5-( tert-butyl tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (32.1 mg, yield: 95%). ES-API: [M+H] + =560.2.
步骤二：((2-(1-氨基-7-(4,5-二甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(32.1mg,0.06mmol)溶于二氯甲烷(4.0mL)，加入三氟乙酸(2.0mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，得到粗品用制备HPLC(碳酸氢铵)纯化得到目标产物7-(4,5-二甲基吡啶-3-基)-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z171,3.5mg,收率：13％)，白色固体。ES-API:[M+H] +＝460.2。 Step 2: ((2-(1-amino-7-(4,5-lutidine-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4- (32.1 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was carried out at room temperature React for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, and the solvent was spin-dried to obtain a crude product which was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(4,5-lutidine-3-yl)- 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z171, 3.5 mg, received rate: 13%), white solid. ES-API: [M+H] + =460.2.
实施例22化合物Z172的合成Example 22 Synthesis of compound Z172
Figure PCTCN2022085658-appb-000112
Figure PCTCN2022085658-appb-000112
步骤一：((2-(1-((叔丁氧基羰基)氨基)-7-氯异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基二甲酸叔丁酯(45.3mg,0.08mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入(4-甲基吡啶-3-基)硼酸(13.2mg,0.10mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(7.2mg,0.01mmol)，碳酸钾(22.1mg,0.16mmol)，在氮气保护下微波110℃搅拌反应2小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物((2-(1-氨基-7-(4-甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.2mg,收率：80％)。ES-API:[M+H] +＝546.2。 Step 1: ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), (4-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours. The reaction solution was extracted with a mixed solution of dichloromethane/methanol (10:1, 10 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol = 3%-7%) to give the product ((2-(1-amino-7-(4-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro- 2H-Pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, yield: 80%). ES-API: [M+H] + =546.2.
步骤二：(2-(1-氨基-7-(4-甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.2mg,0.06mmol)溶于二氯甲烷(4.0mL)，加入三氟乙酸(2.0mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，得到粗品用制备HPLC(碳酸氢铵)纯化得到目标产物4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(5-甲基吡啶-3-基)异喹啉-1-胺(Z172,7.5mg,收率：28％)，白色固体。ES-API:[M+H] +＝446.2。 Step 2: (2-(1-Amino-7-(4-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, and the solvent was spin-dried to obtain a crude product which was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 4-(4-((methylamino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(5-methylpyridin-3-yl)isoquinolin-1-amine (Z172, 7.5 mg, yield: 28 %), white solid. ES-API: [M+H] + =446.2.
实施例23化合物Z173的合成Example 23 Synthesis of compound Z173
Figure PCTCN2022085658-appb-000113
Figure PCTCN2022085658-appb-000113
步骤一：((2-(1-((叔丁氧基羰基)氨基)-7-氯异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基二甲酸叔丁酯(45.3mg,0.08mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入(5-甲基吡啶-3-基)硼酸(13.2mg,0.10mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(7.2mg,0.01mmol)，碳酸钾(22.1mg,0.16mmol)，在氮气保护下微波110℃搅拌反应2小时。反应液加入二氯甲烷/甲醇混合溶液(10：1,10mL)萃取，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物((2-(1-氨基-7-(5-甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.2mg,收率：80％)。ES-API:[M+H] +＝546.2。 Step 1: ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- tert-Butyl 4-yl)methyl)(methyl)carbamate (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (5-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours. The reaction solution was extracted with a mixed solution of dichloromethane/methanol (10:1, 10 mL), followed by adding water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (di Methyl chloride: methanol = 3%-7%) to give the product ((2-(1-amino-7-(5-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro- 2H-Pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, yield: 80%). ES-API: [M+H] + =546.2.
步骤二：((2-(1-氨基-7-(5-甲基吡啶-3-基)异喹啉-4-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(35.2mg,0.06mmol)溶于二氯甲烷(4.0mL)，加入三氟乙酸(2.0mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，得到粗品用制备HPLC(碳酸氢铵)纯化得到目标产物4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(5-甲基吡啶-3-基)异喹啉-1-胺(Z173,7.2mg,收率：27％)，白色固体。ES-API:[M+H] +＝446.2。 Step 2: ((2-(1-Amino-7-(5-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole -4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours . The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, and the solvent was spin-dried to obtain a crude product which was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 4-(4-((methylamino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(5-methylpyridin-3-yl)isoquinolin-1-amine (Z173, 7.2 mg, yield: 27 %), white solid. ES-API: [M+H] + =446.2.
实施例24化合物Z174的合成Example 24 Synthesis of compound Z174
Figure PCTCN2022085658-appb-000114
Figure PCTCN2022085658-appb-000114
步骤一:取叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸酯(68mg,0.1mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(40mg,0.2mmol)，碳酸钾(27mg,0.2mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(10mg)溶于1,4-二氧六环/水(2.5mL)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙酯＝30/70)纯化，得到叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1-甲基-1H-吡唑-5-基)异喹啉-1-基)氨基甲酸酯(40mg,收率55％)。ES-API:[M+H] +＝735。 Step 1: take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (40 mg, 0.2 mmol), potassium carbonate (27 mg, 0.2 mmol), [1,1'-bis( Diphenylphosphine)ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to obtain tert-butyl(tert-butoxycarbonyl)(4-(4-((((tert-butyloxycarbonyl) Butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazole- 5-yl)isoquinolin-1-yl)carbamate (40 mg, 55% yield). ES-API: [M+H] + =735.
步骤二:取叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1-甲基-1H-吡唑-5-基)异喹啉-1-基)氨基甲酸酯(40mg,0.054mmol)溶于无水二氯甲烷(0.5mL)，加入三氟乙酸(0.2mL)，室温反应2小时。LC-MS监测反应完全，反应液减压浓缩至干，加入氨/甲醇溶液(1mL)中和后，再次浓缩，经制备HPLC(碳酸氢铵)纯化得到7-(1-甲基-1H-吡唑-5-基)-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z174,9.1mg,收率38％)。ES-API:[M+H] +＝435。 1H NMR(500MHz,CDCl 3)δ8.95(d,J＝8.5Hz,1H),8.33(s,1H),7.88(s,1H),7.78(dd,J＝8.5,1.5Hz,1H),7.59(d,J＝1.5Hz,1H),6.43(d,J＝1.5Hz,1H),5.55(s,2H),4.66(s,1H),4.11(dd,J＝11.0,3.5Hz,2H),3.99(s,2H),3.99(s,3H),3.61–3.57(m,2H),3.30–3.25(m,1H),2.61(s,3H),1.96–1.83(m,4H). Step 2: take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-5-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, neutralized by adding ammonia/methanol solution (1 mL), concentrated again, and purified by preparative HPLC (ammonium bicarbonate) to obtain 7-(1-methyl-1H- Pyrazol-5-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1- Amine (Z174, 9.1 mg, 38% yield). ES-API: [M+H] + =435. 1 H NMR (500MHz, CDCl 3 ) δ 8.95 (d, J=8.5Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.78 (dd, J=8.5, 1.5Hz, 1H) ,7.59(d,J＝1.5Hz,1H),6.43(d,J＝1.5Hz,1H),5.55(s,2H),4.66(s,1H),4.11(dd,J＝11.0,3.5Hz, 2H), 3.99(s, 2H), 3.99(s, 3H), 3.61–3.57(m, 2H), 3.30–3.25(m, 1H), 2.61(s, 3H), 1.96–1.83(m, 4H) .
实施例25化合物Z175的合成Example 25 Synthesis of compound Z175
Figure PCTCN2022085658-appb-000115
Figure PCTCN2022085658-appb-000115
步骤一:取1,3-双(1,1-二甲基乙基)2-(4-溴-7-氯异喹啉基)亚氨基二碳酸酯(0.45g,1mmol)、联硼酸频那醇酯(0.52g,2mmol)，醋酸钾(0.2g,2mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(50mg)溶于1，4-二氧六环(5mL)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙 酯＝50/50)纯化，得到1,3-双(1,1-二甲基乙基)2-(7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)异喹啉基)亚氨基二碳酸酯(400mg,收率80％)。ES-API:[M+H] +＝505。 Step 1: Take 1,3-bis(1,1-dimethylethyl) 2-(4-bromo-7-chloroisoquinolinyl)iminodicarbonate (0.45g, 1mmol), biboronic acid Nasolate (0.52 g, 2 mmol), potassium acetate (0.2 g, 2 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (50 mg) in 1,4-dioxane (5 mL), stirred at 110°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to obtain 1,3-bis(1,1-dimethylethyl)2-(7 - Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoquinolinyl)iminodicarbonate (400mg, 80% yield ). ES-API: [M+H] + =505.
步骤二:取1,3-双(1,1-二甲基乙基)2-(7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)异喹啉基)亚氨基二碳酸酯(400mg,0.8mmol)、叔丁基((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸酯(310mg,0.8mmol)，碳酸钾(0.22g,1.6mmol),1,1-二(二苯膦基)二茂铁二氯化钯(50mg)溶于1,4-二氧六环/水(2.5mL)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙酯＝30/70)纯化，得到叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸酯(330mg,收率61％)。ES-API:[M+H] +＝689。 Step 2: Take 1,3-bis(1,1-dimethylethyl)2-(7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Boran-2-yl)isoquinolinyl)iminodicarbonate (400 mg, 0.8 mmol), tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate (310 mg, 0.8 mmol), potassium carbonate (0.22 g, 1.6 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (50 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to obtain tert-butyl(tert-butoxycarbonyl)(4-(4-((((tert-butyloxycarbonyl) Butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)aminomethyl acid ester (330 mg, 61% yield). ES-API: [M+H] + =689.
步骤三:取叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸酯(68mg,0.1mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑叔丁基(40mg,0.2mmol)，碳酸及(27mg,0.2mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(10mg)溶于1,4-二氧六环/水(2.5mL)，110℃搅拌2小时。反应液减压浓缩至干，得到粗品通过硅胶柱层析(石油醚/乙酸乙酯＝30/70)纯化，得到叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1-甲基-1H-吡唑-4-基)异喹啉-1-基)氨基甲酸酯(40mg,收率55％)。ES-API:[M+H] +＝735。 Step 3: take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)pyrazole tert-butyl (40 mg, 0.2 mmol), carbonic acid and (27 mg, 0.2 mmol), 1,1-bis(diphenyl) Phosphino)ferrocene palladium dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to obtain tert-butyl(tert-butoxycarbonyl)(4-(4-((((tert-butyloxycarbonyl) Butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazole- 4-yl)isoquinolin-1-yl)carbamate (40 mg, 55% yield). ES-API: [M+H] + =735.
步骤四:取叔丁基(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1-甲基-1H-吡唑-4-基)异喹啉-1-基)氨基甲酸酯(40mg,0.054mmol)溶于无水二氯甲烷(0.5mL)，加入三氟乙酸(0.2mL)，室温反应2小时。LC-MS监测反应完全，反应液减压浓缩至干，加入氨甲醇溶液(1mL)中和后，再次浓缩，经制备HPLC(碳酸氢铵)纯化得到7-(1-甲基-1H-吡唑-4-基)-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z175,8.04mg,收率34％)。ES-API:[M+H] +＝435。 1H NMR(500MHz,DMSO-d 6)δ8.88(d,J＝8.5Hz,1H),8.49(s,1H),8.25(s,1H),8.15(s,1H),8.07(s,1H),7.97(dd,J＝8.5,1.5Hz,1H),7.35(s,2H),4.56(s,1H),4.00–3.89(m,6H),3.80(s,2H),3.50–3.46(m,2H),2.37(s,3H),1.86–1.85(m,2H),1.65–1.61(m,2H). Step 4: take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, neutralized by adding ammonia methanol solution (1 mL), concentrated again, and purified by preparative HPLC (ammonium bicarbonate) to obtain 7-(1-methyl-1H-pyridine) oxazol-4-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z175, 8.04 mg, 34% yield). ES-API: [M+H] + =435. 1 H NMR (500MHz, DMSO-d 6 )δ8.88(d, J=8.5Hz, 1H), 8.49(s, 1H), 8.25(s, 1H), 8.15(s, 1H), 8.07(s, 1H), 7.97(dd, J=8.5, 1.5Hz, 1H), 7.35(s, 2H), 4.56(s, 1H), 4.00–3.89(m, 6H), 3.80(s, 2H), 3.50–3.46 (m, 2H), 2.37 (s, 3H), 1.86–1.85 (m, 2H), 1.65–1.61 (m, 2H).
实施例26化合物Z176的合成Example 26 Synthesis of compound Z176
Figure PCTCN2022085658-appb-000116
Figure PCTCN2022085658-appb-000116
步骤一：将4-溴化吡啶-3-醇(500mg,2.874mmol)、溴环丙烷(1.151mL,14.368mmol)、碳酸钾(1189.66mg,8.621mmol)、碘化钾(95.40mg,0.575mmol)加入到N-甲基吡咯烷酮(8mL)中，微波反应 180℃搅拌5小时，反应完毕加入水(30mL)，乙酸乙酯(30mLx3)，合并有机相，饱和食盐水(30mLx1)洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品经硅胶柱色谱纯化(石油醚/乙酸乙酯＝5/1)得到4-溴-3-(环丙氧基)吡啶(130mg,收率21.13％)ES-API:[M+H] +＝214.0。 Step 1: 4-Bromopyridin-3-ol (500mg, 2.874mmol), bromocyclopropane (1.151mL, 14.368mmol), potassium carbonate (1189.66mg, 8.621mmol), potassium iodide (95.40mg, 0.575mmol) were added into N-methylpyrrolidone (8mL), the microwave reaction was stirred at 180°C for 5 hours, after the reaction was completed, water (30mL), ethyl acetate (30mLx3) were added, the organic phases were combined, washed with saturated brine (30mLx1), and anhydrous sodium sulfate Dry, filter and concentrate to obtain crude product. Purify by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 4-bromo-3-(cyclopropoxy)pyridine (130 mg, yield 21.13%) ES-API :[M+H] + =214.0.
步骤二:将4-溴-3-(环丙氧基)吡啶(80mg,0.374mmol)和联硼酸频那醇酯(189.81mg,0.747mmol)溶解在在1,4-二氧六环(8mL)中，加入1,1-二(二苯膦基)二茂铁二氯化钯(30.52mg,0.037mmol)和醋酸钾(73.36mg,0.747mmol)。氮气保护，在90℃搅拌3小时。反应液过滤，浓缩得到3-环丙氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(120mg,粗品)，不经纯化直接用于下一步。ES-API:[M+H] +＝262.1。 Step 2: Dissolve 4-bromo-3-(cyclopropoxy)pyridine (80mg, 0.374mmol) and pinacol biboronate (189.81mg, 0.747mmol) in 1,4-dioxane (8mL) ), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30.52 mg, 0.037 mmol) and potassium acetate (73.36 mg, 0.747 mmol) were added. Under nitrogen, stir at 90°C for 3 hours. The reaction solution was filtered and concentrated to give 3-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (120 mg, crude product), used directly in the next step without purification. ES-API: [M+H] + = 262.1.
步骤三:将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(60mg,0.087mmol)和3-环丙氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(120mg,粗品)溶解在1,4-二氧六环(8mL)和水(2mL)的溶液中，加入氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)催化剂(12.55mg,0.017mmol)和碳酸钾(36.09mg,0.261mmol)。混合物用氮气脱气并在110℃搅拌2小时。倒入水(30mL)中，用乙酸乙酯(30mL x 3)萃取。将合并有机层用饱和氯化钠溶液(30mL x 1)洗涤，无水硫酸钠干燥，过滤并浓缩。得到粗品通过桂炯柱层析(乙酸乙酯/石油醚＝50/50)纯化，得到(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-环丙氧基吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(20mg,收率29.12％)。ES-API:[M+H] +＝788.3。 Step 3: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 3-cyclopropoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)pyridine (120 mg, crude) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), chlorine (2- Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) catalyst ( 12.55 mg, 0.017 mmol) and potassium carbonate (36.09 mg, 0.261 mmol). The mixture was degassed with nitrogen and stirred at 110°C for 2 hours. Poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by Guijiong column chromatography (ethyl acetate/petroleum ether=50/50) to obtain (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(3-cyclopropoxypyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl Ester (20 mg, 29.12% yield). ES-API: [M+H] + =788.3.
步骤四:将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-环丙氧基吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(20mg,0.025mmol)溶解到二氯甲烷(2mL)中，然后加入三氟乙酸(1mL)，室温搅拌1小时。反应液浓缩，加入氨水(0.5mL)，再次浓缩之后，经制备HPLC(甲酸)纯化得到4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-环丙氧基吡啶-4-基)异喹啉-1-胺(Z176,甲酸盐,6mg,收率48.48％)。ES-API:[M+H] +＝488.2。 Step 4: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(3-cyclopropoxypyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (20 mg, 0.025 mmol) was dissolved in dichloromethane (2 mL) and then added Trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated, ammonia water (0.5 mL) was added, and after concentration again, 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4) was purified by preparative HPLC (formic acid). -yl)thiazol-2-yl)-7-(3-cyclopropoxypyridin-4-yl)isoquinolin-1-amine (Z176, formate, 6 mg, 48.48% yield). ES-API: [M+H] + =488.2.
实施例27化合物Z177的合成Example 27 Synthesis of compound Z177
Figure PCTCN2022085658-appb-000117
Figure PCTCN2022085658-appb-000117
步骤一：向25mL三口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸叔丁酯(50mg,0.073mmol)，3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(34.39mg,0.145mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(10.45mg,0.015mmol)，碳酸钾(30.08mg,0.22mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护。100℃条件下反应2小时，反应液加入乙酸乙酯(30mL)，用饱和食盐水(30mLX3)洗涤次，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲氧基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(30mg,收率:54％)。ES-API:[M+H] +＝762.3。 Step 1: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 25mL three-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.073 mmol), 3-methoxy-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (34.39mg, 0.145mmol), chloro(2-dicyclohexylphosphino-2',6 '-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.45 mg, 0.015 mmol), potassium carbonate (30.08 mg, 0.22 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The reaction was carried out at 100°C for 2 hours, the reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified with a flash silica gel column (ethyl acetate: petroleum ether). =40:100) to obtain the target product (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran -4-yl)thiazol-2-yl)-7-(3-methoxypyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, yield: 54%). ES-API: [M+H] + =762.3.
步骤二：向5mL单口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲氧基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(30mg,0.05mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)，室温搅拌反应30分钟。反应液旋干，粗品用制备HPLC(碳酸氢铵) 纯化得到：4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲氧基吡啶-4-基)异喹啉-1-胺(Z177,10mg,收率：40.6％)。ES-API:[M+H] +＝462.2。 Step 2: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methoxypyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), tris Fluoroacetic acid (3 mL) and dichloromethane (6 mL) were stirred at room temperature for 30 minutes. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain: 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 -yl)-7-(3-methoxypyridin-4-yl)isoquinolin-1-amine (Z177, 10 mg, yield: 40.6%). ES-API: [M+H] + =462.2.
实施例28化合物Z178的合成Example 28 Synthesis of compound Z178
Figure PCTCN2022085658-appb-000118
Figure PCTCN2022085658-appb-000118
步骤一：向25mL三口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)氨基甲酸叔丁酯(50mg,0.073mmol)，3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(31.79mg,0.145mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(10.45mg,0.015mmol)，碳酸钾(30.08mg,0.22mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护。100℃条件下反应2小时。反应液加入乙酸乙酯(30mL)，用饱和食盐水(30mL X3)洗涤，无水硫酸钠干燥，过滤浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(30mg,收率55％)。ES-API:[M+H] +＝746.3。 Step 1: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 25mL three-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.073 mmol), 3-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (31.79mg, 0.145mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.45mg, 0.015mmol), potassium carbonate (30.08mg , 0.22 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The reaction was carried out at 100°C for 2 hours. The reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product and purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target Product (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 2-yl)-7-(3-methylpyridin-4-yl)isoquinolin-1-yl)carbamate tert-butyl ester (30 mg, 55% yield). ES-API: [M+H] + =746.3.
步骤二：向5mL单口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲基吡啶-4-基)异喹啉-1-基)氨基甲酸叔丁酯(30mg,0.05mmol)，三氟乙酸(3mL)和6mL二氯甲烷(6mL)，室温搅拌反应30分钟。反应液旋干，得到粗品用制备HPLC(碳酸氢铵)纯化得到：4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(3-甲基吡啶-4-基)异喹啉-1-胺(Z178,10mg,收率：40.8％)。ES-API:[M+H] +＝446.2。 Step 2: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methylpyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), trifluoro Acetic acid (3 mL) and 6 mL of dichloromethane (6 mL) were stirred at room temperature for 30 minutes. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain: 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 2-yl)-7-(3-methylpyridin-4-yl)isoquinolin-1-amine (Z178, 10 mg, yield: 40.8%). ES-API: [M+H] + =446.2.
实施例29化合物Z179的合成Example 29 Synthesis of compound Z179
Figure PCTCN2022085658-appb-000119
Figure PCTCN2022085658-appb-000119
步骤一：将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(60mg,0.087mmol)和2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(38mg,0.174mmol)溶解在1,4-二氧六环(8mL)和水(2mL)的溶液中，加入氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)催化剂(12.55mg,0.017mmol)和碳酸钾(36.09mg,0.261mmol)。混合物用氮气脱气并在110℃搅拌2小时。倒入水(30mL)中，用乙酸乙酯(30mL x 3)萃取。将合并有机层用饱和氯化钠溶液(30mL x 1)洗涤，无水硫酸钠干燥，过滤并浓缩。得到粗品通过硅胶柱层析(乙酸乙酯/石油醚＝50/50)纯化，得到(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(2-甲基吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(30mg,收率46.2％)。ES-API:[M+H] +＝746.3。 Step 1: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborol-2-yl)pyridine (38 mg, 0.174 mmol) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), and chlorine (2-dioxane) was added Cyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) catalyst (12.55 mg, 0.017 mmol) and potassium carbonate (36.09 mg, 0.261 mmol). The mixture was degassed with nitrogen and stirred at 110°C for 2 hours. Poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50/50) to obtain (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-( Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(2-methylpyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (30 mg , the yield is 46.2%). ES-API: [M+H] + =746.3.
步骤二:将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(2-甲基吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(30mg,0.040mmol)溶解到二氯甲烷(2mL)中，然后加入三氟乙酸(1mL)，室温搅拌1小时。反应液浓缩，加入氨水(0.5mL)，再次浓缩之后，经制备HPLC(甲酸)纯化得到4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(2-甲基吡啶-4-基)异喹啉-1-胺(Z179,7mg,收率40％,甲酸盐)。ES-API:[M+H] +＝446.2。 Step 2: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(2-methylpyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.040 mmol) was dissolved in dichloromethane (2 mL) followed by the addition of trifluoro Acetic acid (1 mL), stirred at room temperature for 1 hour. The reaction solution was concentrated, ammonia water (0.5 mL) was added, and after concentration again, 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4) was purified by preparative HPLC (formic acid). -yl)thiazol-2-yl)-7-(2-methylpyridin-4-yl)isoquinolin-1-amine (Z179, 7 mg, 40% yield, formate salt). ES-API: [M+H] + =446.2.
实施例30化合物Z180的合成Example 30 Synthesis of compound Z180
Figure PCTCN2022085658-appb-000120
Figure PCTCN2022085658-appb-000120
步骤一:将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-氯异喹啉-1-基)亚氨基二碳酸二叔丁酯(60mg,0.087mmol)和1,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(38.64mg,0.174mmol)溶解在1,4-二氧六环(8mL)和水(2mL)的溶液中，加入氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(12.55mg,0.017mmol)和碳酸钾(36.09mg,0.261mmol)。混合物用氮气脱气并在110℃搅拌2小时。倒入水(30mL)中，用乙酸乙酯(30mL x 3)萃取。将合并有几层用饱和氯化钠溶液(30mL x 1)洗涤，无水硫酸钠干燥，过滤并浓缩。得到粗品通过硅胶柱层析(乙酸乙酯/石油醚＝50/50)纯化，得到(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1,5-二甲基-1H-吡唑-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(40mg,收率61.39％)。ES-API:[M+H] +＝749.3。 Step 1: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)pyrazole (38.64 mg, 0.174 mmol) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), added Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (12.55 mg, 0.017 mmol) and potassium carbonate (36.09 mg, 0.261 mmol). The mixture was degassed with nitrogen and stirred at 110°C for 2 hours. Poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined layers were washed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50/50) to obtain (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-( Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinolin-1-yl)iminodi Di-tert-butyl carbonate (40 mg, 61.39% yield). ES-API: [M+H] + =749.3.
步骤二:将(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(1,5-二甲基-1H-吡唑-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(40mg,0.053mmol)溶解到二氯甲烷(5mL)中，然后加入三氟乙酸(2mL)，室温搅拌1小时。反应液浓缩，加入氨水(0.5mL)，再次浓缩之后，经制备HPLC(氨水)纯化得到7-(1,5-二甲基-1H-吡唑-4-基)-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z180,10mg,收率41.74％)。ES-API:[M+H] +＝449.3。 Step 2: (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinolin-1-yl)iminodicarbonate (40 mg, 0.053 mmol) was dissolved in dichloromethane (5 mL) ), then trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, ammonia water (0.5 mL) was added, and after concentration again, 7-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(4-( (Methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z180, 10 mg, 41.74% yield). ES-API: [M+H] + =449.3.
实施例31化合物Z181的合成Example 31 Synthesis of compound Z181
Figure PCTCN2022085658-appb-000121
Figure PCTCN2022085658-appb-000121
步骤一：7-溴-8-氟异喹啉-1-胺(300mg,1.25mmol)和1-甲基咪唑-5-硼酸频哪醇酯(1.04g,4.98mmol)溶于1,4-二氧六环(20mL)和水(4mL)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(137mg,0.19mmol)，碳酸钾(516mg,3.73mmol)，氮气置换三次，反应在100℃下搅拌18小时。反应液浓缩，得到粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-4％)得到目标产物8-氟-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-胺(190mg,收率63.0％)，淡棕色固体。ES-API:[M+H] +＝243.1。 Step 1: 7-Bromo-8-fluoroisoquinolin-1-amine (300mg, 1.25mmol) and 1-methylimidazole-5-boronic acid pinacol ester (1.04g, 4.98mmol) were dissolved in 1,4- Dioxane (20 mL) and water (4 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (137 mg, 0.19 mmol), potassium carbonate (516 mg, 3.73 mmol) , nitrogen was replaced three times, and the reaction was stirred at 100 °C for 18 h. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-4%) to obtain the target product 8-fluoro-7-(1-methyl-1H-imidazol-5-yl) Isoquinolin-1-amine (190 mg, 63.0% yield), pale brown solid. ES-API: [M+H] + = 243.1.
步骤二：8-氟-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-胺(190mg,0.78mmol)溶于N,N-二甲基甲酰胺(6mL)，在冰浴下加入 N-碘代丁二酰亚胺(229mg,1.02mmol)，反应在室温下搅拌18小时。反应液加入冰水，析出的固体过滤，滤饼用水洗涤，真空干燥得到目标产物8-氟-4-碘-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-胺(260mg,收率90.0％)，淡棕色固体。ES-API:[M+H] +＝369.1。 Step 2: 8-Fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (190mg, 0.78mmol) was dissolved in N,N-dimethylformamide (6mL) , N-iodosuccinimide (229 mg, 1.02 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 18 hours. Ice water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 8-fluoro-4-iodo-7-(1-methyl-1H-imidazol-5-yl)isoquinoline-1 - Amine (260 mg, 90.0% yield), pale brown solid. ES-API: [M+H] + =369.1.
步骤三：8-氟-4-碘-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-胺(260mg,0.71mmol)和 二碳酸二叔丁酯(616mg,2.82mmol)悬浮于二氯甲烷(15mL)，室温下加入三乙胺(357mg,4.07mmol)和4-二甲氨基吡啶(10mg,0.08mmol)，反应在室温下搅拌18小时。反应液浓缩，得到粗品用快速硅胶柱纯化((乙酸乙酯/甲醇＝10:1)/石油醚：0-70％)得到目标产物(8-氟-4-碘-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(125mg,收率31.1％)，淡黄色固体。ES-API:[M+H] +＝569.3。 Step 3: 8-Fluoro-4-iodo-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (260mg, 0.71mmol) and di-tert-butyl dicarbonate (616mg, 2.82 mmol) was suspended in dichloromethane (15 mL), triethylamine (357 mg, 4.07 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column ((ethyl acetate/methanol=10:1)/petroleum ether: 0-70%) to obtain the target product (8-fluoro-4-iodo-7-(1-methyl) Di-tert-butyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate (125 mg, yield 31.1%), pale yellow solid. ES-API: [M+H] + =569.3.
步骤四：向50mL圆底烧瓶中加入(8-氟-4-碘-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(125mg,0.22mmol)，双(频哪醇合)二硼(112mg,0.44mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(24mg,0.033mmol)，乙酸钾(65mg,0.66mmol)，N,N-二甲基甲酰胺(2.5mL)，氮气置换三次，反应在90℃反应3小时。反应液加入水(10mL)，析出的固体过滤，滤饼用水洗涤，真空干燥得到目标产物(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(180mg,粗品)，无需进一步纯化即可使用。ES-API:[M-82+H] +＝487.3。 Step 4: Add (8-fluoro-4-iodo-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl into a 50mL round bottom flask Ester (125 mg, 0.22 mmol), bis(pinacol)diboron (112 mg, 0.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24 mg, 0.033 mmol) ), potassium acetate (65 mg, 0.66 mmol), N,N-dimethylformamide (2.5 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 3 hours. Water (10 mL) was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dimethicone) Di-tert-butyl oxaboran-2-yl)-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate (180 mg, crude) without further It can be used after purification. ES-API: [M-82+H] + =487.3.
步骤五：向5mL微波管里加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(60mg,0.15mmol)，(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(180mg,粗品)，碳酸钾(64mg,0.46mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用薄层制备色谱板纯化(二氯甲烷/7M氨甲醇溶液＝20:1)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(30mg,收率26.0％)，淡黄色固体。ES-API:[M+H] +＝753.3。 Step 5: Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (60mg) to a 5mL microwave tube , 0.15 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(1-methyl- 1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (180 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, in a microwave reactor at 110 °C The reaction was carried out for 45 minutes. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by thin-layer preparative chromatography (dichloromethane/7M ammonia methanol solution=20:1) to obtain the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5 -(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)idene Di-tert-butyl aminodicarbonate (30 mg, yield 26.0%), pale yellow solid. ES-API: [M+H] + =753.3.
步骤六：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(1-甲基-1H-咪唑-5-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(30mg,0.04mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(4mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，得到粗品用制备HPLC(碳酸氢铵)纯化得到目标产物8-氟-7-(1-甲基-1H-咪唑-5-基)-4-(4-((甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z181,8mg,收率44.4％)，白色固体。ES-API:[M+H] +＝453.1。 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝8.8Hz,1H),8.28(s,1H),7.85–7.69(m,2H),7.33(s,2H),7.13(s,1H),3.94(dd,J＝10.8,2.8Hz,2H),3.82(s,2H),3.63(t,J＝11.2Hz,3H),3.48(t,J＝11.2Hz,2H),3.34–3.31(m,1H),2.37(s,3H),1.88(d,J＝12.8Hz,2H),1.70–1.52(m,2H). Step six: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.04 mmol) was dissolved in methanol (1 mL), 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 20.0 mmol) was reacted at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 8-fluoro-7-(1-methyl-1H-imidazole-5- yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z181,8mg , yield 44.4%), white solid. ES-API: [M+H] + =453.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.77(d, J=8.8Hz, 1H), 8.28(s, 1H), 7.85-7.69(m, 2H), 7.33(s, 2H), 7.13( s,1H),3.94(dd,J=10.8,2.8Hz,2H),3.82(s,2H),3.63(t,J=11.2Hz,3H),3.48(t,J=11.2Hz,2H), 3.34–3.31 (m, 1H), 2.37 (s, 3H), 1.88 (d, J=12.8Hz, 2H), 1.70–1.52 (m, 2H).
实施例32化合物Z182的合成Example 32 Synthesis of compound Z182
Figure PCTCN2022085658-appb-000122
Figure PCTCN2022085658-appb-000122
步骤一：向25mL三口圆底烧瓶中加入7-溴异喹啉-1-胺(510mg,2.28mmol)，吡啶-4-基硼酸(562mg,4.57mmol)，,1-二(二苯膦基)二茂铁二氯化钯(167mg,0.22mmol)，碳酸钾(948mg,6.85mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护，100℃条件下反应2小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物7-(吡啶-4-基)异喹啉-1-胺(500mg,收率:99％)。ES-API:[M+H] +＝222.1。 Step 1: Add 7-bromoisoquinolin-1-amine (510mg, 2.28mmol), pyridin-4-ylboronic acid (562mg, 4.57mmol), 1-bis(diphenylphosphino) to a 25mL three-necked round bottom flask ) ferrocene palladium dichloride (167 mg, 0.22 mmol), potassium carbonate (948 mg, 6.85 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted at 100°C for 2 hours. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product 7 -(pyridin-4-yl)isoquinolin-1-amine (500 mg, yield: 99%). ES-API: [M+H] + = 222.1.
步骤二：向25mL单口圆底烧瓶中加入7-(吡啶-4-基)异喹啉-1-胺(500mg,2.26mmol)、N-碘代丁二酰亚胺(661mg,2.94mmol)和二甲基甲酰胺(10mL)，氮气保护下，100℃条件下反应1小时。反应液加水过滤，固体旋干得到目标产物4-碘-7-(吡啶-4-基)异喹啉-1-胺(500mg,收率:63.7％)。ES-API:[M+H] +＝348.0 Step 2: Add 7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 2.26mmol), N-iodosuccinimide (661mg, 2.94mmol) and Dimethylformamide (10 mL) was reacted at 100°C for 1 hour under nitrogen protection. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500 mg, yield: 63.7%). ES-API: [M+H] + = 348.0
步骤三：向25mL三口圆底烧瓶中加入4-碘-7-(吡啶-4-基)异喹啉-1-胺(500mg,1.44mmol)，二碳酸二叔丁酯(1.26g,5.76mmol)，三乙胺(728mg,7.2mmol)，4-二甲氨基吡啶(17.6mg,0.144mmol)，二氯甲烷(10mL)，体系用氮气置换三次，然后用氮气球保护，室温条件下反应过夜。反应液加入二氯甲烷(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[4-碘-7-(吡啶-4-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(400mg,收率:51％)。ES-API:[M+H] +＝548.1。 Step 3: add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 1.44mmol), di-tert-butyl dicarbonate (1.26g, 5.76mmol) to a 25mL three-necked round bottom flask ), triethylamine (728 mg, 7.2 mmol), 4-dimethylaminopyridine (17.6 mg, 0.144 mmol), dichloromethane (10 mL), the system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted overnight at room temperature . The reaction solution was added with dichloromethane (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product { tert-Butyl [4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl]{[(2-methylprop-2-yl)oxy]carbonyl}amino}carboxylate (400 mg, received rate: 51%). ES-API: [M+H] + =548.1.
步骤四：向25mL三口圆底烧瓶中加入{[4-碘-7-(吡啶-4-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(150mg,0.274mmol)，联硼酸频那醇酯(139.2mg,0.545mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(30mg,0.04mmol)，乙酸钾(80.68mg,0.82mmol)，二氧六环(10mL)，体系用氮气置换三次，然后用氮气球保护90度条件下反应3小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[4-(二羟基硼烷基)-7-(吡啶-4-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(160mg,粗品)。ES-API:[M+H] +＝466.2。 Step 4: Add {[4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl]{[(2-methylpropan-2-yl)oxy] to a 25mL three-necked round bottom flask Carbonyl}amino}carboxylate tert-butyl ester (150 mg, 0.274 mmol), pinacol diboronate (139.2 mg, 0.545 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30 mg, 0.04 mmol), potassium acetate (80.68 mg, 0.82 mmol), dioxane (10 mL), the system was replaced with nitrogen three times, and then reacted for 3 hours under the protection of a nitrogen balloon at 90 degrees. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product and purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product {[4-(Dihydroxyboranyl)-7-(pyridin-4-yl)isoquinolin-1-yl]{[(2-methylprop-2-yl)oxy]carbonyl}amino}carboxylic acid tert-Butyl ester (160 mg, crude). ES-API: [M+H] + =466.2.
步骤五：向25mL三口圆底烧瓶中加入{[4-(二羟基硼烷基)-7-(吡啶-4-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(160mg,粗品)，({[2-溴-5-(3,4,5,6-四氢-2H-吡喃-4-基)-1,3-噻唑-4-基]甲基}(甲基)氨基)甲酸叔丁酯(60mg,0.153mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(11mg,0.015mmol)，碳酸钾(63.57mg,0.46mmol)，二氧六环(10mL)和水(1mL)，体系用氮气置换三次，然后用氮气球保护100℃条件下反应2小时。反应液加入乙酸乙酯(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁基酯(100mg,2步收率50％)。ES-API:[M+H] +＝732.3。 Step 5: Add {[4-(dihydroxyboranyl)-7-(pyridin-4-yl)isoquinolin-1-yl]{[(2-methylpropan-2 -yl)oxy]carbonyl}amino}carboxylate (160 mg, crude), ({[2-bromo-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl) -1,3-Thiazol-4-yl]methyl}(methyl)amino)carboxylate tert-butyl ester (60 mg, 0.153 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride ( 11 mg, 0.015 mmol), potassium carbonate (63.57 mg, 0.46 mmol), dioxane (10 mL) and water (1 mL), the system was replaced with nitrogen three times, and then reacted under nitrogen balloon protection at 100°C for 2 hours. The reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product ( 4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(pyridine -4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (100 mg, 50% yield over 2 steps). ES-API: [M+H] + =732.3.
步骤六：向5mL单口圆底烧瓶中加入(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁基(100mg,0.15mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)，室温搅拌反应30分钟。反应液旋干，粗品用制备HPLC(碳酸氢铵)纯化得到：4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(吡啶-4-基)异喹啉-1-胺(Z182,40mg,收率：67.8％)。ES-API:[M+H] +＝432.2。 Step 6: Add (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl) to a 5mL single-necked round-bottomed flask ) thiazol-2-yl)-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl (100 mg, 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain: 4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 -yl)-7-(pyridin-4-yl)isoquinolin-1-amine (Z182, 40 mg, yield: 67.8%). ES-API: [M+H] + =432.2.
实施例33化合物Z183的合成Example 33 Synthesis of compound Z183
Figure PCTCN2022085658-appb-000123
Figure PCTCN2022085658-appb-000123
步骤一：7-溴-8-氟异喹啉-1-胺(200mg,0.83mmol)和4-吡啶硼酸(204mg,1.66mmol)溶于1,4-二氧六环(10mL)和水(2.5mL)加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(61mg,0.08mmol)，碳酸钾(344mg,2.49mmol)，氮气置换三次，反应在100℃下搅拌2小时。反应液浓缩。得到粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物8-氟-7-(吡啶-4-基)异喹啉-1-胺(198mg,收率99.8％)，淡棕色固体。ES-API:[M+H] +＝240.1。 Step 1: 7-Bromo-8-fluoroisoquinolin-1-amine (200 mg, 0.83 mmol) and 4-pyridineboronic acid (204 mg, 1.66 mmol) were dissolved in 1,4-dioxane (10 mL) and water ( 2.5 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.08 mmol), potassium carbonate (344 mg, 2.49 mmol), nitrogen was replaced three times, and the reaction was carried out at 100 °C Stir for 2 hours. The reaction solution was concentrated. The obtained crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to obtain the target product 8-fluoro-7-(pyridin-4-yl)isoquinolin-1-amine (198 mg, yield rate 99.8%), light brown solid. ES-API: [M+H] + = 240.1.
步骤二：8-氟-7-(吡啶-4-基)异喹啉-1-胺(198mg,0.83mmol)溶于N,N-二甲基甲酰胺(12mL)在冰浴下加入 N-碘代丁二酰亚胺(242mg,1.08mmol)，反应在室温下搅拌3h。反应液加入冰水，析出的固体过滤，滤饼用水洗涤，在真空干燥得到目标产物8-氟-4-碘-7-(吡啶-4-基)异喹啉-1-胺(270mg,收率89.4％)，棕色固体。ES-API:[M+H] +＝356.0。 Step 2: 8-Fluoro-7-(pyridin-4-yl)isoquinolin-1-amine (198mg, 0.83mmol) was dissolved in N,N-dimethylformamide (12mL) and N- Iodosuccinimide (242 mg, 1.08 mmol) and the reaction was stirred at room temperature for 3 h. Ice water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 8-fluoro-4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (270 mg, collected rate 89.4%), brown solid. ES-API: [M+H] + =356.0.
步骤三：8-氟-4-碘-7-(吡啶-4-基)异喹啉-1-胺(270mg,0.74mmol)和 二碳酸二叔丁酯(646mg,2.96mmol)悬浮于二氯甲烷(15mL)室温下加入三乙胺(374mg,3.70mmol)，和4-二甲氨基吡啶(9mg,0.07mmol)，反应在室温下搅拌18小时。反应液浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：10-50％)得到目标产物(8-氟-4-碘-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(325mg,收率77.7％)，灰白色固体。ES-API:[M+H] +＝566.0。 Step 3: 8-Fluoro-4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (270mg, 0.74mmol) and di-tert-butyl dicarbonate (646mg, 2.96mmol) were suspended in dichloro Methane (15 mL) was added triethylamine (374 mg, 3.70 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) at room temperature, and the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column (ethyl acetate/petroleum ether: 10-50%) to obtain the target product (8-fluoro-4-iodo-7-(pyridin-4-yl)isoquinoline-1 -yl)iminodicarbonate di-tert-butyl ester (325 mg, yield 77.7%), off-white solid. ES-API: [M+H] + =566.0.
步骤四：向50mL圆底烧瓶中加入(8-氟-4-碘-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(150mg,0.27mmol)，双(频哪醇合)二硼(135mg,0.53mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg,0.04mmol)，乙酸钾(78mg,0.80mmol)，N,N-二甲基甲酰胺(3mL)，氮气置换三次，反应在90℃反应2小时。反应液加入水(15mL)，用乙酸乙酯萃取(30mL×2)。合并有机层用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥并浓缩得到粗品(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(195mg)，无需进一步纯化直接用于下一步反应。ES-API:[M-82+H] +＝484.3。 Step 4: Add (8-fluoro-4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (150mg, 0.27mmol) to a 50mL round bottom flask , bis(pinacol)diboron (135mg, 0.53mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29mg, 0.04mmol), potassium acetate (78mg, 0.80 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours. Water (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxan). Boran-2-yl)-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (195 mg) was used in the next reaction without further purification. ES-API: [M-82+H] + =484.3.
步骤五：向5mL微波管里加入：((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁 酯(60mg,0.15mmol)，(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(195mg,粗品)，碳酸钾(64mg,0.46mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚:20-80％)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(75mg,收率65.2％)，淡黄色固体。ES-API:[M+H] +＝750.3。 Step 5: Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-4- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, were reacted in a microwave reactor at 110° C. for 45 minutes. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 20-80%) to obtain the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetramethylene) Hydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(pyridin-4-yl)isoquinolin-1-yl)di-tert-butyl iminodicarbonate (75mg, yield 65.2%), pale yellow solid. ES-API: [M+H] + =750.3.
步骤六：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(吡啶-4-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(75mg,0.12mmol)溶于甲醇(1mL)加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物8-氟-4-(4-((甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(吡啶-4-基)异喹啉-1-胺(Z183,36mg,甲酸盐,收率72.6％)，白色固体。ES-API:[M+H] +＝450.2。 1H NMR(500MHz,DMSO-d 6)δ8.84(d,J＝9.0Hz,1H),8.76–8.68(m,2H),8.35–8.29(m,2H),7.90(t,J＝8.5Hz,1H),7.68(d,J＝5.0Hz,2H),7.40(s,2H),4.01(s,2H),3.94(dd,J＝11.0,4.0Hz,2H),3.48(t,J＝11.0Hz,2H),3.41–3.31(m,1H),1.88(dd,J＝13.0,1.5Hz,2H),1.68–1.54(m,2H). Step six: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (75 mg, 0.12 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL) was added , 20.0 mmol), the reaction was reacted at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 8-fluoro-4-(4-((methylamino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(pyridin-4-yl)isoquinolin-1-amine (Z183, 36 mg, formate, 72.6% yield) , white solid. ES-API: [M+H] + =450.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.84 (d, J=9.0 Hz, 1H), 8.76-8.68 (m, 2H), 8.35-8.29 (m, 2H), 7.90 (t, J=8.5 Hz, 1H), 7.68(d, J＝5.0Hz, 2H), 7.40(s, 2H), 4.01(s, 2H), 3.94(dd, J＝11.0, 4.0Hz, 2H), 3.48(t, J = 11.0Hz, 2H), 3.41–3.31 (m, 1H), 1.88 (dd, J=13.0, 1.5Hz, 2H), 1.68–1.54 (m, 2H).
实施例34化合物Z184的合成Example 34 Synthesis of compound Z184
Figure PCTCN2022085658-appb-000124
Figure PCTCN2022085658-appb-000124
步骤一：7-溴-8-氟异喹啉-1-胺(300mg,1.25mmol)和3-吡啶硼酸(306mg,2.49mmol)溶于1,4-二氧六环(12mL)和水(3mL)加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(91mg,0.12mmol)，碳酸钾(516mg,3.73mmol)，氮气置换三次，反应在100℃下搅拌2小时。反应液浓缩。得到粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物8-氟-7-(吡啶-3-基)异喹啉-1-胺(295mg,收率99.1％)，淡棕色固体。ES-API:[M+H] +＝240.1。 Step 1: 7-Bromo-8-fluoroisoquinolin-1-amine (300 mg, 1.25 mmol) and 3-pyridineboronic acid (306 mg, 2.49 mmol) were dissolved in 1,4-dioxane (12 mL) and water ( 3 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (91 mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), nitrogen was replaced three times, and the reaction was stirred at 100 °C 2 hours. The reaction solution was concentrated. The obtained crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to obtain the target product 8-fluoro-7-(pyridin-3-yl)isoquinolin-1-amine (295 mg, yield rate 99.1%), light brown solid. ES-API: [M+H] + = 240.1.
步骤二：8-氟-7-(吡啶-3-基)异喹啉-1-胺(265mg,1.11mmol)溶于N,N-二甲基甲酰胺(12mL)在冰浴下加入 N-碘代丁二酰亚胺(324mg,1.44mmol)，反应在室温下搅拌3小时。反应液加入冰水，析出的固体过滤，滤饼用水洗涤，真空干燥得到目标产物8-氟-4-碘-7-(吡啶-3-基)异喹啉-1-胺(400mg,收率98.9％)，淡棕色固体。ES-API:[M+H] +＝356.0。 Step 2: 8-Fluoro-7-(pyridin-3-yl)isoquinolin-1-amine (265mg, 1.11mmol) was dissolved in N,N-dimethylformamide (12mL) and N- Iodosuccinimide (324 mg, 1.44 mmol) and the reaction was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 8-fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, yield 98.9%), light brown solid. ES-API: [M+H] + =356.0.
步骤三：8-氟-4-碘-7-(吡啶-3-基)异喹啉-1-胺(400mg,1.10mmol)和 二碳酸二叔丁酯(956mg,4.38 mmol)悬浮于二氯甲烷(25mL)，室温下加入三乙胺(554mg,5.48mmol)和4-二甲氨基吡啶(13mg,0.11mmol)，反应在室温下搅拌18小时。反应液浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到目标产物(8-氟-4-碘-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(450mg,收率72.7％)，灰白色固体。ES-API:[M+H] +＝566.2。 Step 3: 8-Fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, 1.10 mmol) and di-tert-butyl dicarbonate (956 mg, 4.38 mmol) were suspended in dichloro Methane (25 mL), triethylamine (554 mg, 5.48 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated to obtain the crude product, which was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-40%) to obtain the target product (8-fluoro-4-iodo-7-(pyridin-3-yl)isoquinoline-1 -yl) di-tert-butyl iminodicarbonate (450 mg, yield 72.7%), off-white solid. ES-API: [M+H] + =566.2.
步骤四：向50mL圆底烧瓶中加入(8-氟-4-碘-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(150mg,0.27mmol)，双(频哪醇合)二硼(134mg,0.53mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg,0.04mmol)，乙酸钾(78mg,0.80mmol)，N,N-二甲基甲酰胺(3mL)，氮气置换三次，反应在90℃反应2小时。反应液加入水(15mL)，用乙酸乙酯萃取(30mL×2)。合并有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥并浓缩得到粗品(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(190mg)，无需进一步纯化直接用于下一步反应。ES-API:[M-82+H] +＝484.2。 Step 4: Add (8-fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (150mg, 0.27mmol) to a 50mL round bottom flask , bis(pinacol)diboron (134mg, 0.53mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29mg, 0.04mmol), potassium acetate (78mg, 0.80 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours. Water (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa). Boran-2-yl)-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (190 mg) was used in the next reaction without further purification. ES-API: [M-82+H] + =484.2.
步骤五：向5mL微波管里加入：((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(70mg,0.18mmol)，(8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(190mg,粗品)，碳酸钾(74mg,0.54mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(13mg,0.018mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚:20-60％)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(90mg,收率67.1％)，淡黄色固体。ES-API:[M+H] +＝750.3。 Step 5: Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 70 mg, 0.18 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-3- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (13 mg, 0.018 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, reacted in a microwave reactor at 110° C. for 45 min. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 20-60%) to obtain the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrakis) Hydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (90 mg, yield 67.1%), pale yellow solid. ES-API: [M+H] + =750.3.
步骤六：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(90mg,0.12mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物8-氟-4-(4-((甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(吡啶-3-基)异喹啉-1-胺(Z184,甲酸盐,41mg,收率68.0％)，淡黄色固体。ES-API:[M+H] +＝450.2。 1H NMR(500MHz,DMSO-d 6)δ8.90–8.82(m,2H),8.65(dd,J＝5.0,1.5Hz,1H),8.35–8.29(m,2H),8.08(d,J＝8.0Hz,1H),7.89(t,J＝8.5Hz,1H),7.58(dd,J＝8.0,5.0Hz,1H),7.37(s,2H),3.98(s,2H),3.94(dd,J＝11.0,3.5Hz,2H),3.48(t,J＝11.0Hz,2H),3.41–3.33(m,1H),2.47(s,3H),1.88(dd,J＝13.0,1.5Hz,2H),1.68–1.55(m,2H). Step six: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (90 mg, 0.12 mmol) was dissolved in methanol (1 mL), and a 4.0 M solution of hydrogen chloride in dioxane was added ( 5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 8-fluoro-4-(4-((methylamino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(pyridin-3-yl)isoquinolin-1-amine (Z184, formate, 41 mg, 68.0% yield) , pale yellow solid. ES-API: [M+H] + =450.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.90-8.82 (m, 2H), 8.65 (dd, J=5.0, 1.5 Hz, 1H), 8.35-8.29 (m, 2H), 8.08 (d, J =8.0Hz,1H),7.89(t,J=8.5Hz,1H),7.58(dd,J=8.0,5.0Hz,1H),7.37(s,2H),3.98(s,2H),3.94(dd , J＝11.0, 3.5Hz, 2H), 3.48(t, J＝11.0Hz, 2H), 3.41–3.33(m, 1H), 2.47(s, 3H), 1.88(dd, J＝13.0, 1.5Hz, 2H),1.68–1.55(m,2H).
实施例35化合物Z160，Z160-1，Z160-2的合成Example 35 Synthesis of compound Z160, Z160-1, Z160-2
Figure PCTCN2022085658-appb-000125
Figure PCTCN2022085658-appb-000125
步骤一：5-溴-2-((叔丁氧羰基)氨基)噻唑-4-羧酸甲酯(1.5g,4.45mmol)和2-(2,5-二氢呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二噁硼烷(0.96g,4.89mmol)溶于2-甲基四氢呋喃(8mL)和水(2mL)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.33g,0.45mmol)，碳酸钾(1.84g,13.35mmol)，氮气置换三次，反应在85℃下搅拌3小时。将反应冷却至室温，加入乙酸乙酯(80mL)，用水(30mL)，饱和食盐水(50mL)洗涤，用无水硫酸钠干燥并过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-30％)得到目标产物2-((叔丁氧羰基)氨基)-5-(2,5-二氢呋喃-3-基)噻唑-4-羧酸甲酯(1.4g,收率96.6％)，白色固体。ES-API:[M+H] +＝327.1。 Step 1: Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (1.5g, 4.45mmol) and 2-(2,5-dihydrofuran-3-yl)- 4,4,5,5-Tetramethyl-1,3,2-dioxaborane (0.96 g, 4.89 mmol) was dissolved in 2-methyltetrahydrofuran (8 mL) and water (2 mL), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.33 g, 0.45 mmol), potassium carbonate (1.84 g, 13.35 mmol), nitrogen purged three times, and the reaction was stirred at 85°C for 3 hours. The reaction was cooled to room temperature, ethyl acetate (80 mL) was added, washed with water (30 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to obtain the target product 2-((tert-butoxycarbonyl)amino)-5-(2,5-dihydrofuran-3-yl)thiazole -4-Carboxylic acid methyl ester (1.4 g, yield 96.6%), white solid. ES-API: [M+H] + =327.1.
步骤二：2-((叔丁氧羰基)氨基)-5-(2,5-二氢呋喃-3-基)噻唑-4-羧酸甲酯(1.35g,4.14mmol)溶于甲醇(25mL)，加入10％钯碳(1.0g)，在氢气球下室温搅拌反应18小时。反应液用硅藻土过滤，甲醇洗涤，滤液浓缩得到目标产物2-((叔丁氧羰基)氨基)-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(1.25g,收率91.9％)， 白色固体。ES-API:[M+H] +＝329.2。 Step 2: Methyl 2-((tert-butoxycarbonyl)amino)-5-(2,5-dihydrofuran-3-yl)thiazole-4-carboxylate (1.35g, 4.14mmol) was dissolved in methanol (25mL) ), 10% palladium on carbon (1.0 g) was added, and the reaction was stirred at room temperature under a hydrogen balloon for 18 hours. The reaction solution was filtered with celite, washed with methanol, and the filtrate was concentrated to obtain the target product, methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (1.25 g, collected). rate 91.9%), white solid. ES-API: [M+H] + =329.2.
步骤三：2-((叔丁氧羰基)氨基)-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(1.25g,3.81mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(10mL)，反应在室温下反应3小时。反应液浓缩，用饱和碳酸氢钠调pH至8，析出的固体过滤，滤饼用水(10mL)洗涤，真空干燥得到目标产物2-氨基-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(825mg,收率95.0％)，灰白色固体。ES-API:[M+H] +＝229.1。 Step 3: Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (1.25g, 3.81mmol) was dissolved in dichloromethane (10mL), added with trichloromethane Fluoroacetic acid (10 mL), the reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated, adjusted to pH 8 with saturated sodium bicarbonate, the precipitated solid was filtered, the filter cake was washed with water (10 mL), and dried in vacuo to obtain the target product 2-amino-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate Methyl acid (825 mg, 95.0% yield), off-white solid. ES-API: [M+H] + = 229.1.
步骤四：溴化铜(2.28g,10.18mmol)溶于乙腈(15mL)，在室温下滴加亚硝酸叔丁酯(525mg,5.09mmol)，反应加热到60℃，滴加2-氨基-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(775mg,3.40mmol)的乙腈悬浮液(20mL)，反应在60℃搅拌2小时。反应液浓缩，加入二氯甲烷溶解，用1M稀盐酸溶液，1M氯化铵溶液洗涤，无水硫酸钠干燥，过滤浓缩得到目标产物2-溴-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(950mg,收率96.0％)，淡黄色固体。ES-API:[M+H] +＝292.0,293.9。 Step 4: copper bromide (2.28g, 10.18mmol) was dissolved in acetonitrile (15mL), tert-butyl nitrite (525mg, 5.09mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5 was added dropwise - A suspension of methyl (tetrahydrofuran-3-yl)thiazole-4-carboxylate (775 mg, 3.40 mmol) in acetonitrile (20 mL), the reaction was stirred at 60°C for 2 hours. The reaction solution was concentrated, dissolved in dichloromethane, washed with 1M dilute hydrochloric acid solution, 1M ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product 2-bromo-5-(tetrahydrofuran-3-yl)thiazole-4 -Methyl carboxylate (950 mg, yield 96.0%), pale yellow solid. ES-API: [M+H] + = 292.0, 293.9.
步骤五：2-溴-5-(四氢呋喃-3-基)噻唑-4-羧酸甲酯(300mg,1.03mmol)溶于四氢呋喃(5mL)，在冰浴下滴加2.0M硼氢化锂四氢呋喃溶液(1.0mL,2.0mmol)和甲醇(66mg,2.06mmol)，反应在冰浴下搅拌30分钟，然后在室温下搅拌2小时。反应液在冰浴下用水(6mL)和1.0M稀盐酸(3mL)淬灭，乙酸乙酯萃取(30mL×2)。并有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤浓缩得到目标产物(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)甲醇(255mg,收率94.0％)，淡黄色固体。ES-API:[M+H] +＝264.0,266.0。 Step 5: Methyl 2-bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (300 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL), and 2.0 M lithium borohydride solution in tetrahydrofuran was added dropwise under ice bath (1.0 mL, 2.0 mmol) and methanol (66 mg, 2.06 mmol), the reaction was stirred under an ice bath for 30 minutes, then at room temperature for 2 hours. The reaction solution was quenched with water (6 mL) and 1.0 M dilute hydrochloric acid (3 mL) under ice bath, and extracted with ethyl acetate (30 mL×2). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product (2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methanol (255 mg, yield 94.0 %), pale yellow solid. ES-API: [M+H] + = 264.0, 266.0.
步骤六：2-溴-5-(四氢呋喃-3-基)噻唑-4-基)甲醇(470mg,1.78mmol)溶于二氯甲烷(25mL)，在冰浴下加入戴斯-马丁氧化剂(906mg,2.14mmol)，反应在室温下搅拌2小时。反应液加入二氯甲烷(40mL)，依次用饱和碳酸氢钠溶液(10mL)，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物2-溴-5-(四氢呋喃-3-基)噻唑-4-甲醛(230mg,收率49.3％)，淡黄色固体。ES-API:[M+H] +＝262.0,264.0。 Step 6: 2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methanol (470mg, 1.78mmol) was dissolved in dichloromethane (25mL), Dess-Martin oxidant (906mg) was added under ice bath , 2.14 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with dichloromethane (40 mL), washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product 2-bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carbaldehyde (230 mg, yield 49.3%), pale Yellow solid. ES-API: [M+H] + = 262.0, 264.0.
步骤七：2-溴-5-(四氢呋喃-3-基)噻唑-4-甲醛(200mg,0.76mmol)和甲氨盐酸盐(258mg,3.82mmol)悬浮于1，2-二氯甲烷(12mL)和甲醇(4mL)，加入三乙酰基硼氢化钠(322mg,1.53mmol)，反应在室温下反应18小时。反应液用1M氢氧化钠溶液调pH至10，用二氯甲烷萃取(50mL)。有机层用无水硫酸钠干燥，过滤浓缩得到目标产物1-(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)-N-甲基甲胺(205mg,粗品)，黄色液体。ES-API:[M+H] +＝277.0,279.0。 Step 7: 2-Bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carbaldehyde (200 mg, 0.76 mmol) and methylamine hydrochloride (258 mg, 3.82 mmol) were suspended in 1,2-dichloromethane (12 mL) ) and methanol (4 mL), sodium triacetylborohydride (322 mg, 1.53 mmol) was added, and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was adjusted to pH 10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product 1-(2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N-methylmethanamine (205mg, crude product), yellow liquid. ES-API: [M+H] + =277.0, 279.0.
步骤八：1-(2-溴-5-(四氢呋喃-3-基)噻唑-4-基)-N-甲基甲胺(205mg,粗品)和三乙胺(112mg,1.11mmol)溶于二氯甲烷(10mL)，在冰浴下加入 二碳酸二叔丁酯(210mg,0.96mmol)，反应在室温下搅拌1小时。反应液浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物((2-溴-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(235mg,收率82.0％)，粘稠状液体。ES-API:[M+H] +＝377.0,379.0。 Step 8: 1-(2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N-methylmethanamine (205mg, crude) and triethylamine (112mg, 1.11mmol) were dissolved in two Chloromethane (10 mL) was added with di-tert-butyl dicarbonate (210 mg, 0.96 mmol) under an ice bath, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product ((2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methyl) (Methyl) tert-butyl carbamate (235 mg, yield 82.0%), viscous liquid. ES-API: [M+H] + =377.0, 379.0.
步骤九：向5mL微波管里加入((2-溴-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(150mg,0.40mmol)，7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(450mg,粗品)，碳酸钾(165mg,1.19mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg,0.04mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用薄层制备色谱板纯化(二氯甲烷/甲醇＝25:1)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)-7-(7-氟咪唑[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(130mg,收率42.2％)，淡黄色固体。ES-API:[M+H] +＝775.3。 Step 9: Add ((2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (150 mg, 0.40 mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (450 mg, crude), potassium carbonate (165 mg, 1.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (29 mg, 0.04 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, and reacted in a microwave reactor at 110° C. for 45 minutes. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by thin-layer preparative chromatography (dichloromethane/methanol=25:1) to give the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydrofuran- 3-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (130 mg, yield 42.2%), pale yellow solid. ES-API: [M+H] + =775.3.
步骤十：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)-7-(7-氟咪唑[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(130mg,0.17mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(4mL,16.0mmol)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(甲胺基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)异喹啉-1-胺(Z160,45mg,收率54.8％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ9.07(d,J＝9.0Hz,1H),8.84–8.70(m,1H),8.55(s,1H),8.26(s,1H),8.03(dd,J＝9.0,1.5Hz,1H),7.90(s,1H),7.66–7.42(m,3H),7.11–6.99(m,1H),4.10–3.89(m,3H),3.89–3.72(m,3H),3.58(dd,J＝8.0,6.5Hz,1H),2.47–2.41(m,1H),2.38(s,3H),1.95–1.81(m,1H).ES-API:[M+H] +＝475.1。 Step ten: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazole[ 1,2-a]Pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (130 mg, 0.17 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane was added (4 mL, 16.0 mmol) and the reaction was allowed to react for 2 hours at room temperature. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(7-fluoroimidazo[1,2-a]pyridine-3- yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)isoquinolin-1-amine (Z160, 45 mg, 54.8% yield), Pale yellow solid. 1 H NMR (500MHz, DMSO-d 6 )δ9.07(d,J=9.0Hz,1H),8.84-8.70(m,1H),8.55(s,1H),8.26(s,1H),8.03( dd, J=9.0, 1.5Hz, 1H), 7.90 (s, 1H), 7.66–7.42 (m, 3H), 7.11–6.99 (m, 1H), 4.10–3.89 (m, 3H), 3.89–3.72 ( m,3H),3.58(dd,J=8.0,6.5Hz,1H),2.47–2.41(m,1H),2.38(s,3H),1.95–1.81(m,1H).ES-API:[M +H] + =475.1.
步骤十一：7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(甲胺基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)异喹啉-1-胺(Z160,40mg,0.084mmol)悬浮于二氯甲烷(5mL)，室温下加入三乙胺(26mg,0.25mmol)和 二碳酸 二叔丁酯(28mg,0.13mmol)，反应在室温下搅拌1小时。反应液浓缩，粗品用薄层制备色谱板纯化(二氯甲烷/甲醇＝15:1)得到混合物(40mg)，用手性制备拆分(柱型：IG,30*250mm；流动相：正己烷:乙醇:二乙胺＝60:40:2；流速:25ml/min；柱温:室温)得到两个异构体化合物。其中一个结构体任意指定为(R)-(2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(12mg,峰1,保留时间12.907min,产率24.9％)，淡黄色固体。ES-API:[M+H] +＝575.2；另一个异构体任意指定为(S)-(2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(11mg,峰2,保留时间16.237min,产率22.8％)，淡黄色固体。ES-API:[M+H] +＝575.2。 Step eleven: 7-(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazole -2-yl)isoquinolin-1-amine (Z160, 40 mg, 0.084 mmol) was suspended in dichloromethane (5 mL), triethylamine (26 mg, 0.25 mmol) and di- tert- butyl dicarbonate (28 mg) were added at room temperature , 0.13 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was purified by thin-layer preparative chromatography (dichloromethane/methanol=15:1) to obtain a mixture (40 mg), which was resolved by chiral preparative separation (column type: IG, 30*250 mm; mobile phase: n-hexane : ethanol:diethylamine=60:40:2; flow rate: 25ml/min; column temperature: room temperature) to obtain two isomer compounds. One of the structures is arbitrarily designated as (R)-(2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5 -(Tetrahydrofuran-3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (12 mg, peak 1, retention time 12.907 min, yield 24.9%), pale yellow solid. ES-API: [M+H] + = 575.2; another isomer arbitrarily designated as (S)-(2-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridine- 3-yl)isoquinolin-4-yl)-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (11 mg, peak 2, retention time 16.237 min , yield 22.8%), pale yellow solid. ES-API: [M+H] + =575.2.
步骤十二：(R)-(2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(12mg,0.02mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物(R)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(甲胺基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)异喹啉-1-胺(Z160-1,3.4mg,收率34.3％)，淡黄色固体。ES-API:[M+H] +＝475.1。 1H NMR(400MHz,DMSO-d 6)δ9.07(d,J＝8.8Hz,1H),8.76(dd,J＝7.2,6.0Hz,1H),8.55(d,J＝1.2Hz,1H),8.26(s,1H),8.03(dd,J＝8.8,1.6Hz,1H),7.90(s,1H),7.57(dd,J＝10.0,2.5Hz,1H),7.48(s,2H),7.06(td,J＝7.6,2.4Hz,1H),4.08–3.88(m,3H),3.87–3.77(m,3H),3.58(dd,J＝8.0,6.4Hz,1H),2.45–2.34(m,4H),1.95–1.82(m,1H). Step 12: (R)-(2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydrofuran -3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (12 mg, 0.02 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added ), the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product (R)-7-(7-fluoroimidazo[1,2-a] Pyridin-3-yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)isoquinolin-1-amine (Z160-1, 3.4 mg , yield 34.3%), pale yellow solid. ES-API: [M+H] + =475.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.07 (d, J=8.8Hz, 1H), 8.76 (dd, J=7.2, 6.0Hz, 1H), 8.55 (d, J=1.2Hz, 1H) ,8.26(s,1H),8.03(dd,J=8.8,1.6Hz,1H),7.90(s,1H),7.57(dd,J=10.0,2.5Hz,1H),7.48(s,2H), 7.06 (td, J=7.6, 2.4Hz, 1H), 4.08–3.88 (m, 3H), 3.87–3.77 (m, 3H), 3.58 (dd, J=8.0, 6.4Hz, 1H), 2.45–2.34 ( m,4H),1.95–1.82(m,1H).
步骤十三：(S)-(2-(1-氨基-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-4-基)-5-(四氢呋喃-3-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(11mg,0.02mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物(S)-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-(甲胺基)甲基)-5-(四氢呋喃-3-基)噻唑-2-基)异喹啉-1-胺(Z160-2,7mg,收率64.4％,甲酸盐)，淡黄色固体。ES-API:[M+H] +＝475.1。 1H NMR(400MHz,DMSO-d 6)δ9.08(d,J＝8.8Hz,1H),8.80–8.69(m,1H),8.56(s,1H),8.32–8.26(m,2H),8.02(d,J＝8.8Hz,1H),7.90(s,1H),7.64–7.44(m,3H),7.12–7.02(m,1H),4.04–3.93(m,5H),3.85–3.79(m,1H),3.62–3.56(m,1H),2.49–2.42(m,4H),1.98–1.85(m,1H). Step Thirteen: (S)-(2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydrofuran -3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (11 mg, 0.02 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added ), the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product (S)-7-(7-fluoroimidazo[1,2-a]pyridine- 3-yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)isoquinolin-1-amine (Z160-2, 7mg, yield 64.4%, formate), pale yellow solid. ES-API: [M+H] + =475.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.08(d,J=8.8Hz,1H),8.80-8.69(m,1H),8.56(s,1H),8.32-8.26(m,2H), 8.02(d,J=8.8Hz,1H),7.90(s,1H),7.64-7.44(m,3H),7.12-7.02(m,1H),4.04-3.93(m,5H),3.85-3.79( m, 1H), 3.62–3.56 (m, 1H), 2.49–2.42 (m, 4H), 1.98–1.85 (m, 1H).
实施例36化合物Z156的合成Example 36 Synthesis of compound Z156
Figure PCTCN2022085658-appb-000126
Figure PCTCN2022085658-appb-000126
步骤一：2,2-二甲氧基乙烷-1-胺(5.18g,49.26mmol)溶于甲醇(100mL)，室温下加入3-溴-2-氟苯甲醛(10g,49.26mmol)，反应在70℃下搅拌反应2小时。反应冷却至0℃，分批加入硼氢化钠(1.86g,49.26mmol)，反应在室温下搅拌16小时。浓缩去除溶剂，加入冰水(300mL)，用二氯甲烷(100mL×3)萃取。合并有机层用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥并过滤浓缩得到目标产物N-(3-溴-2-氟苄基)-2,2-二甲氧基乙烷-1-胺(14.1g,收率98.0％)，无色液体。ES-API:[M+H] +＝292.0,294.1。 Step 1: 2,2-Dimethoxyethane-1-amine (5.18g, 49.26mmol) was dissolved in methanol (100mL), 3-bromo-2-fluorobenzaldehyde (10g, 49.26mmol) was added at room temperature, The reaction was stirred at 70°C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.86 g, 49.26 mmol) was added portionwise, and the reaction was stirred at room temperature for 16 hours. Concentrate to remove the solvent, add ice water (300 mL), and extract with dichloromethane (100 mL×3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product N-(3-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1 - Amine (14.1 g, 98.0% yield), colorless liquid. ES-API: [M+H] + = 292.0, 294.1.
步骤二：将氯磺酸(31.8mL,482.63mmol)冷却至0℃，缓慢滴加N-(3-溴-2-氟苄基)-2,2-二甲氧基乙烷-1-胺(14.1g,48.26mmol)超过30分钟。反应物在100℃搅拌反应45分钟，然后冷却并倒入冰中(300g)，过滤，滤液在冰浴中冷却，并用50％氢氧化钠溶液调pH至14，用二氯甲烷(150mL×2)萃取，合并有机层用无水硫酸钠干燥并过滤浓缩。粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到目标产物7-溴-8-氟异喹啉(5.5g,产率50.4％)，灰白色固体。ES-API:[M+H] +＝226.0,228.0。 Step 2: Cool chlorosulfonic acid (31.8 mL, 482.63 mmol) to 0 °C, slowly add N-(3-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1-amine dropwise (14.1 g, 48.26 mmol) over 30 minutes. The reactant was stirred at 100°C for 45 minutes, then cooled and poured into ice (300 g), filtered, the filtrate was cooled in an ice bath, and the pH was adjusted to 14 with 50% sodium hydroxide solution, and dichloromethane (150 mL×2 ) extraction, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to give the target product 7-bromo-8-fluoroisoquinoline (5.5 g, yield 50.4%) as an off-white solid. ES-API: [M+H] + = 226.0, 228.0.
步骤三：7-溴-8-氟异喹啉(5.5g,24.33mmol)溶于二氯甲烷(150mL)，冰浴下加入85％间氯过氧苯甲酸(9.88g,48.66mmol)，反应在室温下搅拌反应18小时。反应冷却至0℃，阿计入饱和碳酸氢钠溶液(200mL)，用10％甲醇/二氯甲烷(100mL×2)萃取。合并有机层用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥并过滤浓缩。粗品用石油醚打浆得到目标产物7-溴-8-氟异喹啉2-氧化物(5.7g,收率96.8％)，橙色固体。ES-API:[M+H] +＝241.9,243.9。 Step 3: 7-Bromo-8-fluoroisoquinoline (5.5g, 24.33mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (9.88g, 48.66mmol) was added under ice bath, and the reaction The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, added to saturated sodium bicarbonate solution (200 mL), and extracted with 10% methanol/dichloromethane (100 mL×2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was slurried with petroleum ether to obtain the target product 7-bromo-8-fluoroisoquinoline 2-oxide (5.7 g, yield 96.8%) as an orange solid. ES-API: [M+H] + = 241.9, 243.9.
步骤四：7-溴-8-氟异喹啉2-氧化物(5.7g,23.55mmol)溶于吡啶(100mL)，冰浴下分批加入对甲苯磺酰氯(6.73g,35.32mmol)，反应在室温下搅拌反应18小时。真空下旋掉吡啶，加入乙醇胺(70.5mL,1177.45mmol)，反应在室温下搅拌反应24小时。反应液倒入碎冰中，析出的固体过滤，真空下干燥。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-3％)得到目标产物7-溴-8-氟异喹啉-1-胺(2.5g,产率44.0％)，灰白色固体。ES-API:[M+H] +＝241.0,243.0。 Step 4: 7-Bromo-8-fluoroisoquinoline 2-oxide (5.7 g, 23.55 mmol) was dissolved in pyridine (100 mL), p-toluenesulfonyl chloride (6.73 g, 35.32 mmol) was added in batches under ice bath, and the reaction The reaction was stirred at room temperature for 18 hours. The pyridine was spun off in vacuo, ethanolamine (70.5 mL, 1177.45 mmol) was added, and the reaction was stirred at room temperature for 24 hours. The reaction solution was poured into crushed ice, and the precipitated solid was filtered and dried under vacuum. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-3%) to give the target product 7-bromo-8-fluoroisoquinolin-1-amine (2.5 g, yield 44.0%) as an off-white solid. ES-API: [M+H] + = 241.0, 243.0.
步骤五：向50mL圆底烧瓶中加入7-溴-8-氟异喹啉-1-胺(1.0g,4.15mmol)，双(频哪醇合)二硼(1.58g,6.22mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.30g,0.42mmol)，乙酸钾(1.22g,12.45mmol)，1,4- 二氧六环(25mL)，氮气置换三次，反应在95℃反应18小时。将反应冷却至室温，加入二氯甲烷(30mL)溶解，用硅藻土过滤，乙酸乙酯洗涤，滤液浓缩得到淡棕色(1-氨基-8-氟异喹啉-7-基)硼酸(2.65g,粗品)，该粗品无需进一步纯化即可使用。ES-API:[M+H] +＝207.1。 Step 5: Add 7-bromo-8-fluoroisoquinolin-1-amine (1.0 g, 4.15 mmol), bis(pinacol)diboron (1.58 g, 6.22 mmol) to a 50 mL round-bottomed flask, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.30 g, 0.42 mmol), potassium acetate (1.22 g, 12.45 mmol), 1,4-dioxane (25 mL), The nitrogen was replaced three times, and the reaction was carried out at 95°C for 18 hours. The reaction was cooled to room temperature, dichloromethane (30 mL) was added to dissolve, filtered through celite, washed with ethyl acetate, and the filtrate was concentrated to give light brown (1-amino-8-fluoroisoquinolin-7-yl)boronic acid (2.65 g g, crude), which was used without further purification. ES-API: [M+H] + = 207.1.
步骤六：向100mL圆底烧瓶中加入7-氟-3-碘咪唑并[1,2-a]吡啶(1.0g,3.82mmol)，(1-氨基-8-氟异喹啉-7-基)硼酸(2.65g,粗品)，碳酸钾(1.58g,11.45mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.28g,0.38mmol)，1,4-二氧六环(40mL)和水(10mL)，氮气置换三次，反应在100℃反应4小时。反应液加入水(80mL)，析出的固体过滤，滤饼用水洗涤，在真空干燥。粗品用快速硅胶柱纯化(7.0M氨甲醇溶液/二氯甲烷：0-5％)得到目标产物8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(780mg,收率69.0％)，淡棕色固体。ES-API:[M+H] +＝297.1。 Step 6: Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (1.0 g, 3.82 mmol), (1-amino-8-fluoroisoquinolin-7-yl) to a 100 mL round-bottomed flask ) boric acid (2.65g, crude product), potassium carbonate (1.58g, 11.45mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (0.28g, 0.38mmol), 1,1'-bis(diphenylphosphino)ferrocene] 4-Dioxane (40 mL) and water (10 mL) were replaced with nitrogen three times, and the reaction was carried out at 100° C. for 4 hours. Water (80 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (7.0M ammonia methanol solution/dichloromethane: 0-5%) to give the target product 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl) Isoquinolin-1-amine (780 mg, yield 69.0%), pale brown solid. ES-API: [M+H] + =297.1.
步骤七：8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-胺(730mg,2.46mmol)溶于N,N-二甲基甲酰胺(20mL)，在冰浴下加入 N-碘代丁二酰亚胺(720mg,3.20mmol)，反应在室温下搅拌3小时。反应液加入水，析出的固体过滤，滤饼用水洗涤，在真空干燥得到目标产物8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(980mg,收率94.2％)，淡棕色固体。ES-API:[M+H] +＝423.0。 Step 7: 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (730mg, 2.46mmol) was dissolved in N,N-dimethyl Formamide (20 mL), N-iodosuccinimide (720 mg, 3.20 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 3 hours. Water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuum to obtain the target product 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodine Isoquinolin-1-amine (980 mg, yield 94.2%), light brown solid. ES-API: [M+H] + =423.0.
步骤八：8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘异喹啉-1-胺(980mg,2.32mmol)和 二碳酸二叔丁 酯(2.03g,9.28mmol)悬浮于二氯甲烷(25mL)，室温下加入三乙胺(1.17g,11.61mmol)和4-二甲氨基吡啶(28mg,0.23mmol)，反应在室温下搅拌18小时。反应液加入二氯甲烷(30mL)和水(15mL)，有机层分离，用饱和食盐水(25mL)洗涤，用无水硫酸钠干燥并过滤浓缩，得到粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到目标产物8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘-1-(双(叔丁基氧羰基)氨基)异喹啉(1.35g,收率93.4％)，灰白色固体。ES-API:[M+H] +＝623.1。 Step 8: 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (980 mg, 2.32 mmol) and di-tert-dicarbonate Butyl ester (2.03g, 9.28mmol) was suspended in dichloromethane (25mL), triethylamine (1.17g, 11.61mmol) and 4-dimethylaminopyridine (28mg, 0.23mmol) were added at room temperature, and the reaction was stirred at room temperature 18 hours. The reaction solution was added with dichloromethane (30 mL) and water (15 mL), the organic layer was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by flash silica gel column (ethyl acetate/ Petroleum ether: 0-60%) to obtain the target product 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxy) Carbonyl)amino)isoquinoline (1.35 g, 93.4% yield), off-white solid. ES-API: [M+H] + = 623.1.
步骤九：向50mL圆底烧瓶中加入8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-碘-1-(双(叔丁基氧羰基)氨基)异喹啉(150mg,0.24mmol)，双(频哪醇合)二硼(122mg,0.48mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(26mg,0.036mmol)，乙酸钾(71mg,0.72mmol)，N,N-二甲基甲酰胺(3mL)，氮气置换三次，反应在90℃反应2小时。反应液加入水(20mL)，用乙酸乙酯萃取(30mL×2)。合并有机层用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥并过滤浓缩得到8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(230mg,粗品)，无需进一步纯化即可使用。ES-API:[M-82+H] +＝541.2。 Step 9: Add 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl) to a 50 mL round bottom flask ) amino) isoquinoline (150 mg, 0.24 mmol), bis(pinacol)diboron (122 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.036 mmol), potassium acetate (71 mg, 0.72 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (230 mg, crude ) and was used without further purification. ES-API: [M-82+H] + =541.2.
步骤十：向5mL微波管里加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(80mg,0.20mmol)，8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(双(叔丁基氧羰基)氨基)异喹啉(230mg,粗品)，碳酸钾(85mg,0.61mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(15mg,0.02mmol)，1,4-二氧六环(2.5mL)和水(0.6mL)，用氮气吹1分钟，在微波反应器中110℃下反应45分钟。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤，浓缩。粗品用快速硅胶柱纯化(7M氨甲醇溶液/二氯甲烷:0-3％)得到目标产物(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(60mg,收率36.4％)，淡黄色固体。ES-API:[M+H] +＝807.3。 Step ten: add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (80mg) to a 5mL microwave tube , 0.20 mmol), 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (230 mg, crude), potassium carbonate (85 mg, 0.61 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, react in microwave The reaction was carried out at 110°C for 45 minutes in a vessel. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column (7M ammonia in methanol/dichloromethane: 0-3%) to give the target product (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-( Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinoline-1- (60 mg, yield 36.4%), pale yellow solid. ES-API: [M+H] + =807.3.
步骤十一：(4-(4-((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)异喹啉-1-基)亚氨基二碳酸二叔丁酯(60mg,0.07mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物8-氟-7-(7-氟咪唑并[1,2-a]吡啶-3-基)-4-(4-((甲胺基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z156,20mg,收率50.2％)，淡 黄色固体。 1H NMR(500MHz,DMSO-d 6)δ8.85(d,J＝9.0Hz,1H),8.53–8.45(m,1H),8.31(s,1H),7.94–7.88(m,1H),7.85(s,1H),7.60(dd,J＝10.0,2.5Hz,1H),7.35(s,2H),7.08–7.00(m,1H),3.94(dd,J＝11.0,3.5Hz,2H),3.81(s,2H),3.48(t,J＝11.0Hz,2H),3.38–3.35(m,1H),2.36(s,3H),1.93–1.83(m,2H),1.71–1.55(m,2H).ES-API:[M+H] +＝507.2。 Step eleven: (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8 - Di-tert-butyl fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (60 mg, 0.07 mmol) was dissolved in methanol ( 1 mL), 4.0 M hydrogen chloride dioxane solution (5 mL, 20.0 mmol) was added, and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 8-fluoro-7-(7-fluoroimidazo[1,2-a] Pyridin-3-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z156, 20 mg, yield 50.2%), pale yellow solid. 1 H NMR (500MHz, DMSO-d 6 )δ8.85(d,J=9.0Hz,1H),8.53-8.45(m,1H),8.31(s,1H),7.94-7.88(m,1H), 7.85(s, 1H), 7.60(dd, J=10.0, 2.5Hz, 1H), 7.35(s, 2H), 7.08–7.00(m, 1H), 3.94(dd, J=11.0, 3.5Hz, 2H) ,3.81(s,2H),3.48(t,J＝11.0Hz,2H),3.38-3.35(m,1H),2.36(s,3H),1.93-1.83(m,2H),1.71-1.55(m , 2H).ES-API: [M+H] + =507.2.
实施例37化合物Z185的合成Example 37 Synthesis of compound Z185
Figure PCTCN2022085658-appb-000127
Figure PCTCN2022085658-appb-000127
步骤一：向5mL微波管里加入：1-(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N，N-二甲基甲胺(60mg,0.20mmol)，3-(1,5-二甲基-1H-吡唑-4-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(110mg,粗品)，碳酸钾(82mg,0.59mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(14mg,0.02mmol)，1,4-二氧六环(2mL)和水(0.5mL)，用氮气吹1分钟，在微波反应器中110℃下反应1小时。反应液加入水(10mL)，乙酸乙酯(50mL)萃取。有机层用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品用薄层制备色谱板纯化(7M氨甲醇溶液/二氯甲烷＝15：1)得到目标产物3-(1,5-二甲基-1H-吡唑-4-基)-6-(4-(二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(45mg,收率39.8％)，淡黄色固体。ES-API:[M+H] +＝575.3。 Step 1: Into a 5mL microwave tube, add: 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N,N-dimethylmethanamine (60mg , 0.20 mmol), 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (110 mg, crude), potassium carbonate (82 mg, 0.59 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.02 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, placed in a microwave The reaction was carried out in the reactor at 110°C for 1 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by thin-layer preparative chromatography (7M ammonia methanol solution/dichloromethane=15:1) to obtain the target product 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4 -(Dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)- tert-Butyl carboxylate (45 mg, yield 39.8%), pale yellow solid. ES-API: [M+H] + =575.3.
步骤二：3-(1,5-二甲基-1H-吡唑-4-基)-6-(4-(二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)吡咯[4,3,2-ij]异喹啉-1(2H)-羧酸叔丁酯(45mg,0.08mmol)溶于甲醇(1mL)，加入4.0M氯化氢二氧六环溶液(5mL,20.0mmol)，反应在室温下反应18小时。反应液浓缩，加入7.0M氨甲醇溶液(5mL)，溶剂旋干，粗品用制备HPLC(甲酸)纯化得到目标产物1-(2-(3-(1,5-二甲基-1H-吡唑-4-基)-1,2-二氢吡咯[4,3,2-ij]异喹啉-6-基)-5-(四氢-2H-吡喃-4-基)噻唑-4-基)-N，N-二甲基甲胺(Z185,甲酸盐,28mg,收率69.0％)，淡黄色固体。ES-API:[M+H] +＝475.2。 1H NMR(500MHz,DMSO-d 6)δ8.68–8.46(m,2H),8.25–8.17(m,2H),7.80–7.66(m,2H),4.92(s,2H),3.96–3.91(m,2H),3.82(s,3H),3.62(s,2H),3.45(t,J＝11.0Hz,2H),3.36–3.32(m,1H),2.38(s,3H),2.27(s,6H),1.86(d,J＝12.0Hz,2H),1.66–1.57(m,2H). Step 2: 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(4-(dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4 -yl)thiazol-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (45 mg, 0.08 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride was added Dioxane solution (5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (formic acid) to obtain the target product 1-(2-(3-(1,5-dimethyl-1H-pyrazole) -4-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinolin-6-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-4- yl)-N,N-dimethylmethylamine (Z185, formate, 28 mg, yield 69.0%), pale yellow solid. ES-API: [M+H] + =475.2. 1 H NMR (500MHz, DMSO-d 6 )δ8.68-8.46(m,2H), 8.25-8.17(m,2H), 7.80-7.66(m,2H), 4.92(s,2H), 3.96-3.91 (m, 2H), 3.82(s, 3H), 3.62(s, 2H), 3.45(t, J=11.0Hz, 2H), 3.36–3.32(m, 1H), 2.38(s, 3H), 2.27( s, 6H), 1.86 (d, J=12.0Hz, 2H), 1.66–1.57 (m, 2H).
实施例38化合物Z186的合成Example 38 Synthesis of compound Z186
Figure PCTCN2022085658-appb-000128
Figure PCTCN2022085658-appb-000128
步骤一：将N,N-二异丙基乙胺(6.48mL,37.17mmol)和50％1-丙基磷酸酐的乙酸乙酯溶液(11.82g,18.57mmol)依次加入到3-溴-6-氯-2-吡啶甲酸(2.93g,12.39mmol)，叔丁胺(1.56g,14.87mmol)的二氯甲烷(30mL)溶液中，室温搅拌1小时。反应结束后，加入饱和碳酸钠溶液(50mL)淬灭，并用二氯甲烷(30mLX3)萃取。有机相合并，无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(1-50％乙酸乙酯/石油醚)纯化，得到白色固体3-溴-N-(叔丁基)-6-氯吡啶酰胺(2.5g,收率69％)。ES-API:[M+H] +＝291.1,293.0. Step 1: N,N-diisopropylethylamine (6.48mL, 37.17mmol) and 50% ethyl acetate solution of 1-propylphosphoric anhydride (11.82g, 18.57mmol) were added to 3-bromo-6 -Chloro-2-picolinic acid (2.93 g, 12.39 mmol), tert-butylamine (1.56 g, 14.87 mmol) in dichloromethane (30 mL) solution, stirred at room temperature for 1 hour. After the reaction, it was quenched by adding saturated sodium carbonate solution (50 mL), and extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica gel column (1-50% ethyl acetate/petroleum ether) to give 3-bromo-N-(tert-butyl)-6-chloropicolinamide as a white solid (2.5 g, 69% yield). ES-API: [M+H] + = 291.1, 293.0.
步骤二：氮气保护下，3-溴-N-(叔丁基)-6-氯吡啶酰胺(2.1g,7.02mmol)，(E)-1-乙氧乙烯基-2-硼酸频那醇酯(1.85g,9.36mmol)，三(二亚苄基丙酮)二钯(0.33g,0.36mmol)，2-双环己基膦-2',6'-二甲氧基联苯(0.30g,0.72mmol)和碳酸钾(2.99g,21.61mmol)的1,4-二氧六环(30mL)和水(7mL)的混合物在80℃搅拌1小时。反应液倒入乙酸乙酯(100mL)，并用饱和食盐水(30mL)和水(30mL)依次洗涤。有机相用无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(0-30％乙酸乙酯/石油醚)纯化，得到白色固体(E)-N-(叔丁基)-6-氯-3-(2-乙氧基乙烯基)吡啶酰胺(800mg,收率39％)。ES-API:[M+H] +＝283.2. Step 2: Under nitrogen protection, 3-bromo-N-(tert-butyl)-6-chloropyridine amide (2.1 g, 7.02 mmol), (E)-1-ethoxyethylene-2-boronic acid pinacol ester (1.85g, 9.36mmol), tris(dibenzylideneacetone)dipalladium (0.33g, 0.36mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (0.30g, 0.72mmol) ) and potassium carbonate (2.99 g, 21.61 mmol) in 1,4-dioxane (30 mL) and water (7 mL) were stirred at 80°C for 1 hour. The reaction solution was poured into ethyl acetate (100 mL), and washed successively with saturated brine (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica column (0-30% ethyl acetate/petroleum ether) to give (E)-N-(tert-butyl)-6-chloro-3- as a white solid (2-Ethoxyvinyl)pyridineamide (800 mg, 39% yield). ES-API: [M+H] + = 283.2.
步骤三：冰浴条件下，将(E)-N-(叔丁基)-6-氯-3-(2-乙氧基乙烯基)吡啶酰胺(700mg,2.48mmol)加入到浓硫酸(2mL)中，升温至110℃搅拌2小时。冷却至室温，并缓慢倒入到氢氧化钾(4.23g,75.27mmol)的冰水中。浓缩得到黄色固体2-氯-1,7-萘啶-8(7H)-酮(450mg,粗品)，含硫酸钾。ES-API:[M+H] +＝181.1. Step 3: Add (E)-N-(tert-butyl)-6-chloro-3-(2-ethoxyvinyl)pyridineamide (700 mg, 2.48 mmol) to concentrated sulfuric acid (2 mL) under ice bath conditions. ), the temperature was raised to 110°C and stirred for 2 hours. Cool to room temperature and pour slowly into potassium hydroxide (4.23 g, 75.27 mmol) in ice water. Concentration gave 2-chloro-1,7-naphthyridin-8(7H)-one (450 mg, crude) as a yellow solid containing potassium sulfate. ES-API: [M+H] + = 181.1.
步骤四：氮气保护下，2-氯-1,7-萘啶-8(7H)-酮(450mg,2.49mmol)，1,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(1.11g,4.98mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(26mg,0.04mmol)和碳酸钾(344mg,2.49mmol)的1,4-二氧六环(10mL) 和水(2mL)的混合物在100℃搅拌2小时。反应结束后，反应液浓缩得到2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8(7H)-酮(600mg,粗品)，粗品不经纯化直接用于下一步反应。ES-API:[M+H] +＝241.1. Step 4: Under nitrogen protection, 2-chloro-1,7-naphthyridin-8(7H)-one (450mg, 2.49mmol), 1,5-dimethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.11 g, 4.98 mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.04 mmol) and potassium carbonate (344 mg, 2.49 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100°C for 2 hours. After the reaction, the reaction solution was concentrated to obtain 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridin-8(7H)-one (600mg, crude product), the crude product was not It was used directly in the next reaction after purification. ES-API: [M+H] + = 241.1.
步骤五：冰浴条件下，将氧氯化磷(5mL)加入到粗品2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8(7H)-酮(300mg,1.25mmol)，升温至100℃，搅拌2小时。反应液冷却至室温，减压浓缩。残留物溶于二氯甲烷(30mL)，并用碳酸氢钠溶液调pH至8，分液有机相无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(0-70％乙酸乙酯/石油醚)纯化得到黄色油状物8-氯-2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶(150mg,3步收率46％)。ES-API:[M+H] +＝259.1. Step 5: Add phosphorus oxychloride (5 mL) to crude 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine-8(7H) under ice bath condition )-one (300 mg, 1.25 mmol), the temperature was raised to 100° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and adjusted to pH 8 with sodium bicarbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by filtration and purified with flash silica column (0-70% ethyl acetate/petroleum ether) 8-Chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine (150 mg, 46% over 3 steps) was obtained as a yellow oil. ES-API: [M+H] + = 259.1.
步骤六：将氨水(8mL,122mmol)加入到化合物8-氯-2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶(150mg,0.58mmol)的环丁砜(4mL)溶液中，微波150℃反应10小时。反应结束后，反应液倒入乙酸乙酯(50mL)，依次用饱和食盐水(20mLX3)洗涤，水(20mL)洗涤。有机相用无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(0-10％甲醇/二氯甲烷)纯化，得到2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8-胺(100mg,收率72％)。ES-API:[M+H] +＝240.2. Step 6: Ammonia (8 mL, 122 mmol) was added to compound 8-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine (150 mg, 0.58 mmol) sulfolane (4 mL) solution, microwave reaction at 150 ℃ for 10 hours. After the reaction, the reaction solution was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL×3) and washed with water (20 mL) successively. The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica column (0-10% methanol/dichloromethane) to give 2-(1,5-dimethyl-1H-pyrazol-4-yl)- 1,7-Naphthyridin-8-amine (100 mg, 72% yield). ES-API: [M+H] + = 240.2.
步骤七：将N-碘代丁二酰亚胺(226mg,1mmol)加入2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8-胺(200mg,0.84mmol)的乙腈(4mL)和N,N-二甲基甲酰胺(0.4mL)的混合溶液，室温搅拌2小时。反应结束后，用硫代硫酸钠(20mL)溶液淬灭反应，乙酸乙酯(20mLX3)萃取。有机相合并，用饱和食盐水(30mLX1)洗涤，无水硫酸钠干燥，过滤浓缩并用快速硅胶柱(0-10％甲醇/二氯甲烷)纯化，得到黄色固体2-(1,5-二甲基-1H-吡唑-4-基)-5-碘-1,7-萘啶-8-胺(270mg,收率88％)。ES-API:[M+H] +＝366.0. Step 7: Add N-iodosuccinimide (226 mg, 1 mmol) to 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridin-8-amine (200 mg, 0.84 mmol) of a mixed solution of acetonitrile (4 mL) and N,N-dimethylformamide (0.4 mL), and stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium thiosulfate (20 mL) solution, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered and concentrated, and purified with flash silica gel column (0-10% methanol/dichloromethane) to obtain 2-(1,5-dimethylene) as a yellow solid (270 mg, 88% yield). ES-API: [M+H] + = 366.0.
步骤八：2-(1,5-二甲基-1H-吡唑-4-基)-5-碘-1,7-萘啶-8-胺(270mg,0.74mmol)，二碳酸二叔丁酯(645mg,2.96mmol)，三乙胺(0.514mL,3.70mmol)和4-二甲氨基吡啶(9mg,0.07mmol)的二氯甲烷(10mL)溶液，室温搅拌过夜。反应液浓缩后用快速硅胶柱(0-80％乙酸乙酯/石油醚)纯化，得到白色固体2-甲基丙-2-基((2-(1,5-二甲基吡唑-4-基)-5-碘吡啶并[3,4-b]吡啶-8-基)(((2-甲基丙-2-基)氧基)羰基)氨基)甲酸酯(170mg,收率41％)。ES-API:[M+H] +＝566.2. Step 8: 2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-iodo-1,7-naphthyridin-8-amine (270mg, 0.74mmol), di-tert-butyl dicarbonate A solution of ester (645 mg, 2.96 mmol), triethylamine (0.514 mL, 3.70 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by flash silica gel column (0-80% ethyl acetate/petroleum ether) to obtain 2-methylpropan-2-yl((2-(1,5-dimethylpyrazole-4) as a white solid -yl)-5-iodopyrido[3,4-b]pyridin-8-yl)(((2-methylprop-2-yl)oxy)carbonyl)amino)carboxylate (170 mg, yield 41%). ES-API: [M+H] + = 566.2.
步骤九：氮气保护下，2-甲基丙-2-基((2-(1,5-二甲基吡唑-4-基)-5-碘吡啶并[3,4-b]吡啶-8-基)(((2-甲基丙-2-基)氧基)羰基)氨基)甲酸酯(80mg,0.14mmol)，双联频哪醇棚酸酯(72mg,0.28mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(10mg,0.01mmol)和醋酸钾(28mg,0.28mmol)的N,N-二甲基甲酰胺(2mL)的混合物在100℃搅拌2小时。反应结束后，反应液直接用于下一步反应。ES-API:[M+H +-2Boc]＝366.2。 Step 9: Under nitrogen protection, 2-methylprop-2-yl((2-(1,5-dimethylpyrazol-4-yl)-5-iodopyrido[3,4-b]pyridine- 8-yl)(((2-methylprop-2-yl)oxy)carbonyl)amino)carboxylate (80 mg, 0.14 mmol), bispinacol borate (72 mg, 0.28 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (10 mg, 0.01 mmol) and potassium acetate (28 mg, 0.28 mmol) in N,N-dimethylformamide (2 mL) The mixture was stirred at 100°C for 2 hours. After the reaction, the reaction solution was directly used for the next reaction. ES-API: [M+H + -2Boc]=366.2.
步骤十：氮气保护下，往上述反应液中加入(2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)(甲基)氨基甲酸叔丁酯(111mg,0.28mmol)，碳酸钾(59mg,0.42mmol)和水(0.4mL)，100℃搅拌2小时。反应结束后，反应液溶于乙酸乙酯(20mL)，并用饱和食盐水(10mL)和水(10mL)洗。有机相用无水硫酸钠干燥，过滤浓缩并用快速硅胶柱纯化，得到(叔丁氧基羰基)(5-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8-基)氨基甲酸叔丁酯(60mg,收率57％)。ES-API:[M+H +-2Boc]＝750.3。 Step 10: Under nitrogen protection, add (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)(methyl)carbamic acid tert-butyl ester (111mg) to the above reaction solution , 0.28 mmol), potassium carbonate (59 mg, 0.42 mmol) and water (0.4 mL), stirred at 100 °C for 2 hours. After completion of the reaction, the reaction solution was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica column to give (tert-butoxycarbonyl)(5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)- 5-(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine- 8-yl) tert-butyl carbamate (60 mg, 57% yield). ES-API: [M+H + -2Boc]=750.3.
步骤十一：冰浴条件下，将三氟乙酸(0.5mL)滴加到(叔丁氧基羰基)(5-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-2-(1,5-二甲基-1H-吡唑-4-基)-1,7-萘啶-8-基)氨基甲酸叔丁酯(60mg,80μmol)的二氯甲烷(1mL)溶液中，室温搅拌1小时。反应液浓缩，用7M胺甲醇(5mL)中和，随后浓缩并用制备HPLC(甲酸)纯化，得到白色固体2-(1,5-二甲基-1H-吡唑-4-基)-5-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-1,7-萘啶-8-胺(Z186,甲酸盐,31mg，纯度100％，收率78％)。ES-API:[M+H] +＝450.3。 1H NMR(400MHz,DMSO-d 6)δ9.37(d,J＝8.8Hz,1H),8.31(s,1H),8.29(s,1H),8.17(s,1H),8.02(d,J＝8.8Hz,1H),7.32(s,2H),4.14(s,2H),3.95(dd,J＝11.2,3.6Hz,2H),3.84(s, 3H),3.48(t,J＝11.2Hz,2H),3.43–3.32(m,1H),2.71(s,3H),2.58(s,3H),1.95–1.83(m,2H),1.70–1.55(m,2H). Step 11: Under ice bath conditions, add trifluoroacetic acid (0.5 mL) dropwise to (tert-butoxycarbonyl)(5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl )-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthalene A solution of tert-butyl pyridin-8-yl)carbamate (60 mg, 80 μmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The reaction was concentrated, neutralized with 7M amine methanol (5 mL), then concentrated and purified by preparative HPLC (formic acid) to give 2-(1,5-dimethyl-1H-pyrazol-4-yl)-5- as a white solid (4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-1,7-naphthyridin-8-amine (Z186, formic acid salt, 31 mg, 100% purity, 78% yield). ES-API: [M+H] + =450.3. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.37(d, J=8.8Hz, 1H), 8.31(s, 1H), 8.29(s, 1H), 8.17(s, 1H), 8.02(d, J=8.8Hz, 1H), 7.32(s, 2H), 4.14(s, 2H), 3.95(dd, J=11.2, 3.6Hz, 2H), 3.84(s, 3H), 3.48(t, J=11.2 Hz, 2H), 3.43–3.32 (m, 1H), 2.71 (s, 3H), 2.58 (s, 3H), 1.95–1.83 (m, 2H), 1.70–1.55 (m, 2H).
实施例39化合物Z187的合成Example 39 Synthesis of compound Z187
Figure PCTCN2022085658-appb-000129
Figure PCTCN2022085658-appb-000129
步骤一：向25mL三口圆底烧瓶中加入7-溴-8-氟代喹啉-1-胺(300mg,1.24mmol)，4-甲氧基-3-(4,4,4,5,5-四甲基-1,3,2-二氧化硼酚-2-基)吡啶(586mg,2.49mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(91mg,0.12mmol)，碳酸钾(516mg,3.73mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护100℃条件下反应2小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-胺(580mg,粗品)。ES-API:[M+H] +＝270.1。 Step 1: Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 4-methoxy-3-(4,4,4,5,5 to a 25mL three-necked round bottom flask) -Tetramethyl-1,3,2-boron-2-yl)pyridine (586mg, 2.49mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product 8 -Fluoro-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (580 mg, crude). ES-API: [M+H] + =270.1.
步骤二：向25mL单口圆底烧瓶中加入8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-胺(260mg粗品)、N-碘代丁二酰亚胺(651mg,2.89mmol)和二甲基甲酰胺(10mL)，100℃条件下反应1小时。反应液加水过滤，固体旋干得到目标产物8-氟-4-碘-7-(4-甲氧基吡啶-3-基)异喹啉-1-胺(880mg,2步收率：53％)。ES-API:[M+H] +＝396.0. Step 2: Add 8-fluoro-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (260mg crude product), N-iodosuccinimide to a 25mL single-neck round bottom flask (651 mg, 2.89 mmol) and dimethylformamide (10 mL), reacted at 100° C. for 1 hour. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (880 mg, 2-step yield: 53%) ). ES-API: [M+H] + = 396.0.
步骤三：向25mL三口圆底烧瓶中加入8-氟-4-碘-7-(4-甲氧基吡啶-3-基)异喹啉-1-胺(200mg 0.5mmol)，二碳酸二叔丁酯(441mg,2.02mmol)，三乙胺(256mg,2.53mmol)，4-二甲氨基吡啶(6.1mg,0.05mmol)，二氯甲烷(10mL)。体系用氮气置换三次，然后用氮气球保护室温条件下反应过夜。反应液加入二氯甲烷(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[8-氟-4-碘-7-(4-甲氧基吡啶-3-基)异喹啉-1-基]{[叔丁氧羰基}氨基}甲酸叔丁酯(170mg,收率:56％)。ES-API:[M+H] +＝596.1。 Step 3: Add 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (200mg 0.5mmol), di-tertiary dicarbonate to a 25mL three-necked round-bottomed flask Butyl ester (441 mg, 2.02 mmol), triethylamine (256 mg, 2.53 mmol), 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and then reacted overnight at room temperature under nitrogen balloon protection. The reaction solution was added with dichloromethane (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product { [8-Fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-yl]{[tert-butoxycarbonyl}amino}carboxylate tert-butyl ester (170 mg, yield: 56%). ES-API: [M+H] + =596.1.
步骤四：向25mL三口圆底烧瓶中加入{[8-氟-4-碘-7-(4-甲氧基吡啶-3-基)异喹啉-1-基]{[叔丁氧羰基}氨基}甲酸叔丁酯(130mg,0.21mmol)，联硼酸频那醇酯(110mg,0.43mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(24mg,0.03mmol)，乙酸钾(64mg,0.65mmol)，二氧六环(10mL)。体系用氮气置换三次，然后用氮气球保护90℃条件下反应3小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2基)-8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-基]{[(2-甲基吡啶-2-基)氧基]羰基}氨基}甲酸叔丁酯(90mg,收率:80％)。ES-API:[M+H] +＝596.3。 Step 4: Add {[8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-yl]{[tert-butoxycarbonyl} to a 25mL three-necked round-bottomed flask tert-Butyl amino}carboxylate (130 mg, 0.21 mmol), pinacol diboronate (110 mg, 0.43 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (24 mg, 0.03 mmol) , potassium acetate (64 mg, 0.65 mmol), dioxane (10 mL). The system was replaced with nitrogen three times, and then reacted for 3 hours at 90°C under nitrogen balloon protection. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product { [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2yl)-8-fluoro-7-(4-methoxypyridine-3- yl)isoquinolin-1-yl]{[(2-methylpyridin-2-yl)oxy]carbonyl}amino}carboxylic acid tert-butyl ester (90 mg, yield: 80%). ES-API: [M+H] + =596.3.
步骤五：向25mL三口圆底烧瓶中加入{[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2基)-8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-基]{[(2-甲基吡啶-2-基)氧基]羰基}氨基}甲酸叔丁酯(66mg,0.128mmol)，((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(50mg,0.128mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(9.4mg,0.01mmol)，碳酸钾(53mg,0.38mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护100℃条件下反应2小时。反应液加入乙酸乙酯(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-基)羧酸叔丁酯(90mg,收率90％)。ES-API:[M+H] +＝780.3。 Step 5: Add {[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl)-8-fluoro- tert-Butyl 7-(4-methoxypyridin-3-yl)isoquinolin-1-yl]{[(2-methylpyridin-2-yl)oxy]carbonyl}amino}carboxylate (66 mg, 0.128 g mmol), ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (50 mg, 0.128 mmol), 1 , 1-bis(diphenylphosphino)ferrocene palladium dichloride (9.4 mg, 0.01 mmol), potassium carbonate (53 mg, 0.38 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C. The reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product ( tert-Butoxycarbonyl)(4-(4-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2- (90 mg, 90% yield). ES-API: [M+H] + =780.3.
步骤六：向5mL单口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(4-甲氧基吡啶-3-基)异喹啉-1-基)羧酸叔丁酯(90mg,0.12mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)，室温搅拌反应30分钟。反应液旋干，粗品用制备HPLC(碳酸氢铵)纯化得到：8-氟-7-(4-甲氧基吡啶-3-基)-4-(4((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z187,20mg,收率：36％)。ES-API:[M+H] +＝480.2。 1H NMR(500MHz,DMSO-d 6)δ8.83(d,J＝8.8Hz,1H),8.72(s,1H),8.30(d,J＝9.1Hz,2H),7.97(d,J＝7.9Hz,1H),7.87(t,J＝8.3Hz,1H),7.44(d,J＝8.1Hz,2H),4.07(s,2H),3.95(d,J＝7.5Hz,2H),3.43-3.30(m,4H),2.54(d,J＝15.6Hz,6H),1.89(d,J＝13.3Hz,2H),1.69–1.57(m,2H). Step 6: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(4-methoxypyridin-3-yl)isoquinolin-1-yl)carboxylate tert-butyl ester (90 mg, 0.12 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain: 8-fluoro-7-(4-methoxypyridin-3-yl)-4-(4((methylamino)methyl)- 5-(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinolin-1-amine (Z187, 20 mg, yield: 36%). ES-API: [M+H] + =480.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.83 (d, J=8.8 Hz, 1H), 8.72 (s, 1H), 8.30 (d, J=9.1 Hz, 2H), 7.97 (d, J= 7.9Hz, 1H), 7.87(t, J=8.3Hz, 1H), 7.44(d, J=8.1Hz, 2H), 4.07(s, 2H), 3.95(d, J=7.5Hz, 2H), 3.43 -3.30(m, 4H), 2.54(d, J=15.6Hz, 6H), 1.89(d, J=13.3Hz, 2H), 1.69–1.57(m, 2H).
实施例40化合物Z188的合成Example 40 Synthesis of compound Z188
Figure PCTCN2022085658-appb-000130
Figure PCTCN2022085658-appb-000130
步骤一：向25mL三口圆底烧瓶中加入7-溴-8-氟代喹啉-1-胺(300mg,1.24mmol)，2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶818mg,3.73mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(91mg,0.12mmol)，碳酸钾(516mg,3.73mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，然后用氮气球保护100℃条件下反应2小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-胺(220mg,收率:70％)。ES-API:[M+H] +＝254.1。 Step 1: Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 2-methyl-5-(4,4,5,5-tetramethyl) into a 25mL three-necked round bottom flask base-1,3,2-dioxaborol-2-yl)pyridine 818mg, 3.73mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12mmol) ), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product 8 -Fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-amine (220 mg, yield: 70%). ES-API: [M+H] + =254.1.
步骤二：向25mL单口圆底烧瓶中加入8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-胺(170mg,0.67mmol)、 N-碘代丁二酰亚胺(196mg 0.87mmol)和二甲基甲酰胺(10mL)，氮气保护100℃条件下反应1小时。反应液加水过滤，固体旋干得到目标产物8-氟-4-碘-7-(6-甲基吡啶-3-基)异喹啉-1-胺(170mg,收率:67％)。ES-API:[M+H] +＝380.0. Step 2: Add 8-fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-amine (170mg, 0.67mmol), N-iodosuccinimide to a 25mL single-neck round bottom flask Amine (196 mg 0.87 mmol) and dimethylformamide (10 mL) were reacted under nitrogen protection at 100°C for 1 hour. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 8-fluoro-4-iodo-7-(6-methylpyridin-3-yl)isoquinolin-1-amine (170 mg, yield: 67%). ES-API: [M+H] + = 380.0.
步骤三：向25mL三口圆底烧瓶中加入4-碘-7-(吡啶-4-基)异喹啉-1-胺(170mg 0.45mmol)，二碳酸二叔丁酯(391mg,1.79mmol)，三乙胺(227mg,2.24mmol)，4-二甲氨基吡啶(5.5mg,0.04mmol)，二氯甲烷(10mL)。体系用氮气置换三次，氮气球保护室温条件下反应过夜。反应液加入二氯甲烷(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[8-氟-4-碘-7-(6-甲基吡啶-3-基)异喹啉-1-基]{[叔丁氧羰基}氨基}甲酸叔丁酯(230mg,收率:88.5％)。ES-API:[M+H] +＝580.1。 Step 3: add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (170mg 0.45mmol), di-tert-butyl dicarbonate (391mg, 1.79mmol) to a 25mL three-necked round bottom flask, Triethylamine (227 mg, 2.24 mmol), 4-dimethylaminopyridine (5.5 mg, 0.04 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and the reaction was carried out overnight under nitrogen balloon protection at room temperature. The reaction solution was added with dichloromethane (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product { [8-Fluoro-4-iodo-7-(6-methylpyridin-3-yl)isoquinolin-1-yl]{[tert-butoxycarbonyl}amino}carboxylate tert-butyl ester (230 mg, yield: 88.5 %). ES-API: [M+H] + =580.1.
步骤四：向25mL三口圆底烧瓶中加入{[8-氟-4-碘-7-(6-甲基吡啶-3-基)异喹啉-1-基]{[叔丁氧羰基}氨基}甲酸叔丁酯(230mg,0.397mmol)，联硼酸频那醇酯(201.6mg,0.794mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(43.57mg,0.06mmol)，乙酸钾(116.9mg,1.19mmol)，二氧六环(10mL)。体系用氮气置换三次，氮气球保护90℃条件下反应3小时。反应液加入乙酸乙酯(100mL)，用饱和食盐水(50mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物{[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-基]{[(2-甲基吡啶-2-基)氧基]羰基}氨基}甲酸叔丁酯(300mg,粗品)。ES-API:[M+H] +＝580.3。 Step 4: Add {[8-fluoro-4-iodo-7-(6-methylpyridin-3-yl)isoquinolin-1-yl]{[tert-butoxycarbonyl}amino to a 25mL three-necked round-bottomed flask } tert-butyl formate (230 mg, 0.397 mmol), pinacol diboronate (201.6 mg, 0.794 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (43.57 mg, 0.06 mmol) ), potassium acetate (116.9 mg, 1.19 mmol), dioxane (10 mL). The system was replaced with nitrogen three times, and the reaction was carried out under nitrogen balloon protection at 90°C for 3 hours. The reaction solution was added with ethyl acetate (100 mL), washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate: petroleum ether=40:100) to obtain the target product { [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-8-fluoro-7-(6-methylpyridine-3- yl)isoquinolin-1-yl]{[(2-methylpyridin-2-yl)oxy]carbonyl}amino}carboxylate tert-butyl ester (300 mg, crude). ES-API: [M+H] + =580.3.
步骤五：向25mL三口圆底烧瓶中加入{[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-基]{[(2-甲基吡啶-2-基)氧基]羰基}氨基}甲酸叔丁酯(300mg,粗品)，((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(50mg,0.153mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(9.4mg,0.01mmol)，碳酸钾(53mg,0.38mmol)，二氧六环(10mL)和水(1mL)。体系用氮气置换三次，氮气球保护100℃条件下反应2小时，反应液加入乙酸乙酯(30mL)，用饱和食盐水(30mLX3)洗涤，无水硫酸钠干燥，过滤浓缩，粗品用快速硅胶柱纯化(乙酸乙酯：石油醚＝40:100)得到目标产物(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-基)羧酸叔丁基酯(90mg,2步收率30％)。ES-API:[M+H] +＝764.3。 Step 5: Add {[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-8-fluoro into a 25mL three-necked round bottom flask -7-(6-Methylpyridin-3-yl)isoquinolin-1-yl]{[(2-methylpyridin-2-yl)oxy]carbonyl}amino}carboxylic acid tert-butyl ester (300 mg, crude ), ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (50 mg, 0.153 mmol), 1, 1-Bis(diphenylphosphino)ferrocene palladium dichloride (9.4 mg, 0.01 mmol), potassium carbonate (53 mg, 0.38 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and the reaction was carried out under nitrogen balloon protection at 100°C for 2 hours. The reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was used in a flash silica column. Purification (ethyl acetate:petroleum ether=40:100) gave the target product (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-yl)carboxylate tert-butyl Ester (90 mg, 30% yield over 2 steps). ES-API: [M+H] + =764.3.
步骤六：向5mL单口圆底烧瓶中加入(叔丁氧基羰基)(4-(4-(((叔丁氧基羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟-7-(6-甲基吡啶-3-基)异喹啉-1-基)羧酸叔丁基酯(90mg,0.12mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)，室温搅拌反应30分钟。反应液旋干，粗品用制备HPLC(碳酸氢铵)纯化，得到8-氟-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(6-甲基吡啶-3-基)异喹啉-1-胺(Z188,20mg,收率：36％)。ES-API:[M+H] +＝464.2。 1H NMR(500MHz,DMSO-d 6)δ8.83(d,J＝8.8Hz,1H),8.72(s,1H),8.30(d,J＝9.1Hz,2H),7.97(d,J＝7.9Hz,1H),7.87(t,J＝8.3Hz,1H),7.44(d,J＝8.1Hz,2H),4.07(s,2H),3.95(d,J＝7.5Hz,2H),3.53–3.37(m,4H),2.55(s,3H),2.52(s,3H),1.89(d,J＝13.3Hz,2H),1.70–1.54(m,2H). Step 6: Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-yl)carboxylate tert-butyl ester (90 mg, 0.12 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to give 8-fluoro-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl) )thiazol-2-yl)-7-(6-methylpyridin-3-yl)isoquinolin-1-amine (Z188, 20 mg, yield: 36%). ES-API: [M+H] + =464.2. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.83 (d, J=8.8 Hz, 1H), 8.72 (s, 1H), 8.30 (d, J=9.1 Hz, 2H), 7.97 (d, J= 7.9Hz, 1H), 7.87(t, J=8.3Hz, 1H), 7.44(d, J=8.1Hz, 2H), 4.07(s, 2H), 3.95(d, J=7.5Hz, 2H), 3.53 –3.37(m, 4H), 2.55(s, 3H), 2.52(s, 3H), 1.89(d, J=13.3Hz, 2H), 1.70–1.54(m, 2H).
实施例41化合物Z189的合成Example 41 Synthesis of compound Z189
Figure PCTCN2022085658-appb-000131
Figure PCTCN2022085658-appb-000131
步骤一：在氮气保护下，7-溴-8-氟异喹啉-1-胺(400mg,1.66mmol)溶于干燥二氧六环(4.0mL)，在室温下加入双联硼酸频那醇酯(632mg,2.49mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(122mg,0.17mmol)和醋酸钾(488mg,4.98mmol)，100℃搅拌反应5小时。反应液浓缩，得到粗品(1-氨基-8-氟异喹啉-7-基)硼酸(340mg)。ES-API:[M+H] +＝207.2。 Step 1: Under nitrogen protection, 7-bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dry dioxane (4.0 mL), and bis-boronic acid pinacol was added at room temperature Ester (632 mg, 2.49 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122 mg, 0.17 mmol) and potassium acetate (488 mg, 4.98 mmol), stirred at 100 °C for reaction 5 Hour. The reaction solution was concentrated to obtain crude (1-amino-8-fluoroisoquinolin-7-yl)boronic acid (340 mg). ES-API: [M+H] + = 207.2.
步骤二：(1-氨基-8-氟异喹啉-7-基)硼酸(340mg,1.65mmol)溶于二氧六环(2.0mL)和水(0.5mL)，在室温下加入4-溴-1-乙基-5-甲基-1H-吡唑(300mg,1.59mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(121mg,0.17mmol)，碳酸钾(684mg,4.95mmol)，在氮气保护下油浴100℃搅拌反应5小时。反应液加入乙酸乙酯(10mL)，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-4％)得到产物7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(200mg,收率：45％)。ES-API:[M+H] +＝271.1。 Step 2: (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (340 mg, 1.65 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 4-bromo was added at room temperature -1-ethyl-5-methyl-1H-pyrazole (300 mg, 1.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (121 mg, 0.17 mmol), Potassium carbonate (684 mg, 4.95 mmol) was stirred in an oil bath at 100° C. for 5 hours under nitrogen protection. The reaction solution was added with ethyl acetate (10 mL), followed by water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=1%-4 %) to obtain the product 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (200 mg, yield: 45%). ES-API: [M+H] + = 271.1.
步骤三：7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(180mg,0.67mmol)溶于乙腈(5mL)，加入N-碘代丁二酰亚胺(180mg,0.80mmol)，反应在室温下反应2小时。加入水(10mL)，用二氯甲烷/甲醇混合溶液萃取(10：1,30mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(180mg,收率：68％)，白色固体。ES-API:[M+H] +＝397.0. Step 3: 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (180 mg, 0.67 mmol) was dissolved in acetonitrile (5 mL), added N-Iodosuccinimide (180 mg, 0.80 mmol) and the reaction was allowed to react at room temperature for 2 hours. Water (10 mL) was added, extracted with a mixed solution of dichloromethane/methanol (10:1, 30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane: methanol=1%- 3%) to obtain the product 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (180 mg, yield: 68% ), white solid. ES-API: [M+H] + = 397.0.
步骤四：7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(200mg,0.51mmol)溶于二氯甲烷 (2.0mL)，加入二叔丁基二碳酸酯(441mg,2.02mmol)，三乙胺(0.44mL,2.52mmol)和4-二甲氨基吡啶(6mg,0.05mmol)，反应在室温下反应过夜。向反应液中加入水(10mL)，用乙酸乙酯萃取(30mL×2)，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝1％-3％)得到产物(7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-碘-异喹啉-1-基)氨基二甲酸叔丁酯(180mg,收率：60％)，白色固体。ES-API:[M+H] +＝597.1。 Step four: 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (200 mg, 0.51 mmol) was dissolved in dichloro Methane (2.0 mL), di-tert-butyl dicarbonate (441 mg, 2.02 mmol), triethylamine (0.44 mL, 2.52 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, and the reaction was allowed to react at room temperature overnight. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=1%-3%) to obtain Product (tert-butyl 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamate (180 mg, Yield: 60%), white solid. ES-API: [M+H] + =597.1.
步骤五：(7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-碘-异喹啉-1-基)氨基二甲酸叔丁酯(120mg,0.20mmol)溶于N,N-二甲基甲酰胺(2.0mL)，在室温下加入双联硼酸频那醇酯(77mg,0.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(15mg,0.02mmol)，醋酸钾(59mg,0.60mmol)，置换氮气，氮气保护100℃搅拌反应2小时。反应液浓缩得到(7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)氨基二甲酸叔丁酯(120mg,粗品)。ES-API:[M+H] +＝597.3. Step 5: tert-butyl (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamate ( 120mg, 0.20mmol) was dissolved in N,N-dimethylformamide (2.0mL), at room temperature was added pinacol bis-boronate (77mg, 0.30mmol), [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (15 mg, 0.02 mmol), potassium acetate (59 mg, 0.60 mmol), nitrogen was replaced, and the reaction was stirred at 100° C. for 2 hours under nitrogen protection. The reaction solution was concentrated to obtain (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3 , tert-butyl 2-dioxaborol-2-yl))isoquinolin-1-yl)carbamate (120 mg, crude). ES-API: [M+H] + = 597.3.
步骤六：(7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基))异喹啉-1-基)氨基二甲酸叔丁酯(115mg,0.19mmol)溶于N,N-二甲基甲酰胺(2.0mL)和水(0.5mL)，在室温下加入((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(151mg,0.39mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(14mg,0.02mmol)，碳酸钾(80mg,0.58mmol)，氮气保护下100℃搅拌反应2小时。反应液加入乙酸乙酯(10mL)，依次加水(10mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩并通过硅胶柱层析纯化(二氯甲烷：甲醇＝3％-7％)得到产物((2-(1-氨基-7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-异喹啉-4-基)-5-(四氢-2H-吡喃-4-)基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(60mg,收率：40％)。ES-API:[M+H] +＝781.3。 Step six: (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl))isoquinolin-1-yl)carbamic acid tert-butyl ester (115 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) and water (0.5 mL), and tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate was added at room temperature (151 mg, 0.39 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl) -2-yl)palladium(II) (14 mg, 0.02 mmol), potassium carbonate (80 mg, 0.58 mmol), and the reaction was stirred at 100° C. for 2 hours under nitrogen protection. Ethyl acetate (10 mL) was added to the reaction solution, followed by water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=3%-7 %) to give the product ((2-(1-amino-7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-isoquinolin-4-yl)-5 -(Tetrahydro-2H-pyran-4-)yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (60 mg, yield: 40%). ES-API: [M+H] + =781.3.
步骤七：((2-(1-氨基-7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-异喹啉-4-基)-5-(四氢-2H-吡喃-4-)基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(60mg,0.08mmol)溶于二氯甲烷(2.0mL)，加入三氟乙酸(0.5mL)，反应在室温下反应2小时。反应液浓缩，加入7.0M氨甲醇溶液(5.0mL)，溶剂旋干，粗品用制备HPLC(碳酸氢铵)纯化得到目标产物7-(1-乙基-5-甲基-1H-吡唑-4-基)-8-氟-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z189,9mg,收率：24％)。ES-API:[M+H] +＝481.2。 1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝8.8Hz,1H),8.23(s,1H),7.72(t,J＝8.4Hz,1H),7.61(s,1H),7.21(s,2H),4.16(q,J＝7.2Hz,2H),3.93(dd,J＝10.8,3.6Hz,2H),3.80(s,2H),3.48(t,J＝11.2Hz,2H),3.38–3.34(m,1H),2.36(s,3H),2.34(s,3H),1.93–1.82(m,2H),1.73–1.57(m,2H),1.36(t,J＝7.2Hz,3H). Step 7: ((2-(1-Amino-7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-isoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-)yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (60 mg, 0.08 mmol) was dissolved in dichloromethane (2.0 mL) and trichloromethane was added. Fluoroacetic acid (0.5 mL), and the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, 7.0M ammonia methanol solution (5.0 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(1-ethyl-5-methyl-1H-pyrazole- 4-yl)-8-fluoro-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)isoquinoline-1 - Amine (Z189, 9 mg, yield: 24%). ES-API: [M+H] + =481.2. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.72(d, J=8.8Hz, 1H), 8.23(s, 1H), 7.72(t, J=8.4Hz, 1H), 7.61(s, 1H) ,7.21(s,2H),4.16(q,J＝7.2Hz,2H),3.93(dd,J＝10.8,3.6Hz,2H),3.80(s,2H),3.48(t,J＝11.2Hz, 2H), 3.38–3.34 (m, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 1.93–1.82 (m, 2H), 1.73–1.57 (m, 2H), 1.36 (t, J= 7.2Hz, 3H).
实施例42化合物Z190的合成Example 42 Synthesis of compound Z190
Figure PCTCN2022085658-appb-000132
Figure PCTCN2022085658-appb-000132
步骤一:取5-溴-1-甲基-1H-吡唑(1.6g,10mmol)，环丙基硼酸(2.58g,30mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(160mg,0.24mmol),碳酸钾(4.14g,30mmol)溶于1,4-二氧六环(50ml)和水(10ml)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析(石油醚/乙酸乙酯＝80/20)纯化，得到5-环丙基-1-甲基-1H-吡唑(790mg,收率65％)。ES-API:[M+H]+＝123.1。Step 1: get 5-bromo-1-methyl-1H-pyrazole (1.6g, 10mmol), cyclopropylboronic acid (2.58g, 30mmol), 1,1-bis(diphenylphosphino)ferrocene Palladium chloride (160 mg, 0.24 mmol), potassium carbonate (4.14 g, 30 mmol) were dissolved in 1,4-dioxane (50 ml) and water (10 ml), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to obtain 5-cyclopropyl-1-methyl-1H-pyrazole (790 mg, yield 65%). ). ES-API: [M+H]+=123.1.
步骤二:取5-环丙基-1-甲基-1H-吡唑(244mg,2mmol)溶于乙腈，冰浴下加入N-溴代丁二酰亚胺(430mg,2.4mmol)，室温反应2小时。反应结束后，加入水(10ml)，乙酸乙酯萃取(10mLX3)，有机相饱和碳酸氢钠溶液(10ml)洗，饱和食盐水(10ml)洗，无水硫酸钠干燥，过滤减压浓缩至干得到4-溴-5-环丙基-1-甲基-1H-吡唑(340mg,收率85％)。ES-API:[M+H]+＝201.1。Step 2: get 5-cyclopropyl-1-methyl-1H-pyrazole (244mg, 2mmol) and dissolve it in acetonitrile, add N-bromosuccinimide (430mg, 2.4mmol) under ice bath, react at room temperature 2 hours. After the reaction, water (10ml) was added, extracted with ethyl acetate (10mL×3), the organic phase was washed with saturated sodium bicarbonate solution (10ml), washed with saturated brine (10ml), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure 4-Bromo-5-cyclopropyl-1-methyl-1H-pyrazole (340 mg, 85% yield) was obtained. ES-API: [M+H]+=201.1.
步骤三:取4-溴-5-环丙基-1-甲基-1H-吡唑(200mg,1mmol)，联硼酸频那醇酯(510mg,2mmol),1,1-二(二苯膦基)二茂铁二氯化钯(24mg,0.036mmol)，醋酸钾(196mg,2mmol)溶于1,4-二氧六环(5mL)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析(石油醚/乙酸乙酯＝85/15)纯化，得到5-环丙基-1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(175mg,收率70％)。ES-API:[M+H]+＝249.2。Step 3: get 4-bromo-5-cyclopropyl-1-methyl-1H-pyrazole (200mg, 1mmol), biboronic acid pinacol ester (510mg, 2mmol), 1,1-bis(diphenylphosphine) base) ferrocene palladium dichloride (24 mg, 0.036 mmol), potassium acetate (196 mg, 2 mmol) was dissolved in 1,4-dioxane (5 mL), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=85/15) to obtain 5-cyclopropyl-1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (175 mg, 70% yield). ES-API: [M+H]+=249.2.
步骤四:取5-环丙基-1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(175mg g,0.7mmol)，7-溴-8-氟异喹啉-1-胺(120mg,0.5mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(16mg,0.024mmol)，碳酸钾(138mg,1mmol)溶于1,4-二氧六环(2ml)和水(1ml)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(85mg,收率60％)。ES-API:[M+H]+＝283.1。Step 4: Take 5-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H - Pyrazole (175 mg g, 0.7 mmol), 7-bromo-8-fluoroisoquinolin-1-amine (120 mg, 0.5 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (16 mg, 0.024 mmol), potassium carbonate (138 mg, 1 mmol) was dissolved in 1,4-dioxane (2 ml) and water (1 ml), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -8-Fluoroisoquinolin-1-amine (85 mg, 60% yield). ES-API: [M+H]+=283.1.
步骤五:取7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-胺(85mg g,0.3mmol)溶于N,N-二甲基甲酰胺(1mL)，冰浴下加入N-碘代丁二酰亚胺(68mg g,0.3mmol)，室温反应2小时。反应结束后，加入水(5mL)，析出固体，抽滤得到7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(105mg,收率85％)。ES-API:[M+H]+＝409.0。Step five: get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinoline-1-amine (85mg g, 0.3mmol) is dissolved in N,N -Dimethylformamide (1 mL), N-iodosuccinimide (68 mg g, 0.3 mmol) was added under an ice bath, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to precipitate a solid, and suction filtration to obtain 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinoline -1-amine (105 mg, 85% yield). ES-API: [M+H]+=409.0.
步骤六:取7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟-4-碘异喹啉-1-胺(105mg,0.25mmol)溶于二氯甲烷(5ml)，冰浴下加入三乙胺(50mg,0.5mmol)，DMAP(4mg,0.025mmol)，二碳酸二叔丁酯(110mg,0.5mmol)，室温反应2小时。反应结束后，反应液减压浓缩至干，通过硅胶柱层析(石油醚/乙酸乙酯 ＝70/30)纯化，得到2-甲基丙-2-基{[7-(5-环丙基-1-甲基吡唑-4-基)-8-氟-4-碘异喹啉-1-基]{[(2-甲基丙-2-基)氧]羰基}氨基}甲酸叔丁酯(137mg,收率90％)。ES-API:[M+H]+＝609.2。Step six: get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (105mg, 0.25mmol) dissolved in Dichloromethane (5 ml), triethylamine (50 mg, 0.5 mmol), DMAP (4 mg, 0.025 mmol), di-tert-butyl dicarbonate (110 mg, 0.5 mmol) were added under ice bath, and the reaction was carried out at room temperature for 2 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to obtain 2-methylpropan-2-yl{[7-(5-cyclopropane) tert-1-methylpyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl]{[(2-methylprop-2-yl)oxy]carbonyl}amino}carboxylic acid Butyl ester (137 mg, 90% yield). ES-API: [M+H]+=609.2.
步骤七:取2-甲基丙-2-基{[7-(5-环丙基-1-甲基吡唑-4-基)-8-氟-4-碘异喹啉-1-基]{[(2-甲基丙-2-基)氧]羰基}氨基}甲酸叔丁酯(120mg,0.2mmol)，联硼酸频那醇酯(100mg,0.4mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(8mg g,0.012mmol)，醋酸钾(40mg,0.4mmol)溶于1,4-二氧六环(5mL)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析(石油醚/乙酸乙酯＝70/30)纯化，得到2-甲基丙-2-基{[7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(73mg,收率60％)。ES-API:[M+H]+＝609.3。Step seven: take 2-methylpropan-2-yl{[7-(5-cyclopropyl-1-methylpyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl ]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}carboxylate tert-butyl ester (120mg, 0.2mmol), pinacol biboronate (100mg, 0.4mmol), 1,1-bis( Diphenylphosphino)ferrocene palladium dichloride (8 mg g, 0.012 mmol), potassium acetate (40 mg, 0.4 mmol) was dissolved in 1,4-dioxane (5 mL), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to obtain 2-methylpropan-2-yl{[7-chloro-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1-yl]{[(2-methylpropan-2-yl)oxy] Carbonyl}amino}carboxylate tert-butyl ester (73 mg, 60% yield). ES-API: [M+H]+=609.3.
步骤八:取2-甲基丙-2-基{[7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(73mg,0.12mmol)，((2-溴-5-(四氢-2H-吡喃-4-基)噻唑-4-基)甲基)(甲基)氨基甲酸叔丁酯(46mg,0.12mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(8mg g,0.012mmol)，碳酸钾(48mg,0.34mmol)溶于1,4-二氧六环(2ml)和水(0.5ml)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析(石油醚/乙酸乙酯＝50/50)纯化，得到(叔丁氧羰基)(4-(4-(((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-基)氨基甲酸叔丁酯(40mg,收率41％)。ES-API:[M+H]+＝793.3。Step eight: take 2-methylpropan-2-yl{[7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)isoquinolin-1-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}carboxylate tert-butyl ester (73 mg, 0.12 mmol), ((2-bromo-5-( Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (46 mg, 0.12 mmol), 1,1-bis(diphenylphosphino)diocene Iron palladium dichloride (8 mg g, 0.012 mmol), potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (2 ml) and water (0.5 ml), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to obtain (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl) (yl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(5-cyclopropyl-1-methyl-1H-pyrazole-4 -yl)-8-fluoroisoquinolin-1-yl)carbamate tert-butyl ester (40 mg, 41% yield). ES-API: [M+H]+=793.3.
步骤九:取(叔丁氧羰基)(4-(4-(((叔丁氧羰基)(甲基)氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟异喹啉-1-基)氨基甲酸叔丁酯(40mg,0.05mmol)溶于无水二氯甲烷(0.5mL)，加入三氟乙酸(0.2mL)，室温反应2小时。LC-MS监测反应完全，反应液减压浓缩至干，加入氨甲醇溶液(1mL)中和后，再次浓缩，经制备HPLC(碳酸氢铵)纯化得到7-(5-环丙基-1-甲基-1H-吡唑-4-基)-8-氟-4-(4-((甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)异喹啉-1-胺(Z190,20.1mg,收率80％)ES-API:[M+H]+＝493.1Step 9: Take (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole -2-yl)-7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-yl)carbamic acid tert-butyl ester (40 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was carried out at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, neutralized by adding ammonia methanol solution (1 mL), concentrated again, and purified by preparative HPLC (ammonium bicarbonate) to obtain 7-(5-cyclopropyl-1- Methyl-1H-pyrazol-4-yl)-8-fluoro-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 -yl)isoquinolin-1-amine (Z190, 20.1 mg, 80% yield) ES-API: [M+H]+=493.1
实施例43化合物Z191的合成Example 43 Synthesis of compound Z191
Figure PCTCN2022085658-appb-000133
Figure PCTCN2022085658-appb-000133
步骤一:取2-甲基丙-2-基{[7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异喹啉-1-基]{[(2-甲基丙-2-基)氧基]羰基}氨基}甲酸叔丁酯(90mg,0.148mmol)，1-(2-溴-5-(四氢吡喃-4-基)噻唑-4-基)-N,N-二甲基甲胺(46mg,0.15mmol)，1,1-二(二苯膦基)二茂铁二氯化钯(8mg,0.012mmol)，碳酸钾(48mg,0.34mmol)溶于1,4-二氧六环(2mL)和水(0.5ml)，110℃搅拌2小时。反应液减压浓缩至干，通过硅胶柱层析纯化(石油醚/乙酸乙酯＝50/50)纯化，得到(7-(5-环丙基-1-甲基-1H-吡唑-4-基)-4-(4-((二甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟异喹啉-1-基)氨基甲酸二叔丁酯(40mg,收率38％)。ES-API:[M+H]+＝707.3。Step 1: Take 2-methylpropan-2-yl{[7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)isoquinolin-1-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}carboxylate tert-butyl ester (90 mg, 0.148 mmol), 1-(2-bromo-5- (Tetrahydropyran-4-yl)thiazol-4-yl)-N,N-dimethylmethanamine (46 mg, 0.15 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium (8 mg, 0.012 mmol), potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 ml), and stirred at 110° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to obtain (7-(5-cyclopropyl-1-methyl-1H-pyrazole-4). -yl)-4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8-fluoroisoquinoline-1 -yl) di-tert-butyl carbamate (40 mg, 38% yield). ES-API: [M+H]+=707.3.
步骤二:取(7-(5-环丙基-1-甲基-1H-吡唑-4-基)-4-(4-((二甲基氨基)甲基)-5-(四氢-2H-吡喃-4-基)噻唑-2-基)-8-氟异喹啉-1-基)氨基甲酸二叔丁酯(40mg,0.05mmol)溶于无水二氯甲烷(0.5mL)，加入三氟乙酸(0.2mL)，室温反应2小时。LC-MS监测反应完全，反应液减压浓缩至干，加入氨甲醇溶液(1mL)中和后，再次浓缩，经制备HPLC(碳酸氢铵)纯化得到7-(5-环丙基-1-甲基-1H-吡唑-4-基)-4-(4-((二甲基氨基)甲基)-5-(四氢吡喃-4-基)噻唑-2-基)-8-氟异喹啉-1-胺(Z191,13.7mg,收率54％)ES-API:[M+H]+＝507.2。Step 2: get (7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(4-((dimethylamino)methyl)-5-(tetrahydro Di-tert-butyl -2H-pyran-4-yl)thiazol-2-yl)-8-fluoroisoquinolin-1-yl)carbamate (40 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (0.5 mL) ), trifluoroacetic acid (0.2 mL) was added, and the mixture was reacted at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, neutralized by adding ammonia methanol solution (1 mL), concentrated again, and purified by preparative HPLC (ammonium bicarbonate) to obtain 7-(5-cyclopropyl-1- Methyl-1H-pyrazol-4-yl)-4-(4-((dimethylamino)methyl)-5-(tetrahydropyran-4-yl)thiazol-2-yl)-8- Fluoroisoquinolin-1-amine (Z191, 13.7 mg, 54% yield) ES-API: [M+H]+=507.2.
参照以上实施例的方法通过更改部分原料来合成以下表A、表B或表C的化合物：The following compounds of Table A, Table B or Table C were synthesized by modifying some of the starting materials with reference to the methods of the above examples:
表ATable A
Figure PCTCN2022085658-appb-000134
Figure PCTCN2022085658-appb-000134
Figure PCTCN2022085658-appb-000135
Figure PCTCN2022085658-appb-000135
Figure PCTCN2022085658-appb-000136
Figure PCTCN2022085658-appb-000136
Figure PCTCN2022085658-appb-000137
Figure PCTCN2022085658-appb-000137
Figure PCTCN2022085658-appb-000138
Figure PCTCN2022085658-appb-000138
Figure PCTCN2022085658-appb-000139
Figure PCTCN2022085658-appb-000139
Figure PCTCN2022085658-appb-000140
Figure PCTCN2022085658-appb-000140
表BForm B
Figure PCTCN2022085658-appb-000141
Figure PCTCN2022085658-appb-000141
Figure PCTCN2022085658-appb-000142
Figure PCTCN2022085658-appb-000142
表CForm C
Figure PCTCN2022085658-appb-000143
Figure PCTCN2022085658-appb-000143
Figure PCTCN2022085658-appb-000144
Figure PCTCN2022085658-appb-000144
Figure PCTCN2022085658-appb-000145
Figure PCTCN2022085658-appb-000145
Figure PCTCN2022085658-appb-000146
Figure PCTCN2022085658-appb-000146
Figure PCTCN2022085658-appb-000147
Figure PCTCN2022085658-appb-000147
测试例1HPK1激酶活性测定Test Example 1 HPK1 Kinase Activity Assay
ADP-GloTM Kinase Assay购自Promega；货号：V9102；HPK1购自Carna；货号：07-410；ATP购自Promega；BSA购自Sigma；货号：B2064-100G；MgCl 2购自Shyuanye；货号：R21455；MBP购自Millipore；货号：13-110；Briji-35购自Sigma；货号：B4184-100ML；Tris-HCl购自Sigma；DTT购自Thermo Fisher；货号：R0861；V-storage plate购自corning；货号：3894；ProxiPlate-384-Plates购自PerkinElmer；货号：6008289； ADP-GloTM Kinase Assay from Promega; Item No. V9102; HPK1 from Carna; Item No.: 07-410; ATP from Promega; BSA from Sigma; Item No.: B2064-100G; MgCl 2 from Shyuanye; MBP from Millipore; Item No.: 13-110; Briji-35 from Sigma; Item No. B4184-100ML; Tris-HCl from Sigma; DTT from Thermo Fisher; Item No.: R0861; V-storage plate from corning; Item No. : 3894; ProxiPlate-384-Plates from PerkinElmer; Cat. No. 6008289;
缓冲液配制：使用无菌水配制1×反应缓冲液：40mM Tris-HCl,20mM MgCl 2,0.01％Brij35,50μM DTT,0.1mg/ml BSA，实验当天配制使用。 Buffer preparation: Use sterile water to prepare 1× reaction buffer: 40 mM Tris-HCl, 20 mM MgCl 2 , 0.01% Brij35, 50 μM DTT, 0.1 mg/ml BSA, and use it on the day of the experiment.
1000×储存药板配制：配制1000×化合物储存板，将10mM的化合物储存液用DMSO进行稀释，起始浓度1mM，10个浓度梯度，3.162倍稀释。化合物储存板用封板膜密封，放入-20℃冰箱储存备用。1000× stocking drug plate preparation: prepare 1000× compound stocking plate, dilute 10 mM compound stock solution with DMSO, the initial concentration is 1 mM, 10 concentration gradients, 3.162 times dilution. The compound storage plate was sealed with sealing film and stored in a -20°C refrigerator for later use.
化合物配制和加药：取出1000×储存药板，室温避光融化。然后用反应缓冲液配制5×中间药板，充分混匀。从5×中间药板中转移2μL到384孔板中，设置阴性对照孔和阳性对照孔(加入2μL含0.5％DMSO的反应缓冲液)，每个点重复两次。Compound preparation and dosing: Take out the 1000× storage plate and thaw at room temperature in the dark. Then prepare a 5X intermediate plate with reaction buffer and mix thoroughly. Transfer 2 μL from the 5× intermediate plate to a 384-well plate, set up negative control wells and positive control wells (add 2 μL of reaction buffer containing 0.5% DMSO), and repeat each point twice.
反应液配制和孵育：HPK1蛋白使用反应缓冲液稀释成2.5×工作液，加4μL 2.5×HPK1蛋白分别到含有待测化合物的各孔和阳性对照孔中，阴性对照孔加入4μL不含HPK1蛋白的反应缓冲液。1000rpm离心1分钟，然后于20℃培养箱中孵育15分钟。使用反应缓冲液配制2.5×MBP蛋白和ATP混合工作液，浓度分别为0.5μg/μL和50μM，加4μL MBP和ATP混合工作液到各孔中，1000rpm离心1分 钟，然后于20℃培养箱中孵育90分钟。Reaction solution preparation and incubation: use reaction buffer to dilute HPK1 protein into 2.5× working solution, add 4 μL of 2.5× HPK1 protein to each well containing the test compound and the positive control well, and add 4 μL of HPK1 protein-free protein to the negative control well. reaction buffer. Centrifuge at 1000 rpm for 1 minute, then incubate in a 20°C incubator for 15 minutes. Use reaction buffer to prepare 2.5× MBP protein and ATP mixed working solution, the concentrations are 0.5 μg/μL and 50 μM, respectively, add 4 μL MBP and ATP mixed working solution to each well, centrifuge at 1000 rpm for 1 minute, and then incubator at 20 °C Incubate for 90 minutes.
ADP-Glo检测和读板：加入10μL ADP-Glo到实验板各孔中，1000rpm离心1分钟，于20℃培养箱中孵育60分钟。然后从实验板中转移10μL孵育结束后的溶液到一块新的384孔板中，每孔加入10μL激酶检测试剂，400g离心1分钟，于20℃培养箱中孵育60分钟，用酶标仪读取化学发光信号。ADP-Glo detection and plate reading: Add 10 μL of ADP-Glo to each well of the experimental plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 20°C incubator for 60 minutes. Then transfer 10 μL of the incubation solution from the experimental plate to a new 384-well plate, add 10 μL of kinase detection reagent to each well, centrifuge at 400g for 1 minute, incubate in a 20°C incubator for 60 minutes, and read with a microplate reader Chemiluminescence signal.
数据分析处理：抑制率％＝(1-(实验孔-阴性对照孔)/(阳性对照孔-阴性对照孔))*100％；阴性对照孔：10μM ATP+0.1μg/μL MBP+DMSO；阳性对照孔：1nM HPK1+10μM ATP+0.1μg/μL MBP+DMSO；实验孔：1nM HPK1+10μM ATP+0.1μg/μL MBP+化合物；使用Graphpad Prism 8.0.1分析数据，使用四参数法拟合药效抑制率曲线并计算药物的IC50值。Data analysis and processing: Inhibition rate%=(1-(experimental well-negative control well)/(positive control well-negative control well))*100%; negative control well: 10μM ATP+0.1μg/μL MBP+DMSO; positive Control wells: 1nM HPK1+10μM ATP+0.1μg/μL MBP+DMSO; experimental wells: 1nM HPK1+10μM ATP+0.1μg/μL MBP+compound; use Graphpad Prism 8.0.1 to analyze data, and use four-parameter method to fit drug effects Inhibition rate curves and IC50 values of the drugs were calculated.
从实验结果可知，本发明化合物对HPK1激酶具有较高的抑制活性，IC50值小于10μM(例如0.1nM至10μM)；部分化合物的IC50值甚至小于1μM(例如0.1nM至1μM)或小于500nM(例如0.1nM至500nM)。其中部分化合物的实验结果如表1所示。It can be seen from the experimental results that the compounds of the present invention have high inhibitory activity on HPK1 kinase, and the IC50 value is less than 10 μM (for example, 0.1 nM to 10 μM); the IC50 value of some compounds is even less than 1 μM (for example, 0.1 nM to 1 μM) or less than 500 nM (for example, 0.1 nM to 1 μM). 0.1 nM to 500 nM). The experimental results of some of the compounds are shown in Table 1.
表1Table 1
编号Numbering HPK1激酶活性IC 50(nM) HPK1 kinase activity IC 50 (nM) 编号Numbering HPK1激酶活性IC 50(nM) HPK1 kinase activity IC 50 (nM)
Z1Z1 698.60698.60 Z166Z166 0.290.29
Z2Z2 428.62428.62 Z167Z167 0.430.43
Z3Z3 10.2510.25 Z158Z158 0.620.62
Z4Z4 26.4826.48 Z168Z168 5.745.74
Z5Z5 109.07109.07 Z169Z169 0.40.4
Z6Z6 16.1716.17 Z170Z170 6.836.83
Z7Z7 2.882.88 Z171Z171 1.11.1
Z7-1Z7-1 0.880.88 Z172Z172 1.941.94
Z7-2Z7-2 11.4311.43 Z173Z173 4.554.55
Z8Z8 2.472.47 Z174Z174 10.9510.95
Z70-1Z70-1 2.872.87 Z175Z175 6.566.56
Z70-2Z70-2 26.5726.57 Z176Z176 8.668.66
Z73Z73 0.510.51 Z177Z177 6.056.05
Z165Z165 2.052.05 Z178Z178 2.012.01
Z78Z78 0.460.46 Z179Z179 5.775.77
Z69Z69 1.441.44 Z180Z180 0.430.43
Z161Z161 0.560.56 Z181Z181 2.272.27
Z182Z182 1.871.87 Z183Z183 1.921.92
Z184Z184 5.325.32 Z160-2Z160-2 0.640.64
Z160-1Z160-1 0.430.43 Z156Z156 0.610.61
Z160Z160 0.650.65 Z185Z185 0.240.24
Z186Z186 1.571.57 Z187Z187 0.950.95
Z188Z188 6.226.22 Z189Z189 0.750.75
Z191Z191 1.921.92 Z190Z190 0.670.67
尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。Although the specific embodiments of the present invention have been described in detail, according to all the disclosed teachings, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention, and these changes are all within the protection scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (30)

  1. 式(A)或式(D)所示化合物或其药学上可接受的盐、溶剂合物或前药：The compound represented by formula (A) or formula (D) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
    Figure PCTCN2022085658-appb-100001
    Figure PCTCN2022085658-appb-100001
    各式中，various,
    Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
    R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    Cy2环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy2 ring is C 3-20 -membered cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    R x为氢；或者 R x is hydrogen; or
    R x为Cy2环上一个位置的取代基； R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100002
    其中，     Rx is
    Figure PCTCN2022085658-appb-100002
    in,
    R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
    当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally surrounded by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment; or
    当R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2a为氢、氘或C 1-6烷基(例如甲基)，R 2b为氢、氘或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl), R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond; the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contain one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected from the S1 group are substituted;
    或者or
    R x为
    Figure PCTCN2022085658-appb-100003
    其中，     Rx is
    Figure PCTCN2022085658-appb-100003
    in,
    R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1; or
    R 2e和R 2f各自独立地为氢或C 1-6烷基(例如甲基)； R 2e and R 2f are each independently hydrogen or C 1-6 alkyl (eg, methyl);
    或者or
    R x为
    Figure PCTCN2022085658-appb-100004
    其中，     Rx is
    Figure PCTCN2022085658-appb-100004
    in,
    R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h' , R 2g' are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c , R 2d are each independently hydrogen, C 1-6 alkyl, C 3 -20 cycloalkyl or 3 to 20 membered heterocyclyl; the 3 to 20 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3 to 20 membered heterocyclyl The 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环 杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
    R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；或者当其中两个R 2位于同一个碳原子时，这两个R 2与和它们相连的碳原子共同构成C 3-6单环环烷基或3至6元单环杂环基；所述3至6元单环杂环基含有1个或2个选自N、S或O的杂原子作为环原子；所述C 3-6单环环烷基或3至6元单环杂环基各自独立地任选 地被1、2、3或4个选自S1组的基团所取代； R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom; or when two R 2 are located on the same carbon atom, the two R 2 together with the carbon atom to which they are attached constitute a C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocycle base; the 3- to 6-membered monocyclic heterocyclic group contains 1 or 2 heteroatoms selected from N, S or O as ring atoms; the C 3-6 monocyclic cycloalkyl or 3- to 6-membered unit The cyclic heterocyclyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 3为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 3 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
    R 4为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 4 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
    p为0、1、2或3；p is 0, 1, 2, or 3;
    p1为0、1或2；p1 is 0, 1 or 2;
    q为0或1；q is 0 or 1;
    L 1为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 1 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
    L 2为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 2 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
    X为CR 8或N；其中，R 8为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； X is CR 8 or N; wherein, R 8 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy ;
    Y为CR 9或N；其中，R 9为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； Y is CR 9 or N; wherein, R 9 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy ;
    且式(A)中当X和Y为CH；L 1为一根键时，
    Figure PCTCN2022085658-appb-100005
    不为苯基或卤代苯基；     And in formula (A), when X and Y are CH; L 1 is a bond,
    Figure PCTCN2022085658-appb-100005
    not phenyl or halophenyl;
    上述各基团中，R 5、R 6各自独立地为H、氘、卤素、氰基、羟基、C 1-6烷基、氘代C 1-6烷基或C 1-6烷氧基； In each of the above groups, R 5 and R 6 are each independently H, deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, deuterated C 1-6 alkyl or C 1-6 alkoxy;
    上述各基团中，R 7为H、C 1-6烷基或氘代C 1-6烷基； In the above-mentioned groups, R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl;
    上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3 到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 Substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S2; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
    上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
    各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
    上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or the two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously replaced by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
  2. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，所 述化合物如式(A1)、式(A2)、式(A3)、式(D1)、式(D2)或式(D3)所示：The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the compound is such as formula (A1), formula (A2), formula (A3), Formula (D1), formula (D2) or formula (D3):
    Figure PCTCN2022085658-appb-100006
    Figure PCTCN2022085658-appb-100006
    各式中，R 1、R 2、R 3、R 4、R x、L 1、L 2、Cy1环、Cy2环、m、n、p、p1、q各自定义同前。 In each formula, R 1 , R 2 , R 3 , R 4 , R x , L 1 , L 2 , Cy1 ring, Cy2 ring, m, n, p, p1, and q are as defined above.
  3. 如权利要求2所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，所述化合物如式(A11)、式(A21)、式(A31)、式(D11)、式(D21)或式(D31)所示：The compound of claim 2 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the compound is such as formula (A11), formula (A21), formula (A31), Formula (D11), formula (D21) or formula (D31):
    Figure PCTCN2022085658-appb-100007
    Figure PCTCN2022085658-appb-100007
    各式中，R 1、R 2、R 3、R 4、R x、Cy1环、Cy2环、m、n、p、p1、q各自定义同前。 In each formula, R 1 , R 2 , R 3 , R 4 , R x , Cy1 ring, Cy2 ring, m, n, p, p1, and q are as defined above.
  4. 如权利要求3所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，所述化合物如式(A12)、式(A22)、式(A32)、式(D11)、式(D21)或式(D31)所示：The compound of claim 3 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the compound is such as formula (A12), formula (A22), formula (A32), Formula (D11), formula (D21) or formula (D31):
    Figure PCTCN2022085658-appb-100008
    Figure PCTCN2022085658-appb-100008
    各式中，R 1、R 2、R x、L 1、L 2、Cy1环、Cy2环、m、n、q各自定义同前。 In each formula, R 1 , R 2 , R x , L 1 , L 2 , Cy1 ring, Cy2 ring, m, n, and q are as defined above.
  5. 式(B)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：The compound represented by formula (B) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
    Figure PCTCN2022085658-appb-100009
    Figure PCTCN2022085658-appb-100009
    式中，In the formula,
    Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
    R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双 环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    Cy2环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy2 ring is C 3-20 -membered cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    R x为氢；或者 R x is hydrogen; or
    R x为Cy2环上一个位置的取代基； R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100010
    其中，     Rx is
    Figure PCTCN2022085658-appb-100010
    in,
    R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
    当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment; or
    当R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2a为氢、氘或C 1-6烷基(例如甲基)，R 2b为氢、氘或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl), R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond; the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected from the S1 group are substituted;
    或者or
    R x为
    Figure PCTCN2022085658-appb-100011
    其中，     Rx is
    Figure PCTCN2022085658-appb-100011
    in,
    R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含 有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或者 R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1; or
    R 2e和R 2f各自独立地为氢或C 1-6烷基(例如甲基)； R 2e and R 2f are each independently hydrogen or C 1-6 alkyl (eg, methyl);
    或者or
    R x为
    Figure PCTCN2022085658-appb-100012
    其中，     Rx is
    Figure PCTCN2022085658-appb-100012
    in,
    R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h' , R 2g' are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c , R 2d are each independently hydrogen, C 1-6 alkyl, C 3 -20 cycloalkyl or 3 to 20 membered heterocyclyl; the 3 to 20 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3 to 20 membered heterocyclyl The 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
    R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4 烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；或者当其中两个R 2位于同一个碳原子时，这两个R 2与和它们相连的碳原子共同构成C 3-6单环环烷基或3至6元单环杂环基；所述3至6元单环杂环基含有1个或2个选自N、S或O的杂原子作为环原子；所述C 3-6单环环烷基或3至6元单环杂环基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom; or when two R 2 are located on the same carbon atom, the two R 2 together with the carbon atom to which they are attached constitute a C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocycle base; the 3- to 6-membered monocyclic heterocyclic group contains 1 or 2 heteroatoms selected from N, S or O as ring atoms; the C 3-6 monocyclic cycloalkyl or 3- to 6-membered unit The cyclic heterocyclyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 3为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 3 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
    R 4为H、氘、卤素、氰基、＝O、羟基、C 1-6烷基、氘代C 1-6烷基、或C 1-6烷氧基； R 4 is H, deuterium, halogen, cyano, =O, hydroxy, C 1-6 alkyl, deuterated C 1-6 alkyl, or C 1-6 alkoxy;
    且R 3、R 4不同时为H； And R 3 and R 4 are not H at the same time;
    p为0、1、2或3；p is 0, 1, 2, or 3;
    L 1为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 1 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
    L 2为一根键、-O-、-S-、-C(＝O)-、-NHC(＝O)-、-CR 5R 6-、或-NR 7-； L 2 is a bond, -O-, -S-, -C(=O)-, -NHC(=O)-, -CR 5 R 6 -, or -NR 7 -;
    上述各基团中，R 5、R 6各自独立地为H、氘、卤素、氰基、羟基、C 1-6烷基、氘代C 1-6烷基或C 1-6烷氧基； In each of the above groups, R 5 and R 6 are each independently H, deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, deuterated C 1-6 alkyl or C 1-6 alkoxy;
    上述各基团中，R 7为H、C 1-6烷基或氘代C 1-6烷基； In the above-mentioned groups, R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl;
    上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷 基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
    上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
    各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
    上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or the two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously replaced by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
  6. 式(C)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：The compound represented by formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
    Figure PCTCN2022085658-appb-100013
    Figure PCTCN2022085658-appb-100013
    式中，In the formula,
    Cy1环为C 3-20环烷基、3到20元杂环基、C 6-14芳基或5到20元杂芳基；所述3到20元杂环基、所述5到20元杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Cy1 ring is C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl or 5- to 20-membered heteroaryl; the 3- to 20-membered heterocyclyl, the 5- to 20-membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    R 1为Cy1环上任意位置的取代基；n为0、1、2或3； R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
    R 1选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 1 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heteroaryl Cyclic, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1- 4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 Cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-O-3 to 20 membered Heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl base, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)-NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkyl-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 ring Alkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6-14aryl , -C(=O)-5 or 6-membered monocyclic heteroaryl, - C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl -3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocycle Heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 Cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl , -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O)-NR a R b , -OC(=O)-NR a R b , -NR d -C(=O)-R c , -NR d -C(=O)-NR a R b , -S(=O) 2 -R c , -NR d -S(=O) 2 - R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl- P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy each independently optionally substituted with halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1; the 3- to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    (a)Cy2环为C 6-14芳基时； (a) when Cy2 ring is C 6-14 aryl;
    (a1)R x为Cy2环上一个位置的取代基； (a1) R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100014
    其中，R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；或     Rx is
    Figure PCTCN2022085658-appb-100014
    Wherein, when R 2a and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered The monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the said The 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3 or 4 selected from Group S1 group substituted; or
    R x为
    Figure PCTCN2022085658-appb-100015
    其中，R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；     Rx is
    Figure PCTCN2022085658-appb-100015
    wherein R 2e and R 2f together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains a nitrogen atom and optionally 1 or 2 heterocyclic heteroaryl groups independently selected from N, O, S and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally Or 4 groups selected from S1 group are substituted;
    R 2为Cy2环其余任意位置上的取代基；m为1或2；R 2选自下组：3到20元杂环基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-NH-C 3-20环烷基、-NH-3到20元杂环基、N-5到20元杂芳基、-NH-C 6-14芳基；其中，所述3到20元杂环基、C 3-20环烷基、5到20元杂芳基、C 6-14芳基任选地被1、2、3或4个选自S3组的基团所取代；所述3到20元杂环基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered heteroaryl, -NH-C 6- 14 Aryl; wherein, the 3- to 20-membered heterocyclyl, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optionally replaced by 1, 2, 3 or 4 substituted with a group selected from the S3 group; the 3- to 20-membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    或者or
    (a2)R x为Cy2环上一个位置的取代基； (a2) R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100016
    其中，     Rx is
    Figure PCTCN2022085658-appb-100016
    in,
    R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为C 1-6烷基、C 3-20环烷基或3到20元杂环基；且当R 2c为C 1-6烷基时R 2d不为3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not 3 to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is replaced by 1 , 2, 3 or 4 groups selected from group S1; or
    R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氘，R 2b为氢、氘或C 1-6烷基(例如甲基)且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2a is deuterium, R 2b is hydrogen, Deuterium or C 1-6 alkyl (eg methyl) and the bond between R 2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the The 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclic groups , the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the S1 group;
    或者or
    R x为
    Figure PCTCN2022085658-appb-100017
    其中，     Rx is
    Figure PCTCN2022085658-appb-100017
    in,
    R 2g、R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为C 1-6烷基、C 3-20环烷基或3到20元杂环基；且当R 2c为C 1-6烷基时R 2d不为3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 20-membered heterocyclyl; the 3- to 20-membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from the S1 group;
    或者or
    R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2g，R 2h、R 2h’、R 2g’为氢或氘或C 1-6烷基(例如甲基)，R 2g，R 2h、R 2h’、R 2g’中至少一个为氘；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2g , R 2h , R 2h' , R 2g' is hydrogen or deuterium or C 1-6 alkyl (eg methyl), at least one of R 2g , R 2h , R 2h' and R 2g' is deuterium; The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as a ring and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3, or 4 Replaced by a group selected from group S1;
    或者or
    R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6 烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O ) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O) -NRaRb ,-S ( =O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl group, the 3 to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1 , 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    或者or
    (b)Cy2环为5到20元杂芳基；所述5到20元杂芳基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子；(b) Cy2 ring is a 5- to 20-membered heteroaryl group; the 5- to 20-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    (b1)R x为Cy2环上一个位置的取代基； (b1) R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100018
    其中，     Rx is
    Figure PCTCN2022085658-appb-100018
    in,
    当R 2a和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基时，R 2c为氢；R 2b为氢且R 2a与碳原子之间的键为单键或R 2b为无且R 2a与碳原子之间的键为双键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； When R 2a and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered unit The cyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3 to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 groups selected from group S1 replaced by the regiment;
    R 2e和R 2f与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为1或2；R 2选自下组：3到20元杂环基、-O-C 3-20环烷基、-O-3到20元杂环基、O-5到20元杂芳基、-O-C 6-14芳基、-NH-C 3-20环烷基、-NH-3到20元杂环基、N-5到20元杂芳基、-NH-C 6-14芳基；其中，所述3到20元杂环基、C 3-20环烷基、5到20元杂芳基、C 6-14芳基任选地被1、2、3或4个选自S3组的基团所取代；所述3到20元杂环基含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, O-5 to 20 membered heteroaryl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered Heteroaryl, -NH-C 6-14 aryl; wherein, the 3- to 20-membered heterocyclic group, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optional is substituted with 1, 2, 3 or 4 groups selected from group S3; the 3- to 20-membered heterocyclyl group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    或者or
    (b2)R x为Cy2环上一个位置的取代基； (b2) R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100019
    其中，     Rx is
    Figure PCTCN2022085658-appb-100019
    in,
    R 2a为氢、氘或C 1-6烷基(例如甲基)；R 2b为氢、氘或C 1-6烷基(例如甲基)；R 2a与碳原子之间的键为单键；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代；或者 R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
    R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氘，R 2b为氢、氘或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20 元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2a is deuterium, R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or The 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocycles group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R x为
    Figure PCTCN2022085658-appb-100020
    其中，     Rx is
    Figure PCTCN2022085658-appb-100020
    in,
    R 2g、R 2h、R 2h’、R 2g’各自独立地为氢、氘或C 1-6烷基(例如甲基)；R 2c、R 2d各自独立地为氢、C 1-6烷基、C 3-20环烷基或3到20元杂环基；所述3到20元杂环基含有1、2或3个独立地选自N、O、S的杂原子作为环原子；所述3到20元杂环基被1、2、3或4个选自S1组的基团所取代； R 2g , R 2h , R 2h′ and R 2g′ are each independently hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2c and R 2d are each independently hydrogen, C 1-6 alkyl , C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the The 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2g为氘；R 2h、R 2h’、R 2g’各自独立地为氢、氘或C 1-6烷基(例如甲基)；或者R 2g’为氘；R 2h、R 2h’、R 2g各自独立地为氢、氘或C 1-6烷基(例如甲基)；R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2g is deuterium; R 2h , R 2h' , R 2g' are each independently hydrogen, deuterium or C 1-6 alkyl (eg methyl); or R 2g' is deuterium; R 2h , R 2h' , R 2g are each independently hydrogen, deuterium or C1-6 alkyl (eg methyl); R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl group; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and said 3- to 20-membered heterocyclyl, said 5- or 6-membered monocyclic heteroaryl, said 8 to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、 -C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(= O) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O ) -NRaRb ,-S (=O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl, the C 1-6 alkoxy are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the The 3- to 20-membered heterocyclic group, the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted by 1, 2, substituted by 3 or 4 groups selected from group S1; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    或者or
    (b3)R x为Cy2环上一个位置的取代基； (b3) R x is a substituent at a position on the Cy2 ring;
    R x为
    Figure PCTCN2022085658-appb-100021
    其中，R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基，R 2a为氢或C 1-6烷基(例如甲基)，R 2b为氢或C 1-6烷基(例如甲基)；且R 2a与碳原子之间的键为单键；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代；     Rx is
    Figure PCTCN2022085658-appb-100021
    wherein, R 2c and R 2d together with the atoms to which they are attached together form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, and R 2a is hydrogen or C 1- 6 alkyl (such as methyl), R 2b is hydrogen or C 1-6 alkyl (such as methyl); and the bond between R 2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclic group, The 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from the S4 group;
    或者or
    R x为
    Figure PCTCN2022085658-appb-100022
    其中，R 2g、R 2h、R 2h’、R 2g’各自独立地为氢或C 1-6烷基(例如甲基)；R 2c和R 2d与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代；     Rx is
    Figure PCTCN2022085658-appb-100022
    Wherein, R 2g , R 2h , R 2h' , R 2g' are each independently hydrogen or C 1-6 alkyl (eg methyl); R 2c and R 2d together with the atoms connected to them form a 3 to 20 member Heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8-10 The membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclic group, the 5 or a 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S4;
    或者or
    R 2d和R 2g与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g’为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    或者or
    R 2d和R 2g’与和它们相连的原子共同构成3到20元杂环基、5或6元单环杂芳基或8至10元双环杂芳基；R 2c，R 2h、R 2h’、R 2g为氢、氘或C 1-6烷基(例如甲基)；所述3到20元杂环基、所述5或6元 单环杂芳基或所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代； R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group The aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered The monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
    R 2为Cy2环其余任意位置上的取代基；m为0、1、2或3；R 2选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-O-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-C 1-4烷基-NR aR b、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-NR d-C(＝O)-R c、-C 1-4烷基-NR d-C(＝O)-NR aR b、-C 1-4烷基-S(＝O) 2-R c、-C 1-4烷基-NR d-S(＝O) 2-R c、-C 1-4烷基-S(＝O) 2-NR aR b、-C 1-4烷基-NR d-S(＝O) 2-NR aR b、-C 1-4烷基-羧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C(＝O)-NR aR b、-OC(＝O)-NR aR b、-NR d-C(＝O)-R c、-NR d-C(＝O)-NR aR b、-S(＝O) 2-R c、-NR d-S(＝O) 2-R c、-S(＝O) 2-NR aR b、-NR d-S(＝O) 2-NR aR b、-NR aR b、-OR c、-C 1-4烷基-P(＝O)(C 1-6烷基) 2、-P(＝O)(C 1-6烷基) 2；其中，所述C 1-6烷基、所述C 1-6烷氧基各自独立地任选地被卤素、氘、氰基或羟基取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S1组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3; R 2 is selected from the group consisting of oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20 membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6 membered monocyclic heteroaryl, -O- 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 Alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl -3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl- OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a R b , -C 1-4 alkane base-C(=O)-NR a R b , -C 1-4 alkyl-NR d -C(=O)-R c , -C 1-4 alkyl-NR d -C(=O)- NR a R b , -C 1-4 alkyl-S(=O) 2 -R c , -C 1-4 alkyl-NR d -S(=O) 2 -R c , -C 1-4 alkane base-S(=O) 2 -NR a R b , -C 1-4 alkyl-NR d -S(=O) 2 -NR a R b , -C 1-4 alkyl-carboxy, -C ( =O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3- to 20-membered heterocyclyl, -C(=O)-C 6 -14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkane base-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 Aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic heteroaryl, -C(=O ) -NRaRb ,-OC(=O) -NRaRb , -NRd -C(=O) -Rc , -NRd- C ( = O) -NRaRb ,-S ( =O) 2 -R c , -NR d -S(=O) 2 -R c , -S(=O) 2 -NR a R b , -NR d -S(=O) 2 -NR a R b , -NR a R b , -OR c , -C 1-4 alkyl-P(=O)(C 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently optionally substituted by halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from the group S1; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1 , 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    上述各基团中，各个S3组的基团各自独立地选自下组：C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C(＝O)-C 3-20环烷基、-C(＝O)-3到20元杂环基、-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C(＝O)-NR aR b、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)O-3到20元杂环基、-C(＝O)O-C 6-14芳基、-C(＝O)O-5或6元单环杂芳基、-C(＝O)O-8至10元双环杂芳基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-3到20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-3到20元杂环基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C 1-4烷基-C(＝O)-5或6元单环杂芳基、-C 1-4烷基-C(＝O)-8至10元双环杂芳基、-C 1-4烷基-C(＝O)-NR aR b、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)O-3到20元杂环基、-C 1-4烷基-C(＝O)O-C 6-14芳基、-C 1-4烷基-C(＝O)O-5或6元单环杂芳基、-C 1-4烷基-C(＝O)O-8至10元双环杂芳基；其中，所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； In the above-mentioned groups, the groups of each S3 group are each independently selected from the following group: C 3-20 cycloalkyl, 3 to 20-membered heterocyclic group, C 6-14 aryl, 5 or 6-membered monocyclic heterocyclic group Aryl, 8- to 10-membered bicyclic heteroaryl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-3 to 20-membered heterocyclyl, -C(=O)-C 6-14 Aryl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6- 14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C(=O)-NR a R b , -C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)O-3 to 20-membered heterocyclyl, -C(=O)OC 6-14 aryl, -C(=O)O-5 or 6-membered monocyclic heteroaryl, -C(=O)O-8 to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20 membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl , -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-C(=O)- C 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)-C 6-14 aryl , -C 1-4 alkyl-C(=O)-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-C(=O)-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-C(=O)-NR a R b , -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O) OC 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)OC 6-14 aryl , -C 1-4 alkyl-C(=O)O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-C(=O)O-8 to 10-membered bicyclic heteroaryl; Wherein, the C 3-20 cycloalkyl group, the 3- to 20-membered heterocyclic group, the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic group The heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, The 8- to 10-membered bicyclic heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    上述各基团中，各个S1组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above groups, the groups of each S1 group are independently selected from the following group: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heteroaryl , 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heteroaryl , -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20-membered heterocyclyl, -C≡CC 6-14 aryl, -C≡ C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1 -4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkane base-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkane base-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl- O-5 or 6 membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10 membered bicyclic heteroaryl, -S (=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, -C(=O )OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl , -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S(=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3 to 20 Member heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1- 4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl-C(= O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)- C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl -C 6-1 4 aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl , -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , -C≡ CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl ) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl-NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 -NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O)-NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; The C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, and the C 2-6 alkynyl group are each independently optionally surrounded by 1, 2 or 3 substituted with a group selected from halogen, deuterium, cyano or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclic group, the C 6-14 aryl, the 5 or 6 The single-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from the group S2; the 3- to 20-membered heterocyclic base, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as a ring atom;
    上述各基团中，各个S4组的基团各自独立地选自下组：氧代(＝O)、卤素、氰基、羟基、羧基、硝基、氘代C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-20环烷基、3到20元杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-O-C 3-20环烷基、-O-3到20元杂环基、-O-C 6-14芳基、-O-5或6元单环杂芳基、-O-8至10元双环杂芳基、-C≡C-C 3-20环烷基、-C≡C-3到20元杂环基、-C≡C-C 6-14芳基、-C≡C-5或6元单环杂芳基、-C≡C-8至10元双环杂芳基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-C 3-20环烷基、-C 1-4烷基-O-C 3-20环烷基、-C 1-4烷基-3至20元杂环基、-C 1-4烷基-O-3至20元杂环基、-C 1-4烷基-C 6-14芳基、-C 1-4烷基-O-C 6-14芳基、-C 1-4烷基-5或6元单环杂芳基、-C 1-4烷基-O-5或6元单环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-C 1-4烷基-O-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-20环烷基、-S(＝O) 2-3至20元杂环基、-C(＝O)O-C 1-6烷基、-C(＝O)O-C 3-20环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-20环烷基、-C(＝O)-C 6-14芳基、-NR a1R b1、-C(＝O)-NR a1R b1、-OR c1、-C 1-4烷基-S(＝O) 2-C 1-6烷基、-C 1-4烷基-S(＝O) 2-C 3-20环烷基、-C 1-4烷基-S(＝O) 2-3至20元杂环基、-C 1-4烷基-C(＝O)O-C 1-6烷基、-C 1-4烷基-C(＝O)O-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 1-6烷基、-C 1-4烷基-C(＝O)-C 3-20环烷基、-C 1-4烷基-C(＝O)-C 6-14芳基、-C(＝O)-5或6元单环杂芳基、-C(＝O)-8至10元双环杂芳基、-C(＝O)-C 1-6烷基-C 3-20环烷基、-C(＝O)-C 1-6烷基-3到20元杂环基、-C(＝O)-C 1-6烷基-C 6-14芳基、-C(＝O)-C 1-6烷基-5或6元单环杂芳基、-C(＝O)-C 1-6烷基-8至10元双环杂 芳基、-C 1-4烷基-NR a1R b1、-C 1-4烷基-C(＝O)-NR a1R b1、-C≡C-C(＝O)-NR a1R b1、-C≡C-C 1-4烷基-C(＝O)-NR a1R b1、-C 1-4烷基-OR c1、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2、-C 1-4烷基-NR d1-C(＝O)-R c1、-C 1-4烷基-NR d1-C(＝O)-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-R c1、-C 1-4烷基-S(＝O) 2-NR a1R b1、-C 1-4烷基-NR d1-S(＝O) 2-NR a1R b1、-NR d1-C(＝O)-R c1、-NR d1-C(＝O)-NR a1R b1、-NR d1-S(＝O) 2-R c1、-S(＝O) 2-NR a1R b1、-NR d1-S(＝O) 2-NR a1R b1；其中，除了上述氘代C 1-6烷基外，任意基团中所述C 1-6烷基、所述C 1-6烷氧基、所述C 2-6烯基、所述C 2-6炔基各自独立地任选地被1个、2个或3个选自卤素、氘、氰基或羟基的基团所取代；所述C 3-20环烷基、所述3到20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S2组的基团所取代；所述3到20元杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有1、2、3或4个独立地选自N、O、S的杂原子作为环原子； Among the above-mentioned groups, the groups of each S4 group are independently selected from the following groups: oxo (=O), halogen, cyano, hydroxyl, carboxyl, nitro, deuterated C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 -membered aryl, 5- or 6-membered monocyclic heterocyclyl Aryl, 8- to 10-membered bicyclic heteroaryl, -OC 3-20 cycloalkyl, -O-3 to 20-membered heterocyclyl, -OC 6-14 aryl, -O-5 or 6-membered monocyclic heterocycle Aryl, -O-8 to 10 membered bicyclic heteroaryl, -C≡CC 3-20 cycloalkyl, -C≡C-3 to 20 membered heterocyclyl, -C≡CC 6-14 aryl, - C≡C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, - C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-OC 3-20 cycloalkyl, -C 1-4 alkyl-3 to 20-membered heterocyclyl, -C 1-4 alkyl-O-3 to 20-membered heterocyclyl, -C 1-4 alkyl-C 6-14 aryl, -C 1-4 alkyl-OC 6-14 aryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, -C 1- 4 alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8 to 10-membered bicyclic heteroaryl base, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-20 cycloalkyl, -S(=O) 2 -3- to 20-membered heterocyclic group, - C(=O)OC 1-6 alkyl, -C(=O)OC 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3- 20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -OR c1 , -C 1-4 alkyl-S (=O) 2 -C 1-6 alkyl, -C 1-4 alkyl-S(=O) 2 -C 3-20 cycloalkyl, -C 1-4 alkyl-S(=O) 2 -3- to 20-membered heterocyclyl, -C 1-4 alkyl-C(=O)OC 1-6 alkyl, -C 1-4 alkyl-C(=O)OC 3-20 cycloalkyl, -C 1-4 alkyl-C(=O)-C 1-6 alkyl, -C 1-4 alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 alkyl -C(=O)-C 6-14 aryl, -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C( =O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20-membered heterocyclyl, -C(=O)-C 1 -6Alkyl -C 6-14 Aryl, -C(=O)-C 1-6 alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10-membered bicyclic heteroaryl Aryl, -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C≡CC(=O)-NR a1 R b1 , - C≡CC 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 , -C 1-4 alkyl-NR d1 -C(=O)-R c1 , -C 1-4 alkyl- NR d1 -C(=O)-NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -R c1 , -C 1-4 alkyl-S(=O) 2 - NR a1 R b1 , -C 1-4 alkyl-NR d1 -S(=O) 2 -NR a1 R b1 , -NR d1 -C(=O)-R c1 , -NR d1 -C(=O) -NR a1 R b1 , -NR d1 -S(=O) 2 -R c1 , -S(=O) 2 -NR a1 R b1 , -NR d1 -S(=O) 2 -NR a1 R b1 ; wherein , in addition to the above-mentioned deuterated C 1-6 alkyl, the C 1-6 alkyl, the C 1-6 alkoxy, the C 2-6 alkenyl, the C 2- 6 Alkynyl groups are each independently optionally substituted with 1, 2 or 3 groups selected from halogen, deuterium, cyano or hydroxy; the C 3-20 cycloalkyl, the 3 to 20-membered Heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally surrounded by 1, 2, 3, or 4 is substituted with a group selected from Group S2; the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
    上述各基团中，各个R a、各个R b、各个R a1、各个R b1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4烷基-8至10元双环杂芳基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6单环环烷基、-S(＝O) 2-3至6元单环杂环基、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6单环环烷基、-C(＝O)-3至6元单环杂环基；其中，所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2；或 In the above groups, each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclic group, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocyclic group Cyclic, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic Heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -S(=O) 2 -C 1-6 alkyl, -S(=O) 2 -C 3-6 monocyclic Cycloalkyl, -S(=O) 2 -3- to 6-membered monocyclic heterocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic ring Alkyl, -C(=O)-3- to 6-membered monocyclic heterocyclic group; wherein, the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group , the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy Oxy group, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ; or
    各个R a和R b与和它们相连的氮原子共同形成3到20元杂环基；各个R a1和R b1与和它们相连的氮原子共同形成3到20元杂环基；其中，所述3到20元杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Each of R a and R b together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; each of R a1 and R b1 together with the nitrogen atom connected to them forms a 3- to 20-membered heterocyclic group; wherein the said The 3- to 20-membered heterocyclic groups are each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个R d、各个R d1各自独立地为H、C 1-6烷基或氘代C 1-6烷基； In the above groups, each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
    上述各基团中，各个R c、各个R c1各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-氘代C 1-6烷基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4烷基-C 3-6单环环烷基、-C 1-4烷基-O-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4烷基-3至6元单环杂环基、-C 1-4烷基-O-3至6元单环杂环基、苯基、-C 1-4烷基-苯基、5或6元单环杂芳基、-C 1-4烷基-5或6元单环杂芳基、8至10元双环杂芳基或-C 1-4烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述苯基、所述5或6元单环杂芳基、所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； In the above groups, each R c and each R c1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy base, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3 to 6-membered monocyclic heterocycle base, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5 or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl Aryl or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic, the phenyl, the The 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , - P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，各个S2组的基团各自独立地选自下组：氧代(C＝O)、卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-NH 2、-NHC 1-6 烷基、-N(C 1-6烷基) 2、-C 1-4烷基-P(＝O)-(C 1-6烷基) 2、-P(＝O)-(C 1-6烷基) 2； Among the above groups, the groups of each S2 group are independently selected from the following group: oxo (C=O), halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkoxy base, -N(C 1-6 alkyl) 2 , -C 1-4 alkyl-P(=O)-(C 1-6 alkyl) 2 , -P(=O)-(C 1-6 alkyl) 2 ;
    上述各基团中，所述-C 1-4烷基-或-C 3-6单环环烷基-为未取代的；或者-C 1-4烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-CH 2-羟基、-CH 2-氰基、苯基的基团所取代或者C 1-4烷基上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；-C 3-6单环环烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基的基团所取代。 In each of the above groups, the -C 1-4 alkyl- or -C 3-6 monocyclic cycloalkyl- is unsubstituted; or the hydrogen atoms on the -C 1-4 alkyl- are independently replaced by selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, phenyl The group is substituted or two hydrogen atoms of the same carbon atom on the C 1-4 alkyl group are simultaneously substituted by -(CH 2 ) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; The hydrogen atoms on -C 3-6 monocyclic cycloalkyl- are each independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 substituted with an alkyl group.
  7. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，Cy1环选自下组：The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the Cy1 ring is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100023
    Figure PCTCN2022085658-appb-100023
    上述各个基团上的n个氢原子可以任意地被R 1所取代；n为0、1、2或3；各个R 1各自独立地定义同前。 The n hydrogen atoms on each of the above groups can be optionally substituted by R 1 ; n is 0, 1, 2 or 3; each R 1 is independently defined as before.
  8. 如权利要求7所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100024
    选自下组：     The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100024
    Choose from the following group:
    Figure PCTCN2022085658-appb-100025
    Figure PCTCN2022085658-appb-100025
    Figure PCTCN2022085658-appb-100026
    Figure PCTCN2022085658-appb-100026
    Figure PCTCN2022085658-appb-100027
    Figure PCTCN2022085658-appb-100027
  9. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，Cy2环选自下组：The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the Cy2 ring is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100028
    Figure PCTCN2022085658-appb-100028
  10. 如权利要求1-5任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100029
    中，R x为氢；Cy2环选自下组：     The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100029
    In, R x is hydrogen; Cy2 ring is selected from the following group:
    Figure PCTCN2022085658-appb-100030
    Figure PCTCN2022085658-appb-100030
    且Cy2环可以被1或2个R 2取代；各个R 2各自独立地定义同前。 And the Cy2 ring may be substituted by 1 or 2 R 2 ; each R 2 is independently defined as before.
  11. 如权利要求1-5任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x为氢；m为1或2；
    Figure PCTCN2022085658-appb-100031
    选自下组：     The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein, R x is hydrogen; m is 1 or 2;
    Figure PCTCN2022085658-appb-100031
    Choose from the following group:
    Figure PCTCN2022085658-appb-100032
    Figure PCTCN2022085658-appb-100032
    各式中，各个R 2各自独立地定义同前。 In each formula, each R 2 is independently defined as above.
  12. 如权利要求6所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100033
    选自下组：
    Figure PCTCN2022085658-appb-100034
    各式中，R 2、R x定义同权利要求6中(a)中定义。     The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100033
    Choose from the following group:
    Figure PCTCN2022085658-appb-100034
    In each formula, R 2 and R x are as defined in (a) of claim 6 .
  13. 如权利要求6所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100035
    选自下组：     The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100035
    Choose from the following group:
    Figure PCTCN2022085658-appb-100036
    Figure PCTCN2022085658-appb-100036
    各式中，R 2、R x定义同权利要求6中(b)中定义。 In each formula, R 2 and R x are as defined in (b) of claim 6 .
  14. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100037
    选自下组：     The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100037
    Choose from the following group:
    Figure PCTCN2022085658-appb-100038
    Figure PCTCN2022085658-appb-100038
    各式中，各个R x、R 2各自独立地定义同前。 In each formula, each of R x and R 2 is independently defined as above.
  15. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，
    Figure PCTCN2022085658-appb-100039
    选自下组：     The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein,
    Figure PCTCN2022085658-appb-100039
    Choose from the following group:
    Figure PCTCN2022085658-appb-100040
    Figure PCTCN2022085658-appb-100040
    各式中，各个R x、R 2各自独立地定义同前。 In each formula, each of R x and R 2 is independently defined as above.
  16. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x选自下组： The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R x is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100041
    Figure PCTCN2022085658-appb-100041
    Figure PCTCN2022085658-appb-100042
    Figure PCTCN2022085658-appb-100042
    上述各个基团中环上的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代；The hydrogen atoms on the ring in each of the above groups can be independently optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group;
    上述各个基团中非环上的氢原子可以各自独立地任选地被1或2个选自氘和甲基的基团所取代。The acyclic hydrogen atoms in each of the above groups may each independently be optionally substituted with 1 or 2 groups selected from deuterium and methyl.
  17. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x选自下组： The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R x is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100043
    各式中，各个n1、各个n2各自独立地为0、1、2或3；上述各个基团中的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代。
    Figure PCTCN2022085658-appb-100043
    In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  18. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x选自下组： The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R x is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100044
    各式中，各个n1、各个n2各自独立地为0、1、2或3；上述各个基团中的氢原子可以各自独立地任选地被1、2、3或4个选自S1组的基团所取代。
    Figure PCTCN2022085658-appb-100044
    In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  19. 如权利要求1-5任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x为
    Figure PCTCN2022085658-appb-100045
    其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c、R 2d各自独立地为H、C 1-6烷基、C 3-6单环环烷基或3到6元单环杂环基。     The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein, R x is
    Figure PCTCN2022085658-appb-100045
    Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 Monocyclic heterocyclyl.
  20. 如权利要求6所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x为
    Figure PCTCN2022085658-appb-100046
    其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c、R 2d各自独立地为H、C 1-6烷基、C 3-6单环环烷基或3到6元单环杂环基；且当R 2c为C 1-6烷基时R 2d不为3到6元单环杂环基。     The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R x is
    Figure PCTCN2022085658-appb-100046
    Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 6-membered monocyclic heterocyclyl.
  21. 如权利要求6所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R x为
    Figure PCTCN2022085658-appb-100047
    其中，R 2a为H或氘；R 2b为H、氘或甲基；R 2c和R 2d与和它们相连的氮原子共同构成3到6元单环杂环基、5或6元单环杂芳基或8至10元双环杂芳基；所述3到6元单环杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地含有一个氮原子和任选地1或2个独立地选自N、O、S的杂原子作为环原子；且所述3到6元单环杂环基、所述5或6元单环杂芳基、所述8至10元双环杂芳基各自独立地任选地被1、2、3或4个选自S4组的基团所取代。     The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R x is
    Figure PCTCN2022085658-appb-100047
    Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d together with the nitrogen atom connected to them form a 3- to 6-membered monocyclic heterocyclic group, a 5- or 6-membered monocyclic heterocyclic group Aryl or 8- to 10-membered bicyclic heteroaryl; the 3- to 6-membered monocyclic heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contain One nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 6-membered monocyclic heterocyclyl, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from Group S4.
  22. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，R 2选自下组： The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein R is selected from the group consisting of :
    Figure PCTCN2022085658-appb-100048
    Figure PCTCN2022085658-appb-100048
  23. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药：其中，所述化合物选自下组：The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: wherein the compound is selected from the group consisting of:
    Figure PCTCN2022085658-appb-100049
    Figure PCTCN2022085658-appb-100049
    Figure PCTCN2022085658-appb-100050
    Figure PCTCN2022085658-appb-100050
    Figure PCTCN2022085658-appb-100051
    Figure PCTCN2022085658-appb-100051
    Figure PCTCN2022085658-appb-100052
    Figure PCTCN2022085658-appb-100052
    Figure PCTCN2022085658-appb-100053
    Figure PCTCN2022085658-appb-100053
    Figure PCTCN2022085658-appb-100054
    Figure PCTCN2022085658-appb-100054
    Figure PCTCN2022085658-appb-100055
    Figure PCTCN2022085658-appb-100055
    Figure PCTCN2022085658-appb-100056
    Figure PCTCN2022085658-appb-100056
    Figure PCTCN2022085658-appb-100057
    Figure PCTCN2022085658-appb-100057
    Figure PCTCN2022085658-appb-100058
    Figure PCTCN2022085658-appb-100058
    Figure PCTCN2022085658-appb-100059
    Figure PCTCN2022085658-appb-100059
    Figure PCTCN2022085658-appb-100060
    Figure PCTCN2022085658-appb-100060
    Figure PCTCN2022085658-appb-100061
    Figure PCTCN2022085658-appb-100061
    Figure PCTCN2022085658-appb-100062
    Figure PCTCN2022085658-appb-100062
    Figure PCTCN2022085658-appb-100063
    Figure PCTCN2022085658-appb-100063
    Figure PCTCN2022085658-appb-100064
    Figure PCTCN2022085658-appb-100064
  24. 根据权利要求1所述的式(A)化合物或其药学上可接受的盐、溶剂化物或前药的制备方法，其包括以下制备步骤：The preparation method of the compound of formula (A) or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, comprising the following preparation steps:
    Figure PCTCN2022085658-appb-100065
    Figure PCTCN2022085658-appb-100065
    其中，Cy1环、Cy2环、R 1、m、n、R 2、R 3、R 4、R x、p、L 1、L 2、X、Y的定义如权利要求1所定义； Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , m, n, R 2 , R 3 , R 4 , R x , p, L 1 , L 2 , X, and Y are as defined in claim 1;
    R m和R m’选自可供反应的基团； Rm and Rm' are selected from reactive groups;
    优选地，R m和R m’选自卤素原子、硼酸基或硼酸酯基；条件是：R m选自卤素原子时，R m’选自硼酸基或硼酸酯基，R m’选自卤素原子时，R m选自硼酸基或硼酸酯基； Preferably, R m and R m' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R m is selected from halogen atoms, R m' is selected from boronic acid groups or boronic acid ester groups, and R m' is selected from From a halogen atom, R m is selected from a boronic acid group or a boronic acid ester group;
    所述硼酸基或硼酸酯基选自
    Figure PCTCN2022085658-appb-100066
    或-B(OH) 2。     The boronic acid group or boronic acid ester group is selected from
    Figure PCTCN2022085658-appb-100066
    or -B(OH) 2 .
  25. 根据权利要求1所述的式(D)化合物或其药学上可接受的盐、溶剂化物或前药的制备方法，其包括以下制备步骤：The preparation method of the compound of formula (D) according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising the following preparation steps:
    Figure PCTCN2022085658-appb-100067
    Figure PCTCN2022085658-appb-100067
    其中，Cy1环、Cy2环、R 1、R 2、m、n、R 3、R 4、R x、p1、q、L 1、L 2、X、Y的定义如权利要求1所定义； Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, R 3 , R 4 , R x , p1 , q, L 1 , L 2 , X, and Y are as defined in claim 1;
    R n和R n’选自可供反应的基团； Rn and Rn ' are selected from reactive groups;
    优选地，R n和R n’选自卤素原子、硼酸基或硼酸酯基；条件是：R n选自卤素原子时，R n’选自硼酸基或硼酸酯基，R n’选自卤素原子时，R n选自硼酸基或硼酸酯基； Preferably, R n and R n' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R n is selected from halogen atoms, R n' is selected from boronic acid groups or boronic ester groups, and R n' is selected from From a halogen atom, R n is selected from a boronic acid group or a boronic acid ester group;
    所述硼酸基或硼酸酯基选自
    Figure PCTCN2022085658-appb-100068
    或-B(OH) 2。     The boronic acid group or boronic acid ester group is selected from
    Figure PCTCN2022085658-appb-100068
    or -B(OH) 2 .
  26. 根据权利要求5所述的式(B)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药的制备方法，其包括以下制备步骤：The preparation method of the compound of formula (B) according to claim 5 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, comprising the following preparation steps:
    Figure PCTCN2022085658-appb-100069
    Figure PCTCN2022085658-appb-100069
    其中，Cy1环、Cy2环、R 1、R 2、m、n、R 3、R 4、R x、L 1、L 2、p的定义如权利要求5所定义； Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, R 3 , R 4 , R x , L 1 , L 2 , and p are as defined in claim 5;
    R y和R y’选自可供反应的基团； Ry and Ry' are selected from reactive groups;
    优选地，R y和R y’选自卤素原子、硼酸基或硼酸酯基；条件是：R y选自卤素原子时，R y’选自硼酸基或硼酸酯基，R y’选自卤素原子时，R y选自硼酸基或硼酸酯基； Preferably, R y and R y' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R y is selected from halogen atoms, R y' is selected from boronic acid groups or boronic ester groups, and R y' is selected from When from a halogen atom, R y is selected from a boronic acid group or a boronic acid ester group;
    所述硼酸基或硼酸酯基选自
    Figure PCTCN2022085658-appb-100070
    或-B(OH) 2。     The boronic acid group or boronic acid ester group is selected from
    Figure PCTCN2022085658-appb-100070
    or -B(OH) 2 .
  27. 根据权利要求6所述的式(C)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药的制备方法，其包括以下制备步骤：The preparation method of the compound of formula (C) according to claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, comprising the following preparation steps:
    Figure PCTCN2022085658-appb-100071
    Figure PCTCN2022085658-appb-100071
    其中，Cy1环、Cy2环、R 1、R 2、m、n、R x的定义如权利要求6所定义； Wherein, the definitions of Cy1 ring, Cy2 ring, R 1 , R 2 , m, n, and R x are as defined in claim 6;
    R Z和R Z’选自可供反应的基团； R Z and R Z' are selected from reactive groups;
    优选地，R Z和R Z’选自卤素原子、硼酸基或硼酸酯基；条件是：R Z选自卤素原子时，R Z’选自硼酸基或硼酸酯基，R Z’选自卤素原子时，R Z选自硼酸基或硼酸酯基； Preferably, R Z and R Z' are selected from halogen atoms, boronic acid groups or boronic ester groups; the condition is: when R Z is selected from halogen atoms, R Z' is selected from boronic acid groups or boronic ester groups, and R Z' is selected from When from a halogen atom, R Z is selected from a boronic acid group or a boronic acid ester group;
    所述硼酸基或硼酸酯基选自
    Figure PCTCN2022085658-appb-100072
    或-B(OH) 2。     The boronic acid group or boronic acid ester group is selected from
    Figure PCTCN2022085658-appb-100072
    or -B(OH) 2 .
  28. 一种药物组合物，所述药物组合物包括权利要求1至23中任一项所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier .
  29. 如权利要求1至23中任一项所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或如权利要求28所述药物组合物在制备预防和/或治疗与HPK1活性相关的疾病或病症的药物中的用途。A compound as claimed in any one of claims 1 to 23 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or a pharmaceutical composition as claimed in claim 28 in the preparation of prophylactic and/or therapeutic and Use in the medicament of a disease or condition associated with HPK1 activity.
  30. 如权利要求29所述的用途，其中，所述与HPK1活性相关的疾病或病症为癌症。The use of claim 29, wherein the disease or disorder associated with HPK1 activity is cancer.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143344A1 (en) * 2022-01-30 2023-08-03 微境生物医药科技(上海)有限公司 Novel egfr inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104334532A (en) * 2012-01-30 2015-02-04 霍夫曼-拉罗奇有限公司 Isoquinoline and naphthyridine derivatives
CN109721620A (en) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 HPK1 inhibitors and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104334532A (en) * 2012-01-30 2015-02-04 霍夫曼-拉罗奇有限公司 Isoquinoline and naphthyridine derivatives
CN109721620A (en) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 HPK1 inhibitors and uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 8 July 2021 (2021-07-08), ANONYMOUS : "-1-Isoquinolinamine, 7-(4-methoxyphenyl)-4-[3-(methylsulfonyl)phenyl]- (CA INDEX NAME) ", XP055975813, retrieved from STN Database accession no. 2650657-18-2 *
GAMO, F. J. ET AL.: "Thousands of chemical starting points for antimalarial lead identification", NATURE, vol. 465, 20 May 2010 (2010-05-20), XP002698188, DOI: 10.1038/NATURE09107 *
TRICIA L. MAY-DRACKA, ROBERT ARDUINI, ANDREA BERTOLOTTI-CIARLET, GOVINDA BHISETTI, MARGOT BRICKELMAIER, ELLEN CAHIR-MCFARLAND, IST: "Investigating small molecules to inhibit germinal center kinase-like kinase (GLK/MAP4K3) upstream of PKCθ phosphorylation: Potential therapy to modulate T cell dependent immunity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 28, no. 10, 1 June 2018 (2018-06-01), Amsterdam NL , pages 1964 - 1971, XP055644699, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.03.032 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143344A1 (en) * 2022-01-30 2023-08-03 微境生物医药科技(上海)有限公司 Novel egfr inhibitor

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