WO2023143384A1 - Compound for inhibiting or degrading hpk1 kinase and medical use thereof - Google Patents

Compound for inhibiting or degrading hpk1 kinase and medical use thereof Download PDF

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WO2023143384A1
WO2023143384A1 PCT/CN2023/073180 CN2023073180W WO2023143384A1 WO 2023143384 A1 WO2023143384 A1 WO 2023143384A1 CN 2023073180 W CN2023073180 W CN 2023073180W WO 2023143384 A1 WO2023143384 A1 WO 2023143384A1
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alkyl
membered
substituted
ring
alkoxy
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PCT/CN2023/073180
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Chinese (zh)
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张晨
赵晨飞
袁帅
柴金龙
马俊杰
余彦
唐平明
李瑶
严庞科
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四川海思科制药有限公司
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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
    • C07D517/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound described in general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and Its intermediate, and its use in HPK1 kinase-related diseases such as cancer.
  • Protein kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites and play key roles in various aspects of eukaryotic cell physiology.
  • protein kinases and lipid kinases are involved in signaling events that control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines.
  • protein kinases fall into two classes, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.
  • Hematopoietic progenitor kinase HPK1 Hematopoietic Progenitor Kinase 1, also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1, MAP4K1
  • HPK1 Hematopoietic Progenitor Kinase 1, also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase Kinase 1, MAP4K1
  • TCR T cell receptor
  • HPK1 kinase-deficient mice Compared with wild-type mice, HPK1 kinase-deficient mice exhibited better T cell proliferation activity and anti-tumor immunity under TCR stimulation. At the same time, mice lacking HPK1 kinase did not show a lethal inflammatory response (ACS Med. Chem. Lett. 2021, 12, 443–450). Therefore, HPK1 has become an important class of therapeutic targets and has attracted extensive research and development interest (J.Med.Chem.2022, 65, 8065–8090).
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases This type of compound can be recognized by the proteasome of the cell, causing the degradation of the targeting protein, and can effectively reduce the target protein. protein content in cells.
  • ligands that can bind different targeting proteins By introducing ligands that can bind different targeting proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received extensive attention in recent years. Compared with inhibitors, PROTACs can not only inhibit the kinase activity of the target, but also regulate its scaffold function (Nat. Rev. Drug Discov. 2022, 21, 181–200).
  • the purpose of the present invention is to provide a compound with novel structure, good drug effect, high bioavailability, safer, capable of inhibiting and degrading HPK1 for treating diseases related to HPK1 such as cancer.
  • the present invention provides a compound or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, the compound is selected from the general formula (I ) shown in the compound,
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia) or (Ib),
  • W is selected from CH or N;
  • Z is selected from S or Se
  • Z is selected from S or Se
  • Ba is selected from N or CH
  • L is selected from a bond or -C 1-50 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-20 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-10 hydrocarbyl-, wherein there are 0 to 10 (eg, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 Or 10) the methylene unit is optionally further replaced by -Ak-, -Cy-;
  • each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;
  • each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl,
  • the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N;
  • each R L is independently selected from H or C 1-6 alkyl
  • each R L is independently selected from H or C 1-4 alkyl
  • RL is selected from H, methyl or ethyl
  • each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • each q is independently selected from 0, 1, 2, 3 or 4;
  • each q is independently selected from 0, 1 or 2;
  • each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
  • each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring , 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aromatic
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups which are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, azacyclopentyl, aziridinyl, Piperidine, morpholine, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl , cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclopentyl cyclopentyl, cyclopenty
  • L is selected from -Cyl-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cyl-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-C
  • L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5 -, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -C
  • L is selected from -Cyl-, -Cyl-Ak1-, -Cyl-Cy2-, -Cyl-Ak1-Cy2-, -Cyl-Cy2-Ak2-, -Cyl-Ak1-Cy2-Ak2 -, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Cy3-Ak3-Cy4-;
  • L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;
  • L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;
  • L is selected from -Cy1-CH 2 -Cy2-
  • Cy1 and Cy2 are each independently selected from 4 to 6 membered nitrogen-containing heteromonocyclic rings or 7 to 11 membered nitrogen-containing heterospirocyclic rings (preferably nitrogen Heterobutyl, azacyclopentyl, piperidinyl, piperazinyl, )
  • K is selected from
  • K is selected from Indicates that the ring is selected from an aromatic ring or a non-aromatic ring; in certain embodiments, K is selected from
  • R is selected from H or C 1-6 alkyl
  • R is selected from H or C 1-4 alkyl
  • Rq is selected from H, methyl, ethyl
  • each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, the heterocycle or heteroaryl Aryl contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each E is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle, 8-12 membered heterocycle, 7-12 membered heteroaryl or 5-6 membered heterocycle Aryl, the heterocyclic or heteroaryl group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, oxa Azolyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl;
  • each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, or oxa Azolyl;
  • each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl;
  • each E is independently selected from a benzene ring or a pyridine ring;
  • A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the heterocyclic or heteroaryl containing 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • each of A, H1 or H2 is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, and the heterocycle or heteroaryl Contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • each of A, H1 or H2 is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, Thienyl or oxazolyl;
  • A, H1 or H2 are each independently selected from phenyl or pyridyl;
  • each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, the heterocyclyl or Heteroaryl contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered parallel cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4 -7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, said heteromono
  • the ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopenta[ c] pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridine Base, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, naphthofuryl, thiophene Indolyl, benzimidazolyl, Benzopyrazoly
  • the heterocycle contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, the carbocycle or heterocycle
  • the heterocycle contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so
  • each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
  • each R k7 is independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
  • each Rk7 is independently selected from CH2 , O, N( CH3 ) or NH;
  • each R is independently selected from C, N, or CH;
  • the heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • M is selected from -NH- or -O-;
  • K is selected from one of the structural fragments shown in Table K-1;
  • K is selected from one of the structural fragments shown in Table K-2;
  • n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • p1 or p2 are each independently selected from 0, 1 or 2;
  • B is selected from
  • B is selected from Z is selected from S, Se, Ba is selected from N or CH; in certain embodiments, B is selected from Z 2 is selected from S, Se, Ba is selected from N or CH;
  • Z 1 , Z 2 or Z 3 are each independently selected from S, Se, N, NR z or CR z ;
  • R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3 to 8 membered heterocyclic group, said alkyl, alkoxyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 substitutions selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl Substituted by a group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 Alkyl, C 1-4 alkoxyl, C 3-7 carbocyclyl or 3 to 7 membered heterocyclic group, said alkyl, alkoxyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 substitutions selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl base replaced;
  • Rz is selected from H, F, Cl, Br, I, NH2 , cyano, OH, NHCH3 , NHCH2CH3 , methyl, ethyl, methoxy, ethoxy , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, azetidinyl, piperidinyl, piperazinyl;
  • any two R z are directly connected to form a C 4-8 carbocycle or a 4-8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, said
  • the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
  • any two R z are directly connected to form a C 4-7 carbocycle or a 4-7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the
  • the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
  • any two R z are directly linked to form a 5-membered carbocyclyl, a 6-membered carbocyclyl, or a 7-membered carbocyclyl;
  • R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C 1-4 alkyl-C 3-10 carbocycle, -C 1-4 alkyl-3 to 10-membered heterocycle, C 3-10 carbocycle or 3-10 membered heterocycle, the alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, Substitution of NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy Substituted by a group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R a1 is selected from H, C 1-4 alkyl
  • Ra1 is selected from H, methyl, ethyl
  • R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic carbocycle, -C 1-2 alkyl-C 7-10 double ring carbocycle, -C 1 -2 Alkyl-C 6-10 Spiral carbocycle, -C 1-2 alkyl-C 5-10 bridged ring carbocycle, -C 1-2 alkyl-4 to 8 membered monocyclic heterocycle, -C 1-2 alkyl-7 to 10 Membered ring heterocyclic ring, -C 1-2 alkyl-6 to 10 membered spirocyclic heterocyclic ring, -C 1-2 alkyl -5 to 10 membered bridged ring heterocyclic ring, C 3-6 monocyclic carbocycle, C 7-10 parallel ring carbocycle, C 6-10 spiro carbocycle, C 5-10 bridged ring carbocycle, 4-8 membered monocyclic heterocycle, 7-10 membered parallel ring heterocycle, 6-10 member
  • R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, Ring non-aromatic ring, -C 1-2 alkyl-5 to 6-membered aromatic heterocycle, -C 1-2 alkyl-4 to 8-membered monocyclic non-aromatic heterocycle, C 5-6 monocyclic aromatic ring, C 3-6 monocyclic non-aromatic rings, 5-6 membered aromatic heterocycles, 4-8 membered monocyclic non-aromatic heterocycles, any of the alkyl, aromatic rings, non-aromatic rings, aromatic heterocycles, and non-aromatic heterocycles C 1-4 alkyl, cyano further selected from 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxyl Substit
  • R a2 is selected from one of H, substituted or unsubstituted following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Morpholine, Piperazine, Pyridine, Phenyl, -CH 2 -Cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, -CH 2 -oxolyl, -CH 2 -o
  • R 2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 selected from H, halogen , OH, cyano, C 1-6 alkyl substituents;
  • R 2 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 selected from H, halogen , OH, cyano, C 1-4 alkyl substituents;
  • R is selected from H, methyl, ethyl or cyclopropyl, and said methyl, ethyl or cyclopropyl is optionally further replaced by 0 to 4 selected from H, halogen, OH , cyano, C 1-4 alkyl substituents are substituted;
  • R is selected from H
  • X1 is selected from O, S, NRx
  • X2 is selected from N, CRx ;
  • X is selected from NH, and X is selected from N or CH;
  • X is selected from NH
  • X is selected from N or CH;
  • each R x is independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, said alkane C 1-6 alkyl group , C 1-6 alkyl group, C 1 Substituents of -6 alkoxy or C 3-6 cycloalkyl;
  • each R x is independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkane C 1-4 alkyl , C 1 -4 alkoxy or C 3-6 cycloalkyl substituents;
  • each R x is independently selected from H or C 1-4 alkyl
  • each R x is independently selected from H, methyl, or ethyl
  • Ring B is selected from a benzene ring or a 5 to 6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N;
  • Ring B is selected from benzene rings, pyridine, pyrimidine;
  • each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , - NH(C 3-6 cycloalkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy , cycloalkyl, alkynyl are optionally further substituted by 0 to 4 C 1-6 alkyl, C 1-6 alkyl, C 1-6 selected from H , halogen, OH, cyano, NH 2 , halogen Substituted by alkoxy, C 3-6 cycloalkyl or 4 to 8 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 heteroatoms selected from O, S, N;
  • each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , - NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy , cycloalkyl, alkynyl optionally further substituted by 0 to 4 C 1-4 alkyl, C 1-4 alkyl, C 1-4 selected from H , halogen, OH, cyano, NH 2 , halogen Substituents of alkoxy, C 3-6 cycloalkyl or 4 to 6 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 heteroatoms selected from O, S, N;
  • each R3 is independently selected from H, F, Cl, Br, I, OH, cyano, NH2 , methyl, ethyl, methoxy, cyclopropyl, ethynyl, propane Alkynyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, 2 or 3;
  • B is selected from one of the structural fragments shown in Table B-1;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • L is selected from a bond or -C 1-50 hydrocarbon group-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
  • q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • RL are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
  • Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocyclic ring Alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the aryl, Heteroaryl, cycloalkyl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings are optionally further represented by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2.
  • Z 1 , Z 2 or Z 3 are each independently selected from S, Se, N, NR z or CR z ;
  • R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, the said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • any two R z are directly connected to form a C 4-8 carbocycle or a 4 to 8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C 1-4 alkyl-C 3-10 carbocycle, -C 1-4 alkyl-3 to 10 membered heterocycle, C 3-10 carbocyclic rings or 3-10 membered heterocyclic rings, the alkyl, carbocyclic or heterocyclic rings are optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH 2 , C 1-6 Alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy substituents, said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R 2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-6 alkyl substituents;
  • X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
  • R x are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-6 alkyl, C 1-6 alkoxy or C selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
  • Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
  • Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl or alkynyl C 1-6 alkyl , C 1-6 alkyl, C 1-6 alkoxy, C 3- Substituted by a 6- cycloalkyl group or a 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
  • n is selected from 0, 1, 2, 3 or 4;
  • Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, so
  • R is selected from H or C 1-6 alkyl
  • A is selected from C 3-10 carbocyclic group, C 6-10 aryl group, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, and the heterocyclic ring or heteroaryl group contains 1 to 4 members selected from O , S, N heteroatoms;
  • F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclic group or 5-20 membered heteroaryl, and the heterocyclic group or heteroaryl contains 1 to 4 a heteroatom selected from O, S, N;
  • Each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
  • the group contains 1 to 4 heteroatoms selected from O, S, N;
  • R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocycle or a 3-8 membered heterocycle
  • the heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
  • R k4 are each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, cycloalkane
  • M 3 is selected from -NH- or -O-;
  • the substituent is substituted, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O, S;
  • n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-,
  • q are each independently selected from 0, 1, 2, 3 or 4;
  • RL are each independently selected from H or C 1-6 alkyl
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • RL are each independently selected from H or C 1-4 alkyl
  • R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Alkoxy, C 3-7 carbocyclyl or 3 to 7 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • any two R z are directly connected to form a C 4-7 carbocycle or a 4 to 7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
  • R a1 is selected from H, C 1-4 alkyl
  • R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, -C 1-2 alkyl-C 3-6 monocyclic non-aromatic ring, -C 1-2 alkyl-5 to 6-membered aromatic heterocycle, -C 1-2 alkyl-4 to 8-membered monocyclic non-aromatic heterocycle, C 5-6 monocyclic aromatic ring, C 3-6 monocyclic non-aromatic ring, 5-6 membered aromatic heterocycle, 4-8 membered monocyclic non-aromatic heterocycle, the alkyl, aromatic ring, non-aromatic ring, aromatic heterocycle, non-aromatic heterocycle are optional Further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano Substituents of C 1-4 alky
  • R 2 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-4 alkyl substituents;
  • X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
  • R x are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-4 alkyl, C 1-4 alkoxy or C selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
  • Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
  • Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl or alkynyl C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy , C 3- Substituted by a 6- cycloalkyl group or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
  • n is selected from 0, 1, 2, 3 or 4;
  • the ring is selected from an aromatic ring or a non-aromatic ring
  • Each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocyclic group, the
  • R is selected from H or C 1-4 alkyl
  • the heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
  • R k4 are each independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
  • R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
  • R K6 are each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
  • R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
  • Each R K8 is independently selected from C, N or CH;
  • R k9 are each independently selected from a bond, C( CH3 ) 2 , CO, CH2 , CH2CH2 or SO2 ;
  • A, H1 or H2 are each independently selected from C3-8 carbocycles, benzene rings, 4-7 membered heterocycles or 5-6 membered heteroaryls, and the heterocycles or heteroaryls contain 1 to 4 members selected from Heteroatoms of O, S, N;
  • E are each independently selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring, 8-12 membered heterocyclic group, 7-12 membered heteroaryl group or 5-6 membered heteroaryl group, the heteroaryl
  • the ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
  • F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, the heteromonocyclic, heterocyclic, heterocyclic
  • the spiro ring, heterobridged ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • RL is selected from H, methyl or ethyl
  • q are each independently selected from 0, 1 or 2;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, nitrogen Heterocyclopentyl, aziridinyl, piperidine, morpholine, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropyl Cyclobutyl cyclohexyl, cyclobutyl cyclobutyl, cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclo Propylspiro
  • R z is selected from H, F, Cl, Br, I, NH 2 , cyano, OH, NHCH 3 , NHCH 2 CH 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl Base, cyclohexyl, cyclopentyl, azetidinyl, azacyclopentyl, piperidinyl, piperazinyl;
  • any two Rz are directly connected to form a 5-membered carbocyclyl, a 6-membered carbocyclyl or a 7-membered carbocyclyl;
  • R a2 is selected from one of H, substituted or unsubstituted following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Morpholine, Piperazine, Pyridine, Phenyl, -CH 2 -Cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, -CH 2 -oxolyl, -CH 2 -o
  • R is selected from H
  • X is selected from NH
  • X2 is selected from N or CH;
  • Ring B 1 is selected from benzene ring, pyridine, pyrimidine;
  • R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, NH 2 , methyl, ethyl, methoxy, cyclopropyl, ethynyl, propynyl;
  • E are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
  • A is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
  • F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6,7-dihydro-5H-cyclopentyl [c] pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, Pyridyl, pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, naphthalene And furyl, thienoindolyl, benzimidazolyl,
  • R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
  • p1 or p2 are each independently selected from 0, 1 or 2;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted:
  • K is selected from one of the structural fragments shown in Table K-1;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2- Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
  • L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;
  • K is selected from one of the structural fragments shown in Table K-2;
  • the present invention relates to a compound or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following table One of the structures shown in S-1.
  • the present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to a kind of above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of treatment and Application in medicine for diseases related to HPK1 activity or expression level.
  • the present invention relates to a kind of above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of treatment and Application in drugs for inhibiting or degrading HPK1 related diseases.
  • the present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and the diseases selected from cancer.
  • the preparation specifications comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but Not limited to 1-1500mg, 1-400mg, 1-375mg, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5- 250mg, 5-220mg, 5-200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5-60mg, 5-40mg, 5-20mg, 5-90mg, 5-70mg,
  • the amount of the compound of general formula (I) or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal includes but not limited to 1-1500mg , 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5- 300mg, 5-275mg, 5-250mg, 5-220mg, 5-200mg, 5-175m
  • the preparations comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but Not limited to 1-1500mg/day, 1-400mg/day, 1-375mg/day, 1-350mg/day, 1-325mg/day, 1-300mg/day, 1-275mg/day, 1-250mg/day, 1-220mg/day, 1-200mg/day, 1-175mg/day, 1-150mg/day, 1-125mg/day, 1-100mg/day, 1-80mg/day, 1-60mg/day, 1- 40mg/day, 1-20mg/day, 5-400mg/day, 5-375mg/day, 5-350mg/day, 5-325mg/day, 5-300mg/day, 5-275mg/day, 5-250mg/day day, 5-220mg/day, 5-
  • a pharmaceutical composition configured in a single dose or in divided doses, wherein the single or divided doses comprise the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates , prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but are not limited to 1-1500mg, 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1 -250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375 , 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5-250mg, 5-220mg, 5-200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5 -60
  • the present invention relates to a kit, which may include a composition in a single dose or in divided doses, the kit comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers,
  • the amount of deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal includes but not limited to 1-1500mg, 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg , 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5-250mg, 5-220mg, 5- 200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80
  • imidazo moieties exist in tautomeric forms, including
  • the carbon, hydrogen, oxygen, sulfur, selenium, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the groups and compounds involved in the present invention
  • the carbon, hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium ( D, also called heavy hydrogen), tritium (T, also called super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of selenium Including 74 Se, 76 Se, 77 Se, 78 Se, 80 Se, 82 Se, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F, 18 F and 19 F, chlorine isotopes include 35
  • Halogen means F, Cl, Br or I.
  • Halogen substituted refers to F, Cl, Br or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I.
  • Halo-substituted is simply referred to as "halo”.
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; Alkyl group appearing in this article, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.
  • Cycloalkyl means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or
  • the heteroatom of S, the optionally substituted N in the ring of heterocycloalkyl, S can be oxidized into various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • a heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.
  • alkenyl means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms
  • alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-but Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octen
  • Alkynyl means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the backbone comprising 2 to 10 carbon atoms , including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl include but not limited to ethynyl, propargyl, 1-propynyl, 2 -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl Base-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- Hexynyl, 5-hexynyl, 1-
  • Alkoxy means a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring
  • the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system
  • the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring
  • the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
  • a "carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclic group or “heterocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, the ring optional of heterocyclyl Substituted N and S can be oxidized into various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyrid
  • Spiro ring or “spirocyclic group” refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings.
  • a "spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:
  • Alkyl or “alkyl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane.
  • a "bridged ring” or “bridged ring group” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospiro refers to a “spirocycle” whose ring system consists only of carbon atoms.
  • the definitions of “carbospirocycle”, “spirocyclic carbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing herein are consistent with spirocycle.
  • Carbocyclic “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” refers to a “carbocyclyl” whose ring system consists only of carbon atoms.
  • the definition of “carbocyclyl”, “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” used herein is consistent with that of paracyclyl.
  • Carbobridged ring refers to a “bridged ring” whose ring system consists only of carbon atoms.
  • the definitions of "carbon bridged ring”, “bridged ring carbocyclyl”, “bridged carbocyclyl” or “carbobridged ring” appearing in this article are consistent with those of bridged ring.
  • Heteromonocyclic refers to the “heterocyclic group” or “heterocyclic group” of a monocyclic ring system, and the "heteromonocyclic”, “monocyclic” appearing herein Heterocyclic group” or “heteromonocyclic group", its definition is consistent with heterocycle.
  • Heterocyclyl refers to “heterocycles” that contain heteroatoms.
  • the definition of “heterocyclic ring”, “heterocyclic group”, “heterocyclic heterocyclic group” or “heterocyclic group” used herein is consistent with that of parallel ring.
  • Heterospiro refers to a “spirocycle” that contains heteroatoms.
  • the definitions of “heterospirocycle”, “heterospirocyclyl”, “spirocyclic heterocyclyl” or “heterospirocyclyl” appearing herein are consistent with those of spirocycle.
  • Heterobridged ring refers to a “bridged ring” that contains heteroatoms.
  • the definition of “heterobridged ring”, “heterobridged ring group”, “bridged ring heterocyclic group” or “heterobridged ring group” used herein is consistent with bridged ring.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene, "Aryl” or “aromatic ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include
  • heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.
  • 5-membered ring and 5-membered heteroaromatic ring refers to a 5-membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.
  • 5 and 6-membered heteroaryl ring refers to a 5-6-membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic or alkynyl.
  • Constants 1 to 5 heteroatoms selected from O, S, N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
  • Substituted by 0 to X substituents means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10.
  • substituted by 0 to 4 substituents means substituted by 0, 1, 2, 3 or 4 substituents.
  • substituted by 0 to 5 substituents means substituted by 0, 1, 2, 3, 4 or 5 substituents.
  • the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.
  • X-Y-membered rings (3 ⁇ X ⁇ Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4....Y-membered rings. Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings.
  • 4--7 membered heteromonocyclic ring refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring
  • 5--10-membered heterocyclic ring refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • Alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutical A mixture formed of pharmaceutically acceptable salts or co-crystals and other chemical components, wherein “other chemical components” refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
  • Prodrug refers to a compound of the present invention that can be transformed into a biologically active compound through in vivo metabolism.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups of the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are both solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
  • Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
  • Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomer refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.
  • IC50 is the concentration of drug or inhibitor required to inhibit a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC uses Agilent 1260DAD high-pressure liquid chromatography (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M) or Shimadzu LC-20AT high-pressure liquid chromatography (Xtimate C18 (4.6 ⁇ 50mm, 3 ⁇ m));
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate, the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • Cbz benzyloxycarbonyl
  • TMS trimethylsilyl
  • DIPEA N,N-diisopropylethylamine
  • DMA N,N-dimethyl acetamide
  • LiHMDS lithium bistrimethylsilylamide
  • DMSO dimethyl sulfoxide.
  • the raw material is dissolved in DMA, and after adding acetic acid, react at room temperature to 50°C for 1 to 3 hours, and then add the reducing agent NaBH(OAc) 3 at room temperature to Reductively aminated product was obtained by reaction at 50°C;
  • the final product can be prepared by prep-HPLC:
  • Preparation method 1 Instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm ⁇ 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid), prepared Concentrate under reduced pressure;
  • Preparation method 4 instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm ⁇ 150mm); mobile phase composition: acetonitrile/water (containing 5mmol/L ammonium acetate), and the preparation solution was lyophilized or decompressed concentrate;
  • Preparation method 5 Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid), prepared liquid frozen Dry or concentrate under reduced pressure.
  • Preparation method 7 Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: acetonitrile/water (containing 5mmol/L ammonium acetate), the preparation solution was lyophilized or concentrated under reduced pressure.
  • Embodiment 1 the trifluoroacetate salt of preparation compound 1
  • the second step the preparation of the trifluoroacetic acid salt of compound 1
  • Embodiment 2 the trifluoroacetate salt of preparation compound 2
  • the second step the preparation of the trifluoroacetic acid salt of compound 2
  • Embodiment 3 preparation compound 3
  • Embodiment 4 preparation compound 4
  • Embodiment 5 the trifluoroacetate salt of preparation compound 5
  • the third step the preparation of the trifluoroacetic acid salt of compound 5
  • Embodiment 6 the trifluoroacetate salt of preparation compound 6
  • Embodiment 7 preparation compound 7
  • Embodiment 8 preparation compound 8
  • Embodiment 9 preparation compound 9
  • Embodiment 10 preparation compound 10
  • Embodiment 11 Preparation of compound 11
  • Embodiment 12 Preparation of compound 12
  • Embodiment 14 Preparation of compound 14
  • Embodiment 15 Preparation of compound 15
  • Embodiment 16 Preparation of compound 16
  • 16B (4.2 g, 11.59 mmol) was added into absolute ethanol (100 mL), 10% palladium on carbon (6 g) was added, hydrogen was replaced three times, and reacted at 40° C. for 3 h.
  • Embodiment 17 Preparation of compound 17
  • Dissolve 17A 1000 mg, 1.97 mmol
  • methanol (2 mL) methanol (2 mL)
  • hydrogen chloride in dioxane 4 mol/L, 10 mL
  • Methanol 10 mL
  • triethylamine (1 mL) were added to the concentrate, and concentrated again under reduced pressure.
  • DMA 10mL
  • tert-butyl 3-formylazetidine-1-carboxylate 730mg, 3.94mmol
  • acetic acid 60mg, 1.00mmol
  • stir at 40°C for 2h add Sodium triacetoxyborohydride (1260mg, 5.94mmol) continued to react at 40°C for 4h.
  • Embodiment 18 Preparation of compound 18
  • 16D (250 mg, 0.49 mmol) was added into a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add DMF (10 mL), 18A (258 mg, 0.73 mmol) (synthesized with reference to WO2021170109) and sodium bicarbonate (412 mg, 4.9 mmol) to the concentrate, and react overnight at 50°C.
  • Embodiment 19 Preparation of compound 19
  • compound 19 (100 mg) was obtained from 16A as the starting material, and the final product was prepared by prep-HPLC (preparation method 2) and refined.
  • the third step the preparation of the trifluoroacetic acid salt of compound 20
  • Embodiment 21 Preparation of compound 21
  • 21B (768mg, 2.63mmol) was added (refer to patent WO2016205942A1 for the synthesis method), and reacted at room temperature for 2h.
  • Add saturated sodium bicarbonate solution 50 mL
  • extract with ethyl acetate 200 mL
  • Embodiment 22 Preparation of compound 22
  • Embodiment 23 Preparation of compound 23
  • the first step the preparation of the trifluoroacetate salt of 23A
  • 24A was first de-Boc, and then subjected to nucleophilic substitution reaction with intermediate 1 to obtain compound 24 (60 mg), which was prepared by prep-HPLC (preparation method 2) and refined.
  • 25B is de-Boc first, and further combined with Reductive amination was performed to give 25C (230 mg).
  • the synthesis method of the second step to the fifth step refers to the preparation of compound 19 and compound 11 to obtain compound 27 (37 mg).
  • Compound 28 (23 mg) was prepared by referring to compound 19 and compound 11 in the synthesis method of the second step to the fifth step.
  • Dissolve 1A (150 mg, 0.32 mmol) in methanol (5 mL), add hydrochloric acid-dioxane solution (3 mL, 4M), and react at room temperature for 1 h. Concentrate under reduced pressure, add DMSO (15 mL), DIPEA (3 mL) and 6B (265.17 mg, 0.96 mmol) successively, and react at 100° C. for 3 h.
  • Dissolve 23F (800mg, 1.71mmol) in methanol (10mL), add hydrochloric acid-dioxane solution (6mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add methanol (10 mL) and aqueous ammonia (3 mL) to the concentrate, and concentrate under reduced pressure. Add tert-butyl 4-formylpiperidine-1-carboxylate (729 mg, 3.42 mmol), DMA (20 mL) and acetic acid (103 mg, 1.72 mmol) to the concentrate, stir at room temperature for 2 h, add triacetoxy borohydrogenate Sodium (725mg, 3.42mmol), stirred overnight at room temperature.
  • Dissolve 34A (250mg, 0.44mmol) in methanol (5mL), add hydrochloric acid-dioxane solution (5mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add DMSO (20 mL), DIPEA (5 mL) and intermediate 1 (243 mg, 0.88 mmol) to the concentrate, and react at 100 ° C for 3 h. Cool to room temperature, add water (20 mL), stir for 5 minutes, filter with suction, and purify the filter cake with preparative liquid phase (preparative method 7) to obtain compound 34 (50 mg, yield: 16%).
  • the second step the preparation of the trifluoroacetic acid salt of compound 37
  • 40A (2g, 11.52mmol), tert-butyl piperazine-1-carboxylate (4.29g, 23.03mmol) and potassium carbonate (7.44g, 53.84mmol) were added into DMF (50mL) and reacted overnight at 100°C. Cool to room temperature, pour into 300 mL of ice water, filter with suction, wash the filter cake with water (50 mL), and dry to obtain 40B (3.4 g, yield: 91%).
  • Dissolve 41A (3.0g, 24.28mmol) in DMSO (50mL), add potassium carbonate (16.77g, 121.35mmol), stir at room temperature for 30 minutes, then add 2-bromo-1,3-difluoro-5-iodobenzene (8.51g, 26.69mmol), L-proline (1.12g, 9.73mmol) and cuprous iodide (0.92g, 4.83mmol), react at 90°C for 12h.
  • Dissolve 23F (160mg, 0.34mmol) in dichloromethane (5mL), add hydrochloric acid-dioxane solution (5mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add dichloromethane (10 mL) and aqueous ammonia (3 mL) to the concentrate, and concentrate under reduced pressure. Add 41E (105mg, 0.34mmol), DMA (5mL) and acetic acid (20mg, 0.33mmol) to this concentrate, stir at room temperature for 2h, add sodium triacetoxyborohydride (108mg, 0.51mmol), and stir overnight at room temperature.
  • Embodiment 43 Preparation of compound 43
  • Embodiment 44 Preparation of Compound 44
  • Embodiment 45 Preparation of compound 45
  • Embodiment 46 Preparation of compound 46
  • Embodiment 47 Preparation of compound 47
  • Embodiment 48 Preparation of compound 48
  • Embodiment 49 Preparation of compound 49
  • Embodiment 50 the preparation of compound 50
  • Embodiment 51 Preparation of compound 51
  • the third step to the fifth step refer to the preparation method of compound 20 to obtain the trifluoroacetic acid salt of compound 51 (6 mg).
  • Embodiment 52 Preparation of compound 52
  • Embodiment 53 Preparation of compound 53
  • Embodiment 54 Preparation of compound 54
  • Embodiment 55 Preparation of compound 55
  • Embodiment 56 Preparation of compound 56
  • Embodiment 59 Preparation of compound 59
  • Embodiment 60 the preparation of compound 60
  • Embodiment 61 the preparation of compound 61
  • Embodiment 62 the preparation of compound 62
  • Embodiment 63 the preparation of compound 63
  • Embodiment 64 the preparation of compound 64
  • Embodiment 65 the preparation of compound 65
  • Embodiment 66 the preparation of compound 66
  • Embodiment 67 the preparation of compound 67
  • Embodiment 68 the preparation of compound 68
  • Embodiment 69 Preparation of compound 69
  • Embodiment 70 the preparation of compound 70
  • 70A (7.69g, 43.43mmol), 70B (5.00g, 43.41mmol) and potassium carbonate (12.00g, 86.83mmol) were sequentially added into DMF (50mL) and reacted at 80°C for 12h. Cool to room temperature, add water (150 mL), filter with suction, and dry the filter cake to obtain 70C (11.00 g, yield: 93%).
  • 70J (300mg, 0.88mmol) was added to DMSO (5mL), 2-iodylbenzoic acid (370mg, 1.32mmol) was added, and the reaction was carried out at 50°C for 2h. Cool to room temperature, add saturated aqueous sodium bicarbonate (20mL), extract with ethyl acetate (30mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 70K (280mg, yield: 94% ).
  • Embodiment 71 Preparation of compound 71
  • Embodiment 72 the preparation of compound 72
  • Test Example 1 Detection of SLP76 Phosphorylation Level in Jurkat Cells
  • Jurkat cells derived from ATCC were placed in RPMI-1640 complete medium (adding 10% FBS and 1% double antibody), and cultured at 37°C and 5% CO 2 . Collect the cells in the logarithmic growth phase, adjust the cell density to 5 ⁇ 10 5 cells/well with medium, and add them to a 6-well cell culture plate at a volume of 1 mL/well. Prepare the compound to be tested to 3 times the final concentration, add 500 ⁇ L of different concentrations of the compound to the administration well, add the medium containing 0.3% DMSO to the control well, and incubate for 4 hours at 37°C and 5% CO 2 .
  • CD3 antibody (BD, Cat#555329; final concentration 1 ⁇ g/mL) and incubate at 37° C., 5% CO 2 for 10 minutes. After the incubation, the cells were collected in a 1.5 mL centrifuge tube and washed twice with pre-cooled PBS. After preparing the protease inhibitor mixture, phosphatase inhibitor and lysate at a ratio of 1:1:100, add 10 ⁇ L of lysate to each sample to resuspend the cells, place on ice for 15 minutes, and shake repeatedly until the cells are completely lysed. Centrifuge at 12,000 rpm and 4°C for 15 minutes, collect the supernatant, and use the BCA method to determine the protein content.
  • CD3 antibody BD, Cat#555329; final concentration 1 ⁇ g/mL
  • the protein samples to be tested were diluted to 2 mg/mL and 0.8 mg/mL, and the phosphorylated SLP76 (p-SLP76) and SLP76 total protein levels were detected with an automatic protein expression quantitative analyzer (ProteinSimple) (both antibodies were derived from CST).
  • p-SLP76 phosphorylated SLP76
  • SLP76 total protein levels were detected with an automatic protein expression quantitative analyzer (ProteinSimple) (both antibodies were derived from CST).
  • Table 1 The inhibitory rate of test compounds to p-SLP76 in Jurkat cells at 1 ⁇ M
  • the compounds of the present application have a good inhibitory effect on the phosphorylation of SLP76 in Jurkat cells, for example, compound 11 IC 50 ⁇ 0.1nM.
  • Jurkat cells derived from ATCC were placed in RPMI-1640 complete medium (adding 10% FBS and 1% double antibody), and cultured at 37°C and 5% CO 2 . Collect the cells in the logarithmic growth phase, adjust the cell density to 5 ⁇ 10 5 cells/well with medium, and add them to a 6-well cell culture plate at a volume of 1 mL/well. Prepare the compound to be tested to 2 times the final concentration, add 1 mL of the compound at different concentrations to the administration well, add 0.2% DMSO-containing medium to the control well, and incubate at 37°C, 5% CO 2 for 48 hours.
  • HPK1 inhibition rate was calculated according to A administration well /A control well ⁇ 100%, wherein A administration well was the relative peak area of the administration group, and A control well was the relative peak area of the vehicle control group.
  • DC50 values were calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software.
  • the compound of the present application can degrade HPK1 kinase.
  • Test animals male ICR mice, 25-30g. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice were randomly divided into groups according to body weight. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
  • Intravenous administration vehicle 10% DMA+10% Solutol+80% Saline
  • Oral administration vehicle 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE- ⁇ -CD)
  • the compound of the present invention has good oral absorption.
  • reference compound 1 is as follows, and its synthesis refers to patent WO2016205942A1.
  • Test Example 4 Rat pharmacokinetic test
  • Test animals male SD rats, about 200-220 g, aged 6-8 weeks. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline
  • Oral administration vehicle 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE- ⁇ -CD)
  • mice male Beagle dogs, about 8-10 kg, purchased from Beijing Masi Biotechnology Co., Ltd.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline
  • Oral administration vehicle 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE- ⁇ -CD)
  • the compounds of the present invention have good canine pharmacokinetic properties, for example, the oral bioavailability of compound 11 is 56.5%, and that of the control compound 1 is 13.9%.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • the cells were clamped at -80mV, and the voltage step of the evoked hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s. back to -80mV. Give this voltage stimulation every 10s, and start the administration process after confirming that the hERG potassium current is stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells (n > 2) were tested at each concentration.
  • Inhibition% represents the inhibitory percentage of the compound on the hERG potassium current
  • I and Io represent the amplitudes of the hERG potassium current after and before the drug addition, respectively.
  • X is the Log value of the detected concentration of the test substance
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compound of the present invention has weak inhibition on hERG.
  • the purpose of this study is to use an in vitro test system to evaluate the effect of the test substance on the activity of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP).
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the compounds of the present invention have weak inhibition on CYP enzymes.

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Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a eutectic thereof, an intermediate thereof, and a use thereof for a HPK1 kinase-related disease such as a cancer. B-L-K (I)

Description

一种抑制或降解HPK1激酶的化合物及其在医药中的用途A compound for inhibiting or degrading HPK1 kinase and its use in medicine 技术领域technical field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体，以及在HPK1激酶相关疾病如癌症中的用途。The present invention relates to a compound described in general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and Its intermediate, and its use in HPK1 kinase-related diseases such as cancer.
背景技术Background technique
激酶催化蛋白质、脂类、糖、核苷和其他细胞代谢产物的磷酸化，在真核细胞生理学的各个方面发挥着关键作用。尤其是蛋白激酶和脂类激酶参与控制激活的信号事件，细胞对细胞外介质或刺激如生长因子、细胞因子或趋化因子的反应而生长、分化和存活。一般来说，蛋白质激酶分为两类，一类优先磷酸化酪氨酸残基，另一类优先磷酸化丝氨酸和/或苏氨酸残基。Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites and play key roles in various aspects of eukaryotic cell physiology. In particular protein kinases and lipid kinases are involved in signaling events that control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. In general, protein kinases fall into two classes, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.
造血祖细胞激酶HPK1(Hematopoietic Progenitor Kinase 1,又名Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1,MAP4K1)是一种丝/苏氨酸蛋白激酶，属于MAP4K家族成员，是T细胞受体(TCR)的负信号调节剂。TCR的活化会招募并激活HPK1，从而将SLP76蛋白的Ser376氨基酸残基磷酸化，进而使TCR的信号复合体不稳定，最终抑制T细胞的活化与增殖。与野生型相比，HPK1激酶缺失的小鼠在TCR刺激下展现出了更优的T细胞增殖活性及抗肿瘤的免疫性。同时，HPK1激酶缺失的小鼠并未表现出致死性的炎症反应(ACS Med.Chem.Lett.2021,12,443–450)。因此，HPK1成为了一类重要治疗靶点，吸引了广泛的研发兴趣(J.Med.Chem.2022,65,8065–8090)。Hematopoietic progenitor kinase HPK1 (Hematopoietic Progenitor Kinase 1, also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1, MAP4K1) is a serine/threonine protein kinase that belongs to the MAP4K family and is the T cell receptor (TCR) Negative signal modulator. The activation of TCR will recruit and activate HPK1, thereby phosphorylating the Ser376 amino acid residue of SLP76 protein, thereby destabilizing the TCR signaling complex, and finally inhibiting the activation and proliferation of T cells. Compared with wild-type mice, HPK1 kinase-deficient mice exhibited better T cell proliferation activity and anti-tumor immunity under TCR stimulation. At the same time, mice lacking HPK1 kinase did not show a lethal inflammatory response (ACS Med. Chem. Lett. 2021, 12, 443–450). Therefore, HPK1 has become an important class of therapeutic targets and has attracted extensive research and development interest (J.Med.Chem.2022, 65, 8065–8090).
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。与抑制剂相比，PROTAC不仅可以抑制靶点的激酶活性，还能调节其骨架功能(Nat.Rev.Drug Discov.2022,21,181–200)。PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. This type of compound can be recognized by the proteasome of the cell, causing the degradation of the targeting protein, and can effectively reduce the target protein. protein content in cells. By introducing ligands that can bind different targeting proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received extensive attention in recent years. Compared with inhibitors, PROTACs can not only inhibit the kinase activity of the target, but also regulate its scaffold function (Nat. Rev. Drug Discov. 2022, 21, 181–200).
因此，有必要开发新型的HPK1抑制剂和E3泛素连接酶的PROTAC药物，用于治疗与HPK1相关的肿瘤疾病。Therefore, it is necessary to develop novel HPK1 inhibitors and E3 ubiquitin ligase PROTAC drugs for the treatment of HPK1-related tumor diseases.
发明内容Contents of the invention
本发明的目的在于提供一种结构新颖的、药效好、生物利用度高、更安全、能抑制并降解HPK1的化合物，用于治疗与HPK1相关疾病如癌症。The purpose of the present invention is to provide a compound with novel structure, good drug effect, high bioavailability, safer, capable of inhibiting and degrading HPK1 for treating diseases related to HPK1 such as cancer.
本发明提供一种化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物， The present invention provides a compound or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, the compound is selected from the general formula (I ) shown in the compound,
B-L-K(I)；B-L-K(I);
在某些实施方案中，通式(I)所示的化合物选自通式(Ia)或(Ib)所示化合物，
In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia) or (Ib),
在某些实施方案中，W选自CH或N；In certain embodiments, W is selected from CH or N;
在某些实施方案中，Z1选自S或Se；In certain embodiments, Z is selected from S or Se;
在某些实施方案中，Z2选自S或Se；In certain embodiments, Z is selected from S or Se;
在某些实施方案中，Ba选自N或CH；In certain embodiments, Ba is selected from N or CH;
在某些实施方案中，L选自键或-C1-50烃基-，所述烃基中有0至20个亚甲基单元任选进一步被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-50 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-20烃基-，所述烃基中有0至20个亚甲基单元任选进一步被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-20 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-10烃基-，所述烃基中有0至10个(例如0、1、2、3、4、5、6、7、8、9或10)亚甲基单元任选进一步被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-10 hydrocarbyl-, wherein there are 0 to 10 (eg, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 Or 10) the methylene unit is optionally further replaced by -Ak-, -Cy-;
在某些实施方案中，每个-Ak-各自独立地选自Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8或Ak9；In certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;
在某些实施方案中，每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-任选进一步被0至2个(例如0、1或2个)选自H、卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；In certain embodiments, each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -( CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH =CH-, -Si( RL ) 2 -, -Si(OH)( RL )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O) (R L )-, -S-, -S(=O)-, -S(=O) 2 - or a bond, the -CH 2 - is optionally further replaced by 0 to 2 (such as 0, 1 or 2) selected from H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl , C 1-6 alkyl substituent substituted by cyano group;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、卤素、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O- (CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 -C 1-4 alkyl optionally further substituted by 0 to 2 selected from H, halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen, Substituents of C 1-4 alkyl substituted by hydroxy and C 1-4 alkyl substituted by cyano;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O- (CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further replaced by 0 to 2 selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 1-4 alkane Oxygen substituents are substituted;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被 0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O- (CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - Optionally further 0 to 2 substituents selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, methyl, ethyl, methoxy or ethoxy;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自键、-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH2- , -CH2O- , -OCH2CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N( CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(= O)-;
在某些实施方案中，RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, The heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N;
在某些实施方案中，RL各自独立的选自H或C1-6烷基；In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;
在某些实施方案中，RL各自独立的选自H或C1-4烷基；In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;
在某些实施方案中，RL选自H、甲基或乙基；In certain embodiments, RL is selected from H, methyl or ethyl;
在某些实施方案中，q各自独立的选自0、1、2、3、4、5或6；In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
在某些实施方案中，q各自独立的选自0、1、2、3或4；In certain embodiments, each q is independently selected from 0, 1, 2, 3 or 4;
在某些实施方案中，q各自独立的选自0、1或2；In certain embodiments, each q is independently selected from 0, 1 or 2;
在某些实施方案中，每个-Cy-各自独立地选自Cy1、Cy2、Cy3、Cy4或Cy5；In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
在某些实施方案中，每个-Cy-各自独立地选自键、4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；In certain embodiments, each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring , 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aromatic The aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heteroheterocyclic ring, heterospiro ring or heterobridged ring are optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, Substituents of OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy Substituted, the heteroaryl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings contain 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally further substituted by 0, 1 or 2 =O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键、4-7元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；In certain embodiments, each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterocyclic ring, Heterobridged ring, 3-7-membered monocycloalkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged cycloalkyl, 5-10-membered heteroaryl or 6 -10-membered aryl, the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospiro or heterobridged ring is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy The substituents are substituted, and the heteroaryl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings contain 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally further substituted by 0, 1 or 2 ═O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键、4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述杂单环、杂并环、杂桥环、杂螺环、环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；In certain embodiments, each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from the group consisting of a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterocycle Spiro ring, 7-10 membered nitrogen-containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5 -10-membered heteroaryl or 6-10-membered aryl, said heteromonocyclic, heterocyclic, heterobridged, heterospiro, cycloalkyl, aryl or heteroaryl is optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy substituents, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring or heteroaryl group contains 1 to 4 heterocyclic rings selected from O, S, N Atom, when the heteroatom is selected from S, is optionally further substituted by 0, 1 or 2 =O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己烯基、 哌啶、吗啉、哌嗪、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环戊基并哌啶、环己基并氮杂环丁基、环己基并氮杂环戊基、环己基并氮杂环己基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环戊基并哌啶、氮杂环己基并氮杂环丁基、氮杂环己基并氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基螺氮杂环丁基、环己基螺氮杂环戊基、环己基螺氮杂环己基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环丁基、氮杂环己基螺氮杂环戊基、氮杂环己基螺氮杂环己基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时，任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups which are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, azacyclopentyl, aziridinyl, Piperidine, morpholine, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl , cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclopropyl spirocyclopropyl, cyclopropyl spiro Butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclopentyl Pentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazepinyl, cyclopropylpiperidine, cyclobutyl Cyclobutylazetidinyl, Cyclobutylazetidinyl, Cyclobutylazetidinyl, Cyclobutylazetidinyl, Cyclopentylazetidinyl, Cyclopentylazetidinyl, Cyclopentylazetidinyl Cyclopentyl, Cyclopentylazacyclohexyl, Cyclopentylpiperidine, Cyclohexylazetidinyl, Cyclohexylazacyclopentyl, Cyclohexylazacyclohexyl, Cyclohexylpiperidine Pyridine, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl Azetidinyl, Azacyclopentylazetidinyl, Azacyclopentylazetidinyl, Azacyclopentylpiperidine, Azacyclohexylazetidinyl , azacyclohexyl azepinyl, azacyclohexyl azacyclohexyl, azacyclohexyl piperidine, cyclobutylspiroazetidinyl, cyclobutylspiroazepinyl, Cyclobutylspiroazetidinyl, Cyclopentylspiroazetidinyl, Cyclopentylspiroazetidinyl, Cyclopentylspiroazetidinyl, Cyclohexylspiroazetidinyl, Cyclohexylspiro Azacyclopentyl, cyclohexylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, nitrogen Heterocyclopentylspiroazetidinyl, Azacyclopentylspiroazetidinyl, Azacyclopentylspiroazetidinyl, Azacyclohexylspiroazetidinyl, Azacyclohexylspiro Azacyclopentyl, Azacyclohexylspiroazidine, Cyclobutylspiropiperidine, Cyclopentylspiropiperidine, Cyclohexylspiropiperidine, Azetidinylspiropiperidine, Azacyclopentyl Spiropiperidine, Azacyclohexylspiroidine, When substituted, C 1- optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen 4 alkyl, hydroxyl substituted C 1-4 alkyl or C 1-4 alkoxy substituents;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，任选进一步被0至4个选自H、F、CF3、甲基、＝O、羟甲基、COOH、CN或NH2的取代基所取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or substituted or unsubstituted one of the following groups: When substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF 3 , methyl, =O, hydroxymethyl, COOH, CN or NH 2 ;
在某些实施方案中，L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、 -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9；In certain embodiments, L is selected from -Cyl-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cyl-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3 -Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1 -Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5 -, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2 -Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3 -Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1 -Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
在某些实施方案中，L选自键、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；In certain embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5 -, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1 -Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1 -Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2 -Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3 -Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2 -, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2 -Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
在某些实施方案中，L选自-Cy1-、-Cy1-Ak1-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-；In certain embodiments, L is selected from -Cyl-, -Cyl-Ak1-, -Cyl-Cy2-, -Cyl-Ak1-Cy2-, -Cyl-Cy2-Ak2-, -Cyl-Ak1-Cy2-Ak2 -, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Cy3-Ak3-Cy4-;
在某些实施方案中，L选自键或表L-1所示的基团，其中基团左侧与B连接；In some embodiments, L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;
在某些实施方案中，L选自键或表L-2所示的基团，其中基团左侧与B连接；In certain embodiments, L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;
在某些实施方案中，L选自-Cy1-CH2-Cy2-,Cy1、Cy2各自独立的选自4至6元环含氮杂单环或7至11元含氮杂螺环(优选氮杂环丁基、氮杂环戊基、哌啶基、哌嗪基、)，所述Cy1、Cy2任选被1至4个选自F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代(优选地，任选被1至4个选自F、CF3、甲基、＝O、羟甲基、COOH、CN或NH2的取代基所取代)In certain embodiments, L is selected from -Cy1-CH 2 -Cy2-, Cy1 and Cy2 are each independently selected from 4 to 6 membered nitrogen-containing heteromonocyclic rings or 7 to 11 membered nitrogen-containing heterospirocyclic rings (preferably nitrogen Heterobutyl, azacyclopentyl, piperidinyl, piperazinyl, ), the Cy1 and Cy2 are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy substituents (preferably, optionally 1 to 4 selected from F, CF 3 , methyl, =O, hydroxy Substituents of methyl, COOH, CN or NH2 )
在某些实施方案中，L选自-Cy1-Cy2-CH2-Cy3-,Cy1、Cy2、Cy3各自独立的选自4至6元环 含氮杂单环或7至11元含氮杂螺环(优选氮杂环丁基、氮杂环戊基、哌啶基、哌嗪基、)，所述Cy1、Cy2、Cy3任选被1至4个选自F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代(优选地，任选被1至4个选自F、CF3、甲基、＝O、羟甲基、COOH、CN或NH2的取代基所取代)；In certain embodiments, L is selected from -Cy1-Cy2-CH 2 -Cy3-, Cy1, Cy2, and Cy3 are each independently selected from 4 to 6-membered rings Nitrogen-containing heteromonocyclic or 7- to 11-membered nitrogen-containing spirocyclic rings (preferably azetidinyl, azacyclopentyl, piperidinyl, piperazinyl, ), the Cy1, Cy2, Cy3 are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen substituted C 1 -4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy substituents (preferably, optionally 1 to 4 selected from F, CF 3 , methyl, =O , hydroxymethyl, COOH, CN or NH 2 substituents);
表L-1 L基团













Table L-1 L group













表L-2 L基团

Table L-2 L group

在某些实施方案中，K选自 In certain embodiments, K is selected from
在某些实施方案中，K选自 表示环选自芳香环或非芳香环；在某些实施方案中，K选自 In certain embodiments, K is selected from Indicates that the ring is selected from an aromatic ring or a non-aromatic ring; in certain embodiments, K is selected from
在某些实施方案中，Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或3-12元杂环基，所述的杂环基任选进一步被0至4个(例如0、1、2、3、4个)选自 H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)- , -C(=O)NR q -or 3-12 membered heterocyclic group, said heterocyclic group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3, 4) Substituents of H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group Contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Q各自独立地选自-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或4-7元杂环基，所述的杂环基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, - C(=O)NR q -or 4-7 membered heterocyclic group, said heterocyclic group is optionally further selected from 0 to 4 (for example 0, 1, 2, 3, 4) selected from H, F, Substituents of Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Rq选自H或C1-6烷基；In certain embodiments, R is selected from H or C 1-6 alkyl;
在某些实施方案中，Rq选自H或C1-4烷基；In certain embodiments, R is selected from H or C 1-4 alkyl;
在某些实施方案中，Rq选自H、甲基、乙基；In certain embodiments, Rq is selected from H, methyl, ethyl;
在某些实施方案中，E各自独立地选自C3-10碳环基、C6-10芳基、3-12元杂环基或5-12元杂芳基，所述杂环或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, the heterocycle or heteroaryl Aryl contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，E各自独立地选自C3-8碳环、苯环、4-7元杂环、8-12元杂环、7-12元杂芳基或5-6元杂芳基，所述杂环或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle, 8-12 membered heterocycle, 7-12 membered heteroaryl or 5-6 membered heterocycle Aryl, the heterocyclic or heteroaryl group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基、噁唑基、吲哚啉基、异吲哚啉基、1,2,3,4-四氢喹啉基或1,2,3,4-四氢异喹啉基；In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, oxa Azolyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl;
在某些实施方案中，E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基；In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, or oxa Azolyl;
在某些实施方案中，E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基；In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl;
在某些实施方案中，E各自独立的选自苯环或吡啶环；In certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
在某些实施方案中，A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the heterocyclic or heteroaryl containing 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A、H1或H2各自独立地选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳基，所述杂环或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, each of A, H1 or H2 is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, and the heterocycle or heteroaryl Contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A、H1或H2各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基；In certain embodiments, each of A, H1 or H2 is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, Thienyl or oxazolyl;
在某些实施方案中，A、H1或H2各自独立地选自苯基或吡啶基；In certain embodiments, A, H1 or H2 are each independently selected from phenyl or pyridyl;
在某些实施方案中，F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In some embodiments, each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, the heterocyclyl or Heteroaryl contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，F各自独立地选自3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、4-7元杂单环、4-10元杂并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基或5-10元杂芳基，所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered parallel cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4 -7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, said heteromono The ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，F各自独立地选自环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、氮杂环戊基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、萘并呋喃基、噻吩并吲哚基、苯并咪唑基、 苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并噁唑基、吡啶并咪唑基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基或吡嗪并吡嗪基；In certain embodiments, each F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopenta[ c] pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridine Base, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, naphthofuryl, thiophene Indolyl, benzimidazolyl, Benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzo Oxazolyl, pyridimidazolyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazine base, imidazopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridyl, pyrimidopyrazinyl, pyrimidopyridazinyl , pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
在某些实施方案中，Rk2各自独立地选自键、-C(＝O)-、-S(＝O)2-、-S(＝O)-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from a bond, -C(=O)-, -S(=O) 2 -, -S(=O)-, or -C(R k3 ) 2 -;
在某些实施方案中，Rk2各自独立地选自-C(＝O)-、-S(＝O)2-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from -C(=O)-, -S(=O) 2 - or -C(R k3 ) 2 -;
在某些实施方案中，Rk1或Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R k1 or R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further selected from 0 to 4 Substituents of H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基,所述烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkane or C 1-4 alkoxy group, said alkyl or alkoxy group is optionally further represented by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I , OH, NH 2 are replaced by substituents;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基,所述甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl , isopropyl, methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) are selected from H, F, Cl, Br, I, OH, NH Substituents are substituted;
在某些实施方案中，两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-8元碳环或3-8元杂环，所述碳环或杂环任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In some embodiments, two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocycle or a 3-8 membered heterocycle, the carbocycle or heterocycle The ring is optionally further divided by 0 to 4 (eg 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C Substituted by 1-4 alkyl or C 1-4 alkoxyl, the heterocycle contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-6元碳环或3-7元杂环，所述碳环或杂环任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, the carbocycle or heterocycle The ring is optionally further divided by 0 to 4 (eg 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C Substituted by 1-4 alkyl or C 1-4 alkoxyl, the heterocycle contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so The above-mentioned alkyl, cycloalkyl or heterocyclic group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, Substituents of NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 (such as 1, 2, 3, 4 ) is a heteroatom selected from O, S, N;
在某些实施方案中，Rk4各自独立的选自H、OH、NH2、CF3、CN、C1-4烷基；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
在某些实施方案中，Rk5各自独立地选自C(CH3)2、C(＝O)、CH2、S(＝O)2、 In certain embodiments, each R k5 is independently selected from C(CH 3 ) 2 , C(=O), CH 2 , S(=O) 2 ,
在某些实施方案中，Rk6各自独立地选自C(＝O)、CH、S(＝O)、S(＝O)2、CH2或N； In certain embodiments, each Rk6 is independently selected from C(=O), CH, S(=O), S(=O) 2 , CH2 , or N;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、C(＝O)、CH、N、CH2、O、S、N(CH3)、N(CH2CH3)、N(环丙基)或NH；In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , C(=O), CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
在某些实施方案中，Rk7各自独立地选自CH2、O、N(CH3)或NH；In certain embodiments, each Rk7 is independently selected from CH2 , O, N( CH3 ) or NH;
在某些实施方案中，Rk8各自独立地选自C、N或CH；In certain embodiments, each R is independently selected from C, N, or CH;
在某些实施方案中，Rk9各自独立地选自键、C(CH3)2、C(＝O)、CH2、CH2CH2或S(＝O)2；In certain embodiments, each Rk9 is independently selected from a bond, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ;
在某些实施方案中，M1选自键、-C(＝O)NH-、-NHC(＝O)-、-CH2-C(＝O)NH-、-C(＝O)CH2NH-、5-6元杂芳基，所述的杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、＝O、CF3、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂芳基含有含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, M1 is selected from a bond, -C(=O)NH-, -NHC(=O)-, -CH2- C(=O)NH-, -C(=O) CH2 NH-, 5-6 membered heteroaryl, said heteroaryl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, Substituents of OH, =O, CF 3 , NH 2 , CN, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy Substituted, the heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，M1选自键、-C(＝O)NH-、-CH2-C(＝O)NH-、-C(＝O)CH2NH-、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、呋喃基、噻吩基、噻唑基；In certain embodiments, M1 is selected from a bond, -C(=O)NH-, -CH2 -C(=O)NH-, -C(=O) CH2NH- , pyrrolyl, pyrazole Base, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, thienyl, thiazolyl;
在某些实施方案中，M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；In certain embodiments, M1 is selected from a bond, -CH2 -C(=O)NH- or -C(=O) CH2NH- ;
在某些实施方案中，M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In some embodiments, M is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, said The alkyl, cycloalkyl or heterocyclyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, =O, OH, NH 2. Substituents of C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 (such as 1, 2, 3, 4) selected from O, S, N heteroatoms;
在某些实施方案中，M2选自-NHC(＝O)-CH3、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、氮杂环丁基、氮杂环戊基、苯并氮杂环戊基、苯并氮杂环己基，所述的环丙基、环丁基、氮杂环丁基、氮杂环戊基、苯并氮杂环戊基或苯并氮杂环己基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, M 2 is selected from -NHC(=O)-CH 3 , -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, azetidinyl, nitrogen Heterocyclopentyl, benzazepinyl, benzazepinyl, said cyclopropyl, cyclobutyl, azetidinyl, azepine, benzazepinyl Or benzazepinyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, =O, OH, NH 2 , C 1 Substituents of -4 alkyl or C 1-4 alkoxy;
在某些实施方案中，M3选自-NH-或-O-；In certain embodiments, M is selected from -NH- or -O-;
在某些实施方案中，Rk10选自C1-6烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；In some embodiments, R k10 is selected from C 1-6 alkyl, and said alkyl is optionally further selected from H, F, Substituted by Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl;
在某些实施方案中，Rk10选自甲基、乙基、异丙基、丙基、叔丁基，所述的甲基、乙基、异丙基、丙基、叔丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、＝O、OH、C1-4烷基或C3-6环烷基的取代基所取代；In some embodiments, R k10 is selected from methyl, ethyl, isopropyl, propyl, tert-butyl, and the methyl, ethyl, isopropyl, propyl, tert-butyl are optionally further by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, =O, OH, C 1-4 alkyl or C 3-6 cycloalkyl Substituents are substituted;
在某些实施方案中，G选自6-10元芳基或5-10元杂芳基，所述的芳基或者杂芳基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；In certain embodiments, G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxyl substituted C 1- 4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heteroaryl contains 1 to 4 (eg 1, 2, 3, 4) selected from N, Heteroatoms of O and S;
在某些实施方案中，Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6 烷氧基或C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, each R k11 is independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 Alkoxy or C 1-6 alkylthio or -OC(=O)-C 1-6 alkyl, said alkyl, alkoxy or alkylthio is optionally further replaced by 0 to 4 (for example 0 , 1, 2, 3, 4) are substituted by a substituent selected from H, F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲硫基、乙硫基、丙硫基或-O-C(＝O)-CH3，所述的甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲硫基、乙硫基、丙硫基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, each R k11 is independently selected from H, F, Cl, Br, I, =O, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy radical, propoxy, isopropyloxy, methylthio, ethylthio, propylthio or -OC(=O)-CH 3 , the methyl, ethyl, isopropyl, propyl, Methoxy, ethoxy, propoxy, isopropyloxy, methylthio, ethylthio, propylthio are optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) Substituents selected from H, F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further represented by 0 to 4 Substitution of one (eg 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy base replaced;
在某些实施方案中，Rk12、Rk13各自独立的选自H、甲基、乙基、异丙基、丙基、环丙基或环丁基，所述的甲基、乙基、异丙基、丙基、环丙基或环丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In some embodiments, R k12 and R k13 are each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, and the methyl, ethyl, iso Propyl, propyl, cyclopropyl or cyclobutyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, =0, OH , NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
在某些实施方案中，Rk14选自5-6元杂芳基，所述的杂芳基任选进一步被0至4个(例如0、1、2、3、4个)选自H、F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；In certain embodiments, R k14 is selected from 5-6 membered heteroaryl, and said heteroaryl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkane Oxygen or C 3-6 cycloalkyl substituents are substituted, and the heteroaryl group contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O, S;
在某些实施方案中，K选自表K-1所示的结构片段之一；In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;
在某些实施方案中，K选自表K-2所示的结构片段之一；In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
n1、n2、n3各自独立的选自0、1、2或3；n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1或p2各自独立的选自0、1、2、3、4或5；p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
p1或p2各自独立的选自0、1或2；p1 or p2 are each independently selected from 0, 1 or 2;
表K-1 K基团



Table K-1 K group



表K-2 K基团




Table K-2 K group




在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自Z1选自S、Se，Ba选自N或CH；在某些实施方案中，B选自Z2选自S、Se，Ba选自N或CH；In certain embodiments, B is selected from Z is selected from S, Se, Ba is selected from N or CH; in certain embodiments, B is selected from Z 2 is selected from S, Se, Ba is selected from N or CH;
在某些实施方案中Z1、Z2或Z3各自独立的选自S、Se、N、NRz或CRz；In certain embodiments Z 1 , Z 2 or Z 3 are each independently selected from S, Se, N, NR z or CR z ;
在某些实施方案中，选自选自 In some embodiments, selected from
在某些实施方案中，Rz选自H、卤素、氰基、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-8碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl or 3 to 8 membered heterocyclic group, said alkyl, alkoxyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 substitutions selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl Substituted by a group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，Rz选自H、卤素、氰基、OH、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-7碳环基或3至7元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；In certain embodiments, R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 Alkyl, C 1-4 alkoxyl, C 3-7 carbocyclyl or 3 to 7 membered heterocyclic group, said alkyl, alkoxyl, carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 substitutions selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl base replaced;
在某些实施方案中，Rz选自H、F、Cl、Br、I、NH2、氰基、OH、NHCH3、NHCH2CH3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环己基、环戊基、氮杂环丁基、氮杂环戊基、哌啶基、哌嗪基；In certain embodiments, Rz is selected from H, F, Cl, Br, I, NH2 , cyano, OH, NHCH3 , NHCH2CH3 , methyl, ethyl, methoxy, ethoxy , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, azetidinyl, piperidinyl, piperazinyl;
在某些实施方案中，任意两个Rz直接连接，形成C4-8碳环或者4至8元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In some embodiments, any two R z are directly connected to form a C 4-8 carbocycle or a 4-8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, said The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，任意两个Rz直接连接，形成C4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In some embodiments, any two R z are directly connected to form a C 4-7 carbocycle or a 4-7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，任意两个Rz直接连接，形成5元碳环基、6元碳环基或7元碳环基；In certain embodiments, any two R z are directly linked to form a 5-membered carbocyclyl, a 6-membered carbocyclyl, or a 7-membered carbocyclyl;
在某些实施方案中，R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-6烷基、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(=O)-R a2 , C 1-6 alkyl, C 3-10 carbocycle or 3 to 10 membered heterocycle, said alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1 -6 alkyl or C 1-6 alkoxy substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-4烷基、C3-6单环碳环、4至8元单环杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(=O)-R a2 , C 1-4 alkyl, C 3-6 monocyclic carbocycle, 4 to 8 membered monocyclic heterocycle, any of the alkyl, carbocycle or heterocycle C 1-4 alkyl, cyano further selected from 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxyl Substituted C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，R1选自H、F、Cl、Br、I、氰基、OH、甲氧基、乙氧基、NHRa2、-NHSO2-Ra2、-NHC(＝O)-Ra2、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉或哌嗪；In certain embodiments, R 1 is selected from H, F, Cl, Br, I, cyano, OH, methoxy, ethoxy, NHR a2 , -NHSO 2 -R a2 , -NHC(=O) -R a2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolyl, oxa Cyclohexyl, morpholine or piperazine;
在某些实施方案中，Ra1、Ra2各自独立的选自H、C1-6烷基、-C1-4烷基-C3-10碳环、-C1-4烷基-3至10元杂环、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C 1-4 alkyl-C 3-10 carbocycle, -C 1-4 alkyl-3 to 10-membered heterocycle, C 3-10 carbocycle or 3-10 membered heterocycle, the alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, Substitution of NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy Substituted by a group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，Ra1选自H、C1-4烷基；In certain embodiments, R a1 is selected from H, C 1-4 alkyl;
在某些实施方案中，Ra1选自H、甲基、乙基；In certain embodiments, Ra1 is selected from H, methyl, ethyl;
Ra2选自H、C1-4烷基、-C1-2烷基-C3-6单环碳环、-C1-2烷基-C7-10并环碳环、-C1-2烷基-C6-10 螺环碳环、-C1-2烷基-C5-10桥环碳环、-C1-2烷基-4至8元单环杂环、-C1-2烷基-7至10元并环杂环、-C1-2烷基-6至10元螺环杂环、-C1-2烷基-5至10元桥环杂环、C3-6单环碳环、C7-10并环碳环、C6-10螺环碳环、C5-10桥环碳环、4至8元单环杂环、7至10元并环杂环、6至10元螺环杂环、5至10元桥环杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic carbocycle, -C 1-2 alkyl-C 7-10 double ring carbocycle, -C 1 -2 Alkyl-C 6-10 Spiral carbocycle, -C 1-2 alkyl-C 5-10 bridged ring carbocycle, -C 1-2 alkyl-4 to 8 membered monocyclic heterocycle, -C 1-2 alkyl-7 to 10 Membered ring heterocyclic ring, -C 1-2 alkyl-6 to 10 membered spirocyclic heterocyclic ring, -C 1-2 alkyl -5 to 10 membered bridged ring heterocyclic ring, C 3-6 monocyclic carbocycle, C 7-10 parallel ring carbocycle, C 6-10 spiro carbocycle, C 5-10 bridged ring carbocycle, 4-8 membered monocyclic heterocycle, 7-10 membered parallel ring heterocycle, 6-10 membered spirocycle Heterocycle, 5- to 10-membered bridged ring heterocycle, the alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkane C 1-4 alkyl substituted by halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkyl substituted by cyano or C 1-4 alkoxy substituent, said hetero The ring contains 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，Ra2选自H、C1-4烷基、-C1-2烷基-C3-6单环芳环、-C1-2烷基-C3-6单环非芳香环、-C1-2烷基-5至6元芳杂环、-C1-2烷基-4至8元单环非芳香杂环、C5-6单环芳环、C3-6单环非芳香环、5至6元芳杂环、4至8元单环非芳香杂环，所述的烷基、芳环、非芳香环、芳杂环、非芳香杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的芳杂环、杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, Ring non-aromatic ring, -C 1-2 alkyl-5 to 6-membered aromatic heterocycle, -C 1-2 alkyl-4 to 8-membered monocyclic non-aromatic heterocycle, C 5-6 monocyclic aromatic ring, C 3-6 monocyclic non-aromatic rings, 5-6 membered aromatic heterocycles, 4-8 membered monocyclic non-aromatic heterocycles, any of the alkyl, aromatic rings, non-aromatic rings, aromatic heterocycles, and non-aromatic heterocycles C 1-4 alkyl, cyano further selected from 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxyl Substituted C 1-4 alkyl or C 1-4 alkoxy substituents, the aromatic heterocycle, heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
Ra2选自H、取代或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、哌嗪、吡啶、苯基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉、-CH2-哌嗪、-CH2-吡啶、-CH2-苯基，当被取代时，任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代；R a2 is selected from one of H, substituted or unsubstituted following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Morpholine, Piperazine, Pyridine, Phenyl, -CH 2 -Cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, -CH 2 -oxolyl, -CH 2 -oxanyl, -CH 2 -morpholine, -CH 2 -piperazine, -CH 2 -pyridine, - CH 2 -phenyl, when substituted, is optionally further substituted with 0 to 4 C 1-4 alkyl selected from H , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkyl substituted by cyano or C 1-4 alkoxy substituent;
在某些实施方案中，R2选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-6烷基的取代基所取代；In some embodiments, R 2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 selected from H, halogen , OH, cyano, C 1-6 alkyl substituents;
在某些实施方案中，R2选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-4烷基的取代基所取代；In certain embodiments, R 2 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further selected from 0 to 4 selected from H, halogen , OH, cyano, C 1-4 alkyl substituents;
在某些实施方案中，R2选自H、甲基、乙基或环丙基，所述的甲基、乙基或环丙基任选进一步被0至4个选自H、卤素、OH、氰基、C1-4烷基的取代基所取代；In certain embodiments, R is selected from H, methyl, ethyl or cyclopropyl, and said methyl, ethyl or cyclopropyl is optionally further replaced by 0 to 4 selected from H, halogen, OH , cyano, C 1-4 alkyl substituents are substituted;
在某些实施方案中，R2选自H；In certain embodiments, R is selected from H;
在某些实施方案中，X1选自O、S、NRx，X2选自N、CRx；In certain embodiments, X1 is selected from O, S, NRx , and X2 is selected from N, CRx ;
在某些实施方案中，X1选自NH，X2选自N或CH；In certain embodiments, X is selected from NH, and X is selected from N or CH;
在某些实施方案中，X1选自NH；In certain embodiments, X is selected from NH;
在某些实施方案中，X2选自N或CH；In certain embodiments, X is selected from N or CH;
在某些实施方案中，Rx各自独立的选自H、卤素、氰基、OH、C1-6烷基、C1-6烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代；In certain embodiments, each R x is independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, said alkane C 1-6 alkyl group , C 1-6 alkyl group, C 1 Substituents of -6 alkoxy or C 3-6 cycloalkyl;
在某些实施方案中，Rx各自独立的选自H、卤素、氰基、OH、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；In certain embodiments, each R x is independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkane C 1-4 alkyl , C 1 -4 alkoxy or C 3-6 cycloalkyl substituents;
在某些实施方案中，Rx各自独立的选自H或C1-4烷基；In certain embodiments, each R x is independently selected from H or C 1-4 alkyl;
在某些实施方案中，Rx各自独立的选自H、甲基或乙基； In certain embodiments, each R x is independently selected from H, methyl, or ethyl;
在某些实施方案中，环B1选自苯环或者5至6元杂芳环，所述的杂芳环含有1至3个选自O、S、N的杂原子；In certain embodiments, Ring B is selected from a benzene ring or a 5 to 6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，环B1选自苯环、吡啶、嘧啶；In certain embodiments, Ring B is selected from benzene rings, pyridine, pyrimidine;
在某些实施方案中，R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烷基)、C1-6烷基、C1-6烷氧基、C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基、炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-6烷基、C1-6烷基、C1-6烷氧基、C3-6环烷基或4至8元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , - NH(C 3-6 cycloalkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy , cycloalkyl, alkynyl are optionally further substituted by 0 to 4 C 1-6 alkyl, C 1-6 alkyl, C 1-6 selected from H , halogen, OH, cyano, NH 2 , halogen Substituted by alkoxy, C 3-6 cycloalkyl or 4 to 8 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基、C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基、炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-4烷基、C1-4烷基、C1-4烷氧基、C3-6环烷基或4至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；In certain embodiments, each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , - NH(C 3-6 cycloalkyl), C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy , cycloalkyl, alkynyl optionally further substituted by 0 to 4 C 1-4 alkyl, C 1-4 alkyl, C 1-4 selected from H , halogen, OH, cyano, NH 2 , halogen Substituents of alkoxy, C 3-6 cycloalkyl or 4 to 6 membered heterocyclic rings, the heterocyclic rings contain 1 to 3 heteroatoms selected from O, S, N;
在某些实施方案中，R3各自独立的选自H、F、Cl、Br、I、OH、氰基、NH2、甲基、乙基、甲氧基、环丙基、乙炔基、丙炔基；In certain embodiments, each R3 is independently selected from H, F, Cl, Br, I, OH, cyano, NH2 , methyl, ethyl, methoxy, cyclopropyl, ethynyl, propane Alkynyl;
在某些实施方案中，n选自0、1、2、3或4；In certain embodiments, n is selected from 0, 1, 2, 3 or 4;
在某些实施方案中，n选自0、1、2或3；In certain embodiments, n is selected from 0, 1, 2 or 3;
在某些实施方案中，B选自表B-1所示的结构片段之一；In certain embodiments, B is selected from one of the structural fragments shown in Table B-1;
表B-1 B基团


Table B-1 Group B


作为本发明的第一种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
L选自键或-C1-50烃基-，所述烃基中有0至20个亚甲基单元任选进一步被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbon group-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-任选进一步被0至2个选自H、卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, - NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C( =O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH=CH-, -Si( R L ) 2 -, -Si(OH)( RL )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)( RL )-, - S-, -S(=O)-, -S(=O) 2 - or a bond, the -CH 2 - is optionally further replaced by 0 to 2 selected from H, halogen, OH, CN, NH 2 , Substituents of C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl ;
q各自独立的选自0、1、2、3、4、5或6；q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述杂芳基含有1至4个选自O、S、N的杂原子； RL are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
每个-Cy-各自独立地选自键、4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocyclic ring Alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the aryl, Heteroaryl, cycloalkyl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings are optionally further represented by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2. Substituents of =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy, the heteroaryl Base, heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally further 0, 1 or 2 One=O replaces;
B选自 B from
Z1、Z2或Z3各自独立的选自S、Se、N、NRz或CRz；Z 1 , Z 2 or Z 3 are each independently selected from S, Se, N, NR z or CR z ;
Rz选自H、卤素、氰基、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-8碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, the said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
作为选择，任意两个Rz直接连接，形成C4-8碳环或者4至8元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Alternatively, any two R z are directly connected to form a C 4-8 carbocycle or a 4 to 8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-6烷基、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、 卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(= O)-R a2 , C 1-6 alkyl, C 3-10 carbocycle or 3 to 10 membered heterocycle, said alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1 -6 alkoxy substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2各自独立的选自H、C1-6烷基、-C1-4烷基-C3-10碳环、-C1-4烷基-3至10元杂环、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C 1-4 alkyl-C 3-10 carbocycle, -C 1-4 alkyl-3 to 10 membered heterocycle, C 3-10 carbocyclic rings or 3-10 membered heterocyclic rings, the alkyl, carbocyclic or heterocyclic rings are optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH 2 , C 1-6 Alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy substituents, said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
R2选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-6烷基的取代基所取代；R 2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-6 alkyl substituents;
X1选自O、S、NRx，X2选自N、CRx；X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
Rx各自独立的选自H、卤素、氰基、OH、C1-6烷基、C1-6烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代；R x are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-6 alkyl, C 1-6 alkoxy or C selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
环B1选自苯环或者5至6元杂芳环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烷基)、C1-6烷基、C1-6烷氧基、C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基或炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-6烷基、C1-6烷基、C1-6烷氧基、C3-6环烷基或4至8元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl or alkynyl C 1-6 alkyl , C 1-6 alkyl, C 1-6 alkoxy, C 3- Substituted by a 6- cycloalkyl group or a 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
K选自 K selected from
Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或3-12元杂环基，所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, so The heterocyclic group mentioned above is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1- 4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rq选自H或C1-6烷基；R is selected from H or C 1-6 alkyl;
A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环或杂芳基含有1至4个选自O、S、N的杂原子；A is selected from C 3-10 carbocyclic group, C 6-10 aryl group, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, and the heterocyclic ring or heteroaryl group contains 1 to 4 members selected from O , S, N heteroatoms;
F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S、N的杂原子；F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclic group or 5-20 membered heteroaryl, and the heterocyclic group or heteroaryl contains 1 to 4 a heteroatom selected from O, S, N;
Rk2各自独立地选自键、-CO-、-SO2-、-SO-或-C(Rk3)2-；Each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
Rk1或Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；R k1 or R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further replaced by 0 to 4 selected from H, F, Cl, Br , I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heterocycle The group contains 1 to 4 heteroatoms selected from O, S, N;
或者两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-8元碳环或3-8元杂环，所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S、N的杂原子；Or two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocycle or a 3-8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by O to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；R k4 are each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, cycloalkane The group or the heterocyclic group is optionally further replaced by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1- 4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from a bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子； M2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclic group, the alkyl, cycloalkyl Or the heterocyclic group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
Rk10选自C1-6烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3 Substituents of -6 cycloalkyl are substituted;
Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基或C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 are each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, C 1-4 Substituents of alkyl or C 1-4 alkoxy;
Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, F, Substituted by Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
Rk14选自5-6元杂芳基，所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、 ＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O、S的杂原子；R k14 is selected from 5-6 yuan heteroaryl, and the heteroaryl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkoxy or C 3-6 cycloalkyl The substituent is substituted, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O, S;
G选自6-10元芳基或5-10元杂芳基，所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O、S的杂原子；G is selected from 6-10 membered aryl groups or 5-10 membered heteroaryl groups, and the aryl group or heteroaryl group is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, = O, CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkoxy or C 3-6 cycloalkyl Replaced by a substituent, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, S;
n1、n2、n3各自独立的选自0、1、2或3；n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
作为本发明的第二种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2- Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2- Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4- Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2- Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7- Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、卤素、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further C 1-4 substituted by 0 to 2 selected from H, halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxyl Alkyl, cyano substituted C 1-4 alkyl substituents;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键、4-7元杂单环、4-10元杂并环、5-12元杂 螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterocyclic ring, Spiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 Member heteroaryl or 6-10 member aryl, said aryl, heteroaryl, cycloalkyl, heteromonocycle, heteroheterocycle, heterospiro ring or heterobridged ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C Substituted by 1-4 alkoxy substituents, the heteroaryl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings contain 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;
q各自独立的选自0、1、2、3或4；q are each independently selected from 0, 1, 2, 3 or 4;
RL各自独立的选自H或C1-6烷基； RL are each independently selected from H or C 1-6 alkyl;
其余定义与本发明第一种实施方案相同。The rest of the definitions are the same as the first embodiment of the present invention.
作为本发明的第三种实施方案，前述通式(I)所所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、C1-4烷基、C1-4烷氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further Substituted by 0 to 2 substituents selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 1-4 alkoxy ;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键、4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述杂单环、杂并环、杂桥环、杂螺环、环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, 4-7 membered nitrogen-containing heteromonocyclic ring, 4-10 membered nitrogen-containing heterocyclic ring, 5-12 membered nitrogen-containing heterospirocyclic ring, 7-10 membered Nitrogen-containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl are optionally further replaced by 0 to 4 members selected from H, F, Cl , Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy The substituent of the base is substituted, and the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from When S, optionally further substituted by 0, 1 or 2 ═O;
RL各自独立的选自H或C1-4烷基； RL are each independently selected from H or C 1-4 alkyl;
Rz选自H、卤素、氰基、OH、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-7碳环基或3至7元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Alkoxy, C 3-7 carbocyclyl or 3 to 7 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
作为选择，任意两个Rz直接连接，形成C4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Alternatively, any two R z are directly connected to form a C 4-7 carbocycle or a 4 to 7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-4烷基、C3-6单环碳环、4至8元单环杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(= O)-R a2 , C 1-4 alkyl, C 3-6 monocyclic carbocyclic ring, 4 to 8 membered monocyclic heterocyclic ring, said alkyl, carbocyclic or heterocyclic ring is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkane Substituent group or C 1-4 alkoxy group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
Ra1选自H、C1-4烷基；R a1 is selected from H, C 1-4 alkyl;
Ra2选自H、C1-4烷基、-C1-2烷基-C3-6单环芳环、-C1-2烷基-C3-6单环非芳香环、-C1-2烷基-5至6元芳杂环、-C1-2烷基-4至8元单环非芳香杂环、C5-6单环芳环、C3-6单环非芳香环、5至6元芳杂环、4至8元单环非芳香杂环，所述的烷基、芳环、非芳香环、芳杂环、非芳香杂环任选 进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的芳杂环、杂环含有1至3个选自O、S、N的杂原子；R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, -C 1-2 alkyl-C 3-6 monocyclic non-aromatic ring, -C 1-2 alkyl-5 to 6-membered aromatic heterocycle, -C 1-2 alkyl-4 to 8-membered monocyclic non-aromatic heterocycle, C 5-6 monocyclic aromatic ring, C 3-6 monocyclic non-aromatic ring, 5-6 membered aromatic heterocycle, 4-8 membered monocyclic non-aromatic heterocycle, the alkyl, aromatic ring, non-aromatic ring, aromatic heterocycle, non-aromatic heterocycle are optional Further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano Substituents of C 1-4 alkyl or C 1-4 alkoxy, the aromatic heterocycle and heterocycle contain 1 to 3 heteroatoms selected from O, S, N;
R2选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-4烷基的取代基所取代；R 2 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-4 alkyl substituents;
X1选自O、S、NRx，X2选自N、CRx；X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
Rx各自独立的选自H、卤素、氰基、OH、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R x are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-4 alkyl, C 1-4 alkoxy or C selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
环B1选自苯环或者5至6元杂芳环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基、C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基或炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-4烷基、C1-4烷基、C1-4烷氧基、C3-6环烷基或4至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl or alkynyl C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy , C 3- Substituted by a 6- cycloalkyl group or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
K选自 K selected from
表示环选自芳香环或非芳香环； Indicates that the ring is selected from an aromatic ring or a non-aromatic ring;
Q各自独立地选自-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或4-7元杂环基，所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；Each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocyclic group, the The heterocyclic group is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkane Oxygen substituents are substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rq选自H或C1-4烷基；R is selected from H or C 1-4 alkyl;
Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基,所述烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkane Oxygen group, the alkyl or alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH ;
或者两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-6元碳环或3-7元杂环，所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S、N的杂原子；Or two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by O to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
Rk4各自独立的选自H、OH、NH2、CF3、CN、C1-4烷基；R k4 are each independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
Rk5各自独立地选自C(CH3)2、CO、CH2、SO2、 R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；R K6 are each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
Rk8各自独立地选自C、N或CH；Each R K8 is independently selected from C, N or CH;
Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2； R k9 are each independently selected from a bond, C( CH3 ) 2 , CO, CH2 , CH2CH2 or SO2 ;
A、H1或H2各自独立地选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳基，所述杂环或杂芳基含有1至4个选自O、S、N的杂原子；A, H1 or H2 are each independently selected from C3-8 carbocycles, benzene rings, 4-7 membered heterocycles or 5-6 membered heteroaryls, and the heterocycles or heteroaryls contain 1 to 4 members selected from Heteroatoms of O, S, N;
E各自独立地选自C3-8碳环、苯环、4-7元杂环、8-12元杂环基、7-12元杂芳基或5-6元杂芳基，所述杂环或杂芳基含有1至4个选自O、S、N的杂原子；E are each independently selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring, 8-12 membered heterocyclic group, 7-12 membered heteroaryl group or 5-6 membered heteroaryl group, the heteroaryl The ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
F各自独立地选自3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、4-7元杂单环、4-10元杂并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基或5-10元杂芳基，所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S、N的杂原子；F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, the heteromonocyclic, heterocyclic, heterocyclic The spiro ring, heterobridged ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
其余定义与本发明第一种或第二种实施方案相同。The remaining definitions are the same as in the first or second embodiment of the present invention.
作为本发明的第四种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further Substituted by 0 to 2 substituents selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, methyl, ethyl, methoxy or ethoxy;
RL选自H、甲基或乙基； RL is selected from H, methyl or ethyl;
q各自独立的选自0、1或2；q are each independently selected from 0, 1 or 2;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己烯基、哌啶、吗啉、哌嗪、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环戊基并哌啶、环己基并氮杂环丁基、环己基并氮杂环戊基、环己基并氮杂环己基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环戊基并哌啶、氮杂环己基并氮杂环丁基、氮杂环己基并氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基螺氮杂环丁基、环己基螺氮杂环戊基、环己基螺氮杂环己基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环丁基、氮杂环己基螺氮杂环戊基、氮杂环己基螺氮杂环己基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时，任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, nitrogen Heterocyclopentyl, aziridinyl, piperidine, morpholine, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropyl Cyclobutyl cyclohexyl, cyclobutyl cyclobutyl, cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclo Propylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspiro Cyclohexyl, Cyclopentylspirocyclopentyl, Cyclopentylspirocyclohexyl, Cyclohexylspirocyclohexyl, Cyclopropylazetidinyl, Cyclopropylazepinyl, Cyclopropylazepine Cyclohexyl, cyclopropylpiperidine, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazepine, cyclobutylpiperidine, cyclopentyl Azetidinyl, Cyclopentylazetidinyl, Cyclopentylazetidinyl, Cyclopentylpiperidine, Cyclohexylazetidinyl, Cyclohexylazetidinyl, Cyclohexyl azetidinyl, cyclohexyl piperidine, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, nitrogen Heterocyclopentyl-piperidine, azacyclopentyl-azetidinyl, azacyclopentyl-azetidinyl, azacyclopentyl-azetidinyl, azacyclopentyl-azetidinyl, azacyclopentyl-piperidine Pyridine, Azacyclohexylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylazetidinyl, Azacyclohexylpiperidine, Cyclobutylspiroazetidinyl Cyclobutylspiroazacyclopentyl, cyclobutylspiroazepinexyl, cyclopentylspiroazetidinyl, cyclopentylspiroazepinyl, cyclopentylspiroazepinexyl, Cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidinylspiroazetidinyl, Azacyclopentylspiroazetidinyl, Azacyclopentylspiroazepinyl, Azacyclopentylspiroazepinyl, Azacyclohexyl Spiroazetidinyl, Azacyclohexylspiroazacyclopentyl, Azacyclohexylspiroazepinyl, Cyclobutylspiropiperidine, Cyclopentylspiropiperidine, Cyclohexylspiropiperidine, Azepine Cyclobutyl spiropiperidine, Azacyclopentyl spiropiperidine, Azacyclohexyl spiropiperidine, When substituted, C 1- optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen 4 alkyl, hydroxyl substituted C 1-4 alkyl or C 1-4 alkoxy substituents;
选自 selected from
Rz选自H、F、Cl、Br、I、NH2、氰基、OH、NHCH3、NHCH2CH3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环己基、环戊基、氮杂环丁基、氮杂环戊基、哌啶基、哌嗪基；R z is selected from H, F, Cl, Br, I, NH 2 , cyano, OH, NHCH 3 , NHCH 2 CH 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl Base, cyclohexyl, cyclopentyl, azetidinyl, azacyclopentyl, piperidinyl, piperazinyl;
作为选择，任意两个Rz直接连接，形成5元碳环基、6元碳环基或7元碳环基；Alternatively, any two Rz are directly connected to form a 5-membered carbocyclyl, a 6-membered carbocyclyl or a 7-membered carbocyclyl;
R1选自H、F、Cl、Br、I、氰基、OH、甲氧基、乙氧基、NHRa2、-NHSO2-Ra2、-NHC(＝O)-Ra2、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉或哌嗪；R 1 is selected from H, F, Cl, Br, I, cyano, OH, methoxy, ethoxy, NHR a2 , -NHSO 2 -R a2 , -NHC(=O)-R a2 , cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azecyclohexyl, oxetanyl, oxolyl, oxanyl, morpholine or piperidine Zinc;
Ra2选自H、取代或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、哌嗪、吡啶、苯基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉、-CH2-哌嗪、-CH2-吡啶、-CH2-苯基，当被取代时，任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代；R a2 is selected from one of H, substituted or unsubstituted following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Morpholine, Piperazine, Pyridine, Phenyl, -CH 2 -Cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, -CH 2 -oxolyl, -CH 2 -oxanyl, -CH 2 -morpholine, -CH 2 -piperazine, -CH 2 -pyridine, - CH 2 -phenyl, when substituted, is optionally further substituted with 0 to 4 C 1-4 alkyl selected from H , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkyl substituted by cyano or C 1-4 alkoxy substituent;
R2选自H；R is selected from H;
X1选自NH； X is selected from NH;
X2选自N或CH； X2 is selected from N or CH;
环B1选自苯环、吡啶、嘧啶；Ring B 1 is selected from benzene ring, pyridine, pyrimidine;
R3各自独立的选自H、F、Cl、Br、I、OH、氰基、NH2、甲基、乙基、甲氧基、环丙基、乙炔基、丙炔基； R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, NH 2 , methyl, ethyl, methoxy, cyclopropyl, ethynyl, propynyl;
K选自 K selected from
E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基；E are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
A各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基；A is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
F各自独立地选自环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊 [c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、氮杂环戊基、哌啶基、吗啉基、吡啶基、吡啶酮基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、萘并呋喃基、噻吩并吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并噁唑基、吡啶并咪唑基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基或吡嗪并吡嗪基；F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6,7-dihydro-5H-cyclopentyl [c] pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, Pyridyl, pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, naphthalene And furyl, thienoindolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzopyridyl, benzopyrazine Base, benzopyrimidinyl, benzopyridazinyl, benzoxazolyl, pyridimidazolyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl , imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidine Pyridyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyrazinyl, pyridazinopyridazinyl, pyridazinopyrazine or pyrazinopyrazinyl;
Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
p1或p2各自独立的选自0、1或2；p1 or p2 are each independently selected from 0, 1 or 2;
其余定义与本发明第一种、第二种或第三种实施方案相同。The remaining definitions are the same as the first, second or third embodiment of the present invention.
作为本发明的第五种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自键、-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH -, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O) CH2NH- , -CH2C (=O)NH-, -C(=O)NH- or -NHC(=O)-;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：

Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted:

当被取代时，任选进一步被0至4个选自H、F、CF3、甲基、＝O、羟甲基、COOH、CN或NH2的取代基所取代；When substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF 3 , methyl, =O, hydroxymethyl, COOH, CN or NH 2 ;
B选自表B-1所示的结构片段之一；B is selected from one of the structural fragments shown in Table B-1;
K选自表K-1所示的结构片段之一；K is selected from one of the structural fragments shown in Table K-1;
其余定义与本发明第一种、第二种、第三种或第四种实施方案相同。The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.
作为本发明的第六种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
L选自键、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2- Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3- , -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3- , -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4- , -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1- Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2- Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3- Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4- Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
其余定义与本发明第一种、第二种、第三种、第四种或第五种实施方案相同。The remaining definitions are the same as the first, second, third, fourth or fifth embodiment of the present invention.
作为本发明的第七种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
L选自键或表L-1所示的基团，其中基团左侧与B连接；L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;
其余定义与本发明第一种、第二种、第三种、第四种、第五种或第六种实施方案相同。The remaining definitions are the same as those of the first, second, third, fourth, fifth or sixth embodiment of the present invention.
作为本发明的第八种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
L选自键或表L-2所示的基团，其中基团左侧与B连接；L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;
K选自表K-2所示的结构片段之一； K is selected from one of the structural fragments shown in Table K-2;
其余定义与本发明第一种、第二种、第三种、第四种、第五种、第六种、第七种实施方案相同。All the other definitions are the same as the first, second, third, fourth, fifth, sixth and seventh embodiments of the present invention.
本发明涉及一种下述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下表S-1中所示结构之一。The present invention relates to a compound or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following table One of the structures shown in S-1.
表S-1























Table S-1























本发明涉及一种药物组合物，包括本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutically acceptable carrier.
本发明涉及一种本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与HPK1活性或表达量相关疾病的药物中的应用。The present invention relates to a kind of above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of treatment and Application in medicine for diseases related to HPK1 activity or expression level.
本发明涉及一种本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解HPK1相关疾病的药物中的应用。The present invention relates to a kind of above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of treatment and Application in drugs for inhibiting or degrading HPK1 related diseases.
本发明涉及的本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的应用，所述的疾病选自癌症。The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and the diseases selected from cancer.
包含本发明所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的制剂规格包括但不限于1-1500mg、1-400mg、1-375、1-350mg、1-325mg、1-300mg、1-275mg、1-250mg、1-220mg、1-200mg、1-175mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-40mg、1-20mg、5-400mg、5-375、5-350mg、5-325mg、5-300mg、5-275mg、5-250mg、5-220mg、5-200mg、5-175mg、5-150mg、5-125mg、5-100mg、5-80mg、5-60mg、5-40mg、5-20mg、5-90mg、5-70mg、5-50mg、5-30mg、10-400mg、10-375、10-350mg、10-325mg、10-300mg、10-275mg、10-250mg、10-220mg、10-200mg、10-175mg、10-150mg、10-125mg、10-100mg、10-80mg、10-60mg、10-40mg、10-20mg、10-90mg、10-70mg、10-50mg、10-30mg；在一些实施方案中该制剂规格包括但不限于1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg。The preparation specifications comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but Not limited to 1-1500mg, 1-400mg, 1-375mg, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5- 250mg, 5-220mg, 5-200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5-60mg, 5-40mg, 5-20mg, 5-90mg, 5-70mg, 5-50mg, 5-30mg, 10-400mg, 10-375, 10-350mg, 10-325mg, 10-300mg, 10-275mg, 10-250mg, 10-220mg, 10-200mg, 10-175mg, 10- 150mg, 10-125mg, 10-100mg, 10-80mg, 10-60mg, 10-40mg, 10-20mg, 10-90mg, 10-70mg, 10-50mg, 10-30mg; in some embodiments the formulation specification Including but not limited to 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg.
包含本发明所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的单位制剂中的所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用量包括但不限于1-1500mg、1-400mg、1-375、1-350mg、1-325mg、1-300mg、1-275mg、1-250mg、1-220mg、1-200mg、 1-175mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-40mg、1-20mg、5-400mg、5-375、5-350mg、5-325mg、5-300mg、5-275mg、5-250mg、5-220mg、5-200mg、5-175mg、5-150mg、5-125mg、5-100mg、5-80mg、5-60mg、5-40mg、5-20mg、5-90mg、5-70mg、5-50mg、5-30mg、10-400mg、10-375、10-350mg、10-325mg、10-300mg、10-275mg、10-250mg、10-220mg、10-200mg、10-175mg、10-150mg、10-125mg、10-100mg、10-80mg、10-60mg、10-40mg、10-20mg、10-90mg、10-70mg、10-50mg、10-30mg；在一些实施方案中单位制剂中的所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用量包括但不限于1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg。In the unit preparation comprising the compound of general formula (I) of the present invention or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal The amount of the compound of general formula (I) or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal includes but not limited to 1-1500mg , 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5- 300mg, 5-275mg, 5-250mg, 5-220mg, 5-200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5-60mg, 5-40mg, 5-20mg, 5-90mg, 5-70mg, 5-50mg, 5-30mg, 10-400mg, 10-375, 10-350mg, 10-325mg, 10-300mg, 10-275mg, 10-250mg, 10-220mg, 10- 200mg, 10-175mg, 10-150mg, 10-125mg, 10-100mg, 10-80mg, 10-60mg, 10-40mg, 10-20mg, 10-90mg, 10-70mg, 10-50mg, 10-30mg; In some embodiments, the compound of general formula (I) or its stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co- Crystal dosage includes but not limited to 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg.
包含本发明所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的制剂提供包括但不限于1-1500mg/天、1-400mg/天、1-375/天、1-350mg/天、1-325mg/天、1-300mg/天、1-275mg/天、1-250mg/天、1-220mg/天、1-200mg/天、1-175mg/天、1-150mg/天、1-125mg/天、1-100mg/天、1-80mg/天、1-60mg/天、1-40mg/天、1-20mg/天、5-400mg/天、5-375/天、5-350mg/天、5-325mg/天、5-300mg/天、5-275mg/天、5-250mg/天、5-220mg/天、5-200mg/天、5-175mg/天、5-150mg/天、5-125mg/天、5-100mg/天、5-80mg/天、5-60mg/天、5-40mg/天、5-20mg/天、5-90mg/天、5-70mg/天、5-50mg/天、5-30mg/天、10-400mg/天、10-375/天、10-350mg/天、10-325mg/天、10-300mg/天、10-275mg/天、10-250mg/天、10-220mg/天、10-200mg/天、10-175mg/天、10-150mg/天、10-125mg/天、10-100mg/天、10-80mg/天、10-60mg/天、10-40mg/天、10-20mg/天、10-90mg/天、10-70mg/天、10-50mg/天、10-30mg/天范围内的单剂量或分剂量形式给药；在一些实施方案中包括但不限于1mg/天、5mg/天、10mg/天、15mg/天、20mg/天、25mg/天、30mg/天、35mg/天、40mg/天、45mg/天、50mg/天、55mg/天、65mg/天、70mg/天、75mg/天、80mg/天、85mg/天、90mg/天、95mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天、200mg/天、210mg/天、220mg/天、230mg/天、240mg/天、250mg/天范围内的单剂量或分剂量形式给药。The preparations comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but Not limited to 1-1500mg/day, 1-400mg/day, 1-375mg/day, 1-350mg/day, 1-325mg/day, 1-300mg/day, 1-275mg/day, 1-250mg/day, 1-220mg/day, 1-200mg/day, 1-175mg/day, 1-150mg/day, 1-125mg/day, 1-100mg/day, 1-80mg/day, 1-60mg/day, 1- 40mg/day, 1-20mg/day, 5-400mg/day, 5-375mg/day, 5-350mg/day, 5-325mg/day, 5-300mg/day, 5-275mg/day, 5-250mg/day day, 5-220mg/day, 5-200mg/day, 5-175mg/day, 5-150mg/day, 5-125mg/day, 5-100mg/day, 5-80mg/day, 5-60mg/day, 5-40mg/day, 5-20mg/day, 5-90mg/day, 5-70mg/day, 5-50mg/day, 5-30mg/day, 10-400mg/day, 10-375/day, 10- 350mg/day, 10-325mg/day, 10-300mg/day, 10-275mg/day, 10-250mg/day, 10-220mg/day, 10-200mg/day, 10-175mg/day, 10-150mg/day day, 10-125mg/day, 10-100mg/day, 10-80mg/day, 10-60mg/day, 10-40mg/day, 10-20mg/day, 10-90mg/day, 10-70mg/day, 10-50 mg/day, 10-30 mg/day in single or divided doses; in some embodiments including but not limited to 1 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day day, 25mg/day, 30mg/day, 35mg/day, 40mg/day, 45mg/day, 50mg/day, 55mg/day, 65mg/day, 70mg/day, 75mg/day, 80mg/day, 85mg/day, 90mg/day, 95mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day, 180mg/day, 190mg/day, 200mg/day Day, 210mg/day, 220mg/day, 230mg/day, 240mg/day, 250mg/day in the form of single dose or divided doses.
配置成单剂量或分剂量形式的药物组合物，其中该单剂量或分剂量形式包含本发明所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用量包括但不限于1-1500mg、1-400mg、1-375、1-350mg、1-325mg、1-300mg、1-275mg、1-250mg、1-220mg、1-200mg、1-175mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-40mg、1-20mg、5-400mg、5-375、5-350mg、5-325mg、5-300mg、5-275mg、5-250mg、5-220mg、5-200mg、5-175mg、5-150mg、5-125mg、5-100mg、5-80mg、5-60mg、5-40mg、5-20mg、5-90mg、5-70mg、5-50mg、5-30mg、10-400mg、10-375、10-350mg、10-325mg、10-300mg、10-275mg、10-250mg、10-220mg、10-200mg、10-175mg、10-150mg、10-125mg、10-100mg、10-80mg、10-60mg、10-40mg、10-20mg、10-90mg、10-70mg、10-50mg、10-30mg。A pharmaceutical composition configured in a single dose or in divided doses, wherein the single or divided doses comprise the compound of general formula (I) of the present invention or its stereoisomers, tautomers, deuteriums, solvates , prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals include but are not limited to 1-1500mg, 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg, 1-275mg, 1 -250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375 , 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5-250mg, 5-220mg, 5-200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5 -60mg, 5-40mg, 5-20mg, 5-90mg, 5-70mg, 5-50mg, 5-30mg, 10-400mg, 10-375, 10-350mg, 10-325mg, 10-300mg, 10-275mg , 10-250mg, 10-220mg, 10-200mg, 10-175mg, 10-150mg, 10-125mg, 10-100mg, 10-80mg, 10-60mg, 10-40mg, 10-20mg, 10-90mg, 10 -70mg, 10-50mg, 10-30mg.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或分剂量形式的组合物，该试剂盒包含本发明所述通式(I)化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的用量包括但不限于1-1500mg、1-400mg、1-375、1-350mg、1-325mg、1-300mg、1-275mg、1-250mg、1-220mg、1-200mg、1-175mg、1-150mg、1-125mg、1-100mg、 1-80mg、1-60mg、1-40mg、1-20mg、5-400mg、5-375、5-350mg、5-325mg、5-300mg、5-275mg、5-250mg、5-220mg、5-200mg、5-175mg、5-150mg、5-125mg、5-100mg、5-80mg、5-60mg、5-40mg、5-20mg、5-90mg、5-70mg、5-50mg、5-30mg、10-400mg、10-375、10-350mg、10-325mg、10-300mg、10-275mg、10-250mg、10-220mg、10-200mg、10-175mg、10-150mg、10-125mg、10-100mg、10-80mg、10-60mg、10-40mg、10-20mg、10-90mg、10-70mg、10-50mg、10-30mg。The present invention relates to a kit, which may include a composition in a single dose or in divided doses, the kit comprising the compound of general formula (I) of the present invention or its stereoisomers, tautomers, The amount of deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal includes but not limited to 1-1500mg, 1-400mg, 1-375, 1-350mg, 1-325mg, 1-300mg , 1-275mg, 1-250mg, 1-220mg, 1-200mg, 1-175mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-40mg, 1-20mg, 5-400mg, 5-375, 5-350mg, 5-325mg, 5-300mg, 5-275mg, 5-250mg, 5-220mg, 5- 200mg, 5-175mg, 5-150mg, 5-125mg, 5-100mg, 5-80mg, 5-60mg, 5-40mg, 5-20mg, 5-90mg, 5-70mg, 5-50mg, 5-30mg, 10-400mg, 10-375, 10-350mg, 10-325mg, 10-300mg, 10-275mg, 10-250mg, 10-220mg, 10-200mg, 10-175mg, 10-150mg, 10-125mg, 10- 100mg, 10-80mg, 10-60mg, 10-40mg, 10-20mg, 10-90mg, 10-70mg, 10-50mg, 10-30mg.
本发明中通式化合物的结构中的的咪唑并部分以互变异构形式存在,包括了根据IUPAC定则，这些结构(A)和(B)产生不同的命名。应理解，虽然结构以特定形式展示或命名，但本发明还包括其互变异构体。In the structure of the general formula compound in the present invention The imidazo moieties exist in tautomeric forms, including These structures (A) and (B) yield different nomenclature according to IUPAC rules. It is to be understood that although a structure is shown or named in a particular form, the invention also includes tautomers thereof.
如结构中的咪唑并部分以互变异构形式存在,包括了 as in the structure The imidazo moieties exist in tautomeric forms, including
除非有相反的陈述，在本申请说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims of this application have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、硒、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，硒的同位素包括74Se、76Se、77Se、78Se、80Se、82Se，氮的同位素包括14N和15N，氟的同位素包括17F、18F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, selenium, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the groups and compounds involved in the present invention The carbon, hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium ( D, also called heavy hydrogen), tritium (T, also called super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of selenium Including 74 Se, 76 Se, 77 Se, 78 Se, 80 Se, 82 Se, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F, 18 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, bromine isotopes include 79 Br and 81 Br.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，为1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"Halogen substituted" refers to F, Cl, Br or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halo".
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; Alkyl group appearing in this article, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、 S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or The heteroatom of S, the optionally substituted N in the ring of heterocycloalkyl, S can be oxidized into various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. A heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。"Alkenyl" means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms, alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-but Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octene base, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-Hexadiene, etc.; alkenyl groups appearing in this text have the same definition as this one. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，包括但不限于在主链上有2至6个碳原子，主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"Alkynyl" means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the backbone comprising 2 to 10 carbon atoms , including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl include but not limited to ethynyl, propargyl, 1-propynyl, 2 -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl Base-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- Hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, Bivalent, trivalent or quadrivalent.
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"Alkoxy" means a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, A "carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、 四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, the ring optional of heterocyclyl Substituted N and S can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazole Base, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl , benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl , azaadamantyl, oxaspiro[3.3]heptyl, A "heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n的杂原子。

。“螺环”或“螺环基”可以是一价、二价、三价或四价。"Spiro ring" or "spirocyclic group" refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Optional may contain 0 to 5 heteroatoms selected from N, O or S(=O) n .

. A "spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： "Acyl ring" or "annyl ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more ( including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain from 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to be selected from N, S(=O) n or O, n being 0, 1 or 2). The number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:
“并环”或“并环基”可以是一价、二价、三价或四价。"Alkyl" or "alkyl" may be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个环共用两个不直接连接的原子的多环基团，可以含有0个或多个双键，并环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two rings sharing two atoms that are not directly connected, may contain 0 or more double bonds, and the ring system Any ring in may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane. A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与螺环一致。"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definitions of "carbospirocycle", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein are consistent with spirocycle.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与并环一致。"Carbocyclic", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" whose ring system consists only of carbon atoms. The definition of "carbocyclyl", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" used herein is consistent with that of paracyclyl.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与桥环一致。"Carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged cycloyl" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring" appearing in this article are consistent with those of bridged ring.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出现的“杂单环”、“单环杂环基”或“杂单环基”，其定义与杂环一致。"Heteromonocyclic", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to the "heterocyclic group" or "heterocyclic group" of a monocyclic ring system, and the "heteromonocyclic", "monocyclic" appearing herein Heterocyclic group" or "heteromonocyclic group", its definition is consistent with heterocycle.
“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。本文中出现的“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”，其定义与并环一致。"Heterocyclyl", "heterocyclyl", "heterocyclic heterocyclyl" or "heterocyclyl" refers to "heterocycles" that contain heteroatoms. The definition of "heterocyclic ring", "heterocyclic group", "heterocyclic heterocyclic group" or "heterocyclic group" used herein is consistent with that of parallel ring.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。本文中出现的“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”，其定义与螺环一致。"Heterospiro", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" that contains heteroatoms. The definitions of "heterospirocycle", "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" appearing herein are consistent with those of spirocycle.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。本文中出现的“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”，其定义与桥环一致。"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "heterobridged ring group" refers to a "bridged ring" that contains heteroatoms. The definition of "heterobridged ring", "heterobridged ring group", "bridged ring heterocyclic group" or "heterobridged ring group" used herein is consistent with bridged ring.
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene, "Aryl" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含 "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include
本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。Where heteroaryl appears herein, its definition is consistent with this definition. Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.
“5元环并5元杂芳环”是指5并5元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了吡咯并吡咯环、吡唑并吡咯环、吡唑并吡唑环、吡咯并呋喃环、吡唑并呋喃环、吡咯并噻吩环、吡唑并噻吩环。"5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.
“5并6元杂芳环”是指5并6元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了苯并5元杂芳基、6元杂芳环并5元杂芳环。"5 and 6-membered heteroaryl ring" refers to a 5-6-membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。"Substituted" or "substituted" means substituted by 1 or more (including but not limited to 2, 3, 4 or 5) substituents including but not limited to H, F, Cl, Br, I , Alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m - C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , -(CH 2 ) m S(=O) n R a , -(CH 2 ) m -ene -R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c Such groups, wherein R b and R c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Sulfonyl, as an option, R b and R c can form a five or six membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic or alkynyl.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10. For example, "substituted by 0 to 4 substituents" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "substituted by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.
X-Y元的环(3≤X＜Y，Y选自4至12之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。X-Y-membered rings (3≤X<Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4....Y-membered rings. Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。 "Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutical A mixture formed of pharmaceutically acceptable salts or co-crystals and other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。"Prodrug" refers to a compound of the present invention that can be transformed into a biologically active compound through in vivo metabolism. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups of the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are both solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"Tautomer" refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。" IC50 " is the concentration of drug or inhibitor required to inhibit a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.) by half.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代三氟乙酸(CF3COOD)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated trifluoroacetic acid (CF 3 COOD), deuterated chloroform ( CDCl 3 ), deuterated methanol (CD 3 OD), internal standard tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)或Shimadzu LC–20AT高压液相色谱仪(Xtimate C18(4.6×50mm,3μm))；The determination of HPLC uses Agilent 1260DAD high-pressure liquid chromatography (Zorbax SB-C18 100×4.6mm, 3.5μM) or Shimadzu LC-20AT high-pressure liquid chromatography (Xtimate C18 (4.6×50mm, 3μm));
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate, the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
Boc：叔丁氧基羰基；Ts：对甲苯磺酰基；Cbz：苄氧羰基；TMS：三甲基硅基；DIPEA：N,N-二异丙基乙胺；DMA:N,N-二甲基乙酰胺；LiHMDS：双三甲基硅基胺基锂；DMSO：二甲基亚砜。Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl; DIPEA: N,N-diisopropylethylamine; DMA: N,N-dimethyl acetamide; LiHMDS: lithium bistrimethylsilylamide; DMSO: dimethyl sulfoxide.
中间体1为2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮。Intermediate 1 is 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione.
实施例涉及到的部分反应类型及其条件如下：The partial reaction types and conditions thereof that embodiment relates to are as follows:
1)脱氨基Boc保护，原料溶于氯化氢的二氧六环溶液(4mol/L)反应得到脱Boc的产物，反 应液可直接减压浓缩后加入一定量的1,4-二氧六环和三乙胺，进一步减压浓缩后直接用于下一步反应；1) Deamination Boc protection, the raw material is dissolved in the dioxane solution (4mol/L) of hydrogen chloride to react to obtain the product of de-Boc, and the reaction The reaction solution can be directly concentrated under reduced pressure and then added a certain amount of 1,4-dioxane and triethylamine, and then directly used for the next reaction after further concentrated under reduced pressure;
2)还原胺化反应：仲胺与含有C＝O的化合物反应得到产物，首先原料溶于DMA，加入醋酸后，室温～50℃反应1～3h，然后加入还原剂NaBH(OAc)3室温～50℃反应得到还原胺化的产物；2) Reductive amination reaction: secondary amine reacts with a compound containing C=O to obtain a product. First, the raw material is dissolved in DMA, and after adding acetic acid, react at room temperature to 50°C for 1 to 3 hours, and then add the reducing agent NaBH(OAc) 3 at room temperature to Reductively aminated product was obtained by reaction at 50°C;
3)亲核取代反应：仲胺与F代的芳基或F代的杂芳基溶于DMSO中，加入DIPEA或碳酸氢钠后，80℃～100℃反应得到产物。3) Nucleophilic substitution reaction: secondary amine and F-substituted aryl or F-substituted heteroaryl are dissolved in DMSO, and after adding DIPEA or sodium bicarbonate, react at 80°C to 100°C to obtain the product.
终产物可以采用prep-HPLC制备得到：The final product can be prepared by prep-HPLC:
制备方法1)仪器：waters 2767制备液相；色谱柱：XBridge@Prep C18(30mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸)，制备液减压浓缩；Preparation method 1) Instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid), prepared Concentrate under reduced pressure;
制备方法2)将制备方法1得到的制备液加入饱和碳酸氢钠溶液，用二氯甲烷、乙酸乙酯或二氯甲烷/甲醇混合溶剂(v/v＝10/1)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩得到。Preparation method 2) Add the preparation solution obtained in preparation method 1 into saturated sodium bicarbonate solution, extract with dichloromethane, ethyl acetate or dichloromethane/methanol mixed solvent (v/v=10/1), and the organic phase is anhydrous It was obtained by drying over sodium sulfate, filtering, and concentrating under reduced pressure.
制备方法3)仪器：waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：乙腈，水(含5mmol/L的醋酸铵)，制备液冻干或减压浓缩；Preparation method 3) Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: acetonitrile, water (ammonium acetate containing 5mmol/L), the preparation solution was lyophilized or concentrated under reduced pressure;
制备方法4)：仪器：waters 2767制备液相；色谱柱：XBridge@Prep C18(30mm×150mm)；流动相组成：乙腈/水(含5mmol/L的醋酸铵)，制备液冻干或减压浓缩；Preparation method 4): instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: acetonitrile/water (containing 5mmol/L ammonium acetate), and the preparation solution was lyophilized or decompressed concentrate;
制备方法5)：仪器：waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.1％三氟乙酸)，制备液冻干或减压浓缩。Preparation method 5): Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid), prepared liquid frozen Dry or concentrate under reduced pressure.
制备方法6)：制备方法5得到的制备液加入饱和碳酸氢钠溶液，用二氯甲烷、乙酸乙酯或二氯甲烷/甲醇混合溶剂(v/v＝10/1)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩。Preparation method 6): the preparation solution obtained in preparation method 5 was added to saturated sodium bicarbonate solution, extracted with dichloromethane, ethyl acetate or dichloromethane/methanol mixed solvent (v/v=10/1), and the organic phase was anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure.
制备方法7)：仪器：waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：乙腈/水(含5mmol/L醋酸铵)，制备液冻干或减压浓缩。Preparation method 7): Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: acetonitrile/water (containing 5mmol/L ammonium acetate), the preparation solution was lyophilized or concentrated under reduced pressure.
本领域技术人员可以根据反应进展调整反应的温度。Those skilled in the art can adjust the temperature of the reaction according to the progress of the reaction.
实施例1：制备化合物1的三氟乙酸盐
Embodiment 1: the trifluoroacetate salt of preparation compound 1
第一步：1B的制备Step 1: Preparation of 1B
1A(98mg，0.21mmol)(参照专利CN109721620合成所得)加入氯化氢的二氧六环溶液(4mol/L,5mL),室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和三乙胺(0.5mL)，真空浓缩。向浓缩物中加入DMA(30mL)，4-甲酰基哌啶-1-羧酸叔丁酯(90mg,0.42mmol)，醋酸(0.05mL)，室温搅拌2h后，加入三乙酰氧基硼氢化钠(134mg,0.63mmol)，室温反应过夜。加入30mL水，用乙酸乙酯萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝30:1)得1B(66mg,收率：56％)。1A (98 mg, 0.21 mmol) (synthesized with reference to patent CN109721620) was added with hydrogen chloride in dioxane solution (4 mol/L, 5 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and triethylamine (0.5 mL), and concentrate in vacuo. Add DMA (30mL), tert-butyl 4-formylpiperidine-1-carboxylate (90mg, 0.42mmol), acetic acid (0.05mL) to the concentrate, stir at room temperature for 2h, then add sodium triacetoxyborohydride (134mg, 0.63mmol), react overnight at room temperature. Add 30mL of water, extract with ethyl acetate (3×50mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=30:1) to give 1B (66mg, Yield: 56%).
LCMS m/z＝564.3[M+H]+ LCMS m/z=564.3[M+H] +
第二步：化合物1的三氟乙酸盐的制备The second step: the preparation of the trifluoroacetic acid salt of compound 1
1B(66mg，0.12mmol)加入氯化氢的二氧六环溶液(4mol/L,5mL),室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和氨水(1mL)，真空浓缩。向浓缩物中加入DMSO(10mL)，中间体1(47 mg,0.17mmol)，DIPEA(84mg,0.65mmol)，90℃搅拌3h。冷却至室温，倒入20mL冰水中，过滤，滤饼继续用prep-HPLC(制备方法1)纯化得化合物1的三氟乙酸盐(18mg)。1B (66 mg, 0.12 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 5 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and ammonia (1 mL), and concentrate in vacuo. DMSO (10 mL) was added to the concentrate, Intermediate 1 (47 mg, 0.17mmol), DIPEA (84mg, 0.65mmol), stirred at 90°C for 3h. Cooled to room temperature, poured into 20 mL of ice water, filtered, and the filter cake was further purified by prep-HPLC (preparation method 1) to obtain the trifluoroacetic acid salt of compound 1 (18 mg).
LCMS m/z＝720.3[M+H]+ LCMS m/z=720.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),11.06(s,1H),10.49(s,1H),9.00(s,1H),8.27(s,1H),8.06–7.98(m,1H),7.73–7.66(m,1H),7.65–7.59(m,1H),7.41–7.35(m,1H),7.32–7.26(m,1H),7.22(d,1H),7.15(d,1H),5.07(dd,1H),4.19–4.07(m,2H),3.73–3.61(m,2H),3.24–2.97(m,7H),2.97–2.79(m,1H),2.71–2.52(m,2H),2.36–1.96(m,6H),1.94–1.80(m,2H),1.43–1.20(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.21(s,1H),11.06(s,1H),10.49(s,1H),9.00(s,1H),8.27(s,1H),8.06– 7.98(m,1H),7.73–7.66(m,1H),7.65–7.59(m,1H),7.41–7.35(m,1H),7.32–7.26(m,1H),7.22(d,1H), 7.15(d,1H),5.07(dd,1H),4.19–4.07(m,2H),3.73–3.61(m,2H),3.24–2.97(m,7H),2.97–2.79(m,1H), 2.71–2.52(m,2H),2.36–1.96(m,6H),1.94–1.80(m,2H),1.43–1.20(m,2H).
实施例2：制备化合物2的三氟乙酸盐
Embodiment 2: the trifluoroacetate salt of preparation compound 2
第一步：2A的制备Step 1: Preparation of 2A
1B(85mg，0.15mmol)加入氯化氢的二氧六环溶液(4mol/L,5mL)，室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和氨水(1mL)，真空浓缩。向此浓缩物中加入DMA(10mL)，1A-1(60mg,0.3mmol)，0.05mL醋酸，50℃搅拌2h。冷却至室温。加入三乙酰氧基硼氢化钠(95mg,0.45mmol)，室温反应过夜。加入30mL水，乙酸乙酯萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝20:1)得2A(60mg,收率：62％)1B (85 mg, 0.15 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 5 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and ammonia (1 mL), and concentrate in vacuo. To this concentrate was added DMA (10 mL), 1A-1 (60 mg, 0.3 mmol), 0.05 mL acetic acid, and stirred at 50° C. for 2 h. Cool to room temperature. Sodium triacetoxyborohydride (95mg, 0.45mmol) was added and reacted overnight at room temperature. Add 30mL of water, extract with ethyl acetate (3×50mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=20:1) to give 2A (60mg, yield Rate: 62%)
LCMS m/z＝647.4[M+H]+ LCMS m/z=647.4[M+H] +
第二步：化合物2的三氟乙酸盐的制备The second step: the preparation of the trifluoroacetic acid salt of compound 2
参考实施例1第二步的合成方法和精制方法，以2A先脱氨基Boc后，再与中间体1反应得到，得到化合物2的三氟乙酸盐(10mg)。Referring to the synthesis method and purification method of the second step of Example 1, it was obtained by deamination of Boc with 2A, and then reacted with Intermediate 1 to obtain the trifluoroacetic acid salt of Compound 2 (10 mg).
LCMS m/z＝803.3[M+H]+ LCMS m/z=803.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),11.06(s,1H),10.52(s,1H),9.17(s,1H),8.24(s,1H),7.98(d,1H),7.72(d,1H),7.64–7.58(m,1H),7.45–7.39(m,1H),7.36–7.29(m,1H),7.22(d,1H),7.13(d,1H),5.08(dd,1H),4.35–4.18(m,2H),3.74–3.59(m,3H),3.31–2.79(m,13H),2.72–2.53(m,2H),2.26–1.94(m,9H),1.83–1.59(m,2H),1.57–1.34(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.19(s,1H),11.06(s,1H),10.52(s,1H),9.17(s,1H),8.24(s,1H),7.98( d,1H),7.72(d,1H),7.64–7.58(m,1H),7.45–7.39(m,1H),7.36–7.29(m,1H),7.22(d,1H),7.13(d, 1H),5.08(dd,1H),4.35–4.18(m,2H),3.74–3.59(m,3H),3.31–2.79(m,13H),2.72–2.53(m,2H),2.26–1.94( m,9H),1.83–1.59(m,2H),1.57–1.34(m,2H).
实施例3：制备化合物3
Embodiment 3: preparation compound 3
第一步：3A的制备Step 1: Preparation of 3A
1A(435mg，0.93mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)中，室温反应1h。真空浓缩，加入1,4-二氧六环(20mL)和三乙胺(0.5mL)，真空浓缩。向此浓缩物中加入DMA(30mL)，1A-1(371mg,1.86mmol)，0.05mL醋酸，50℃搅拌2h，加入三乙酰氧基硼氢化钠(591mg,2.79mmol)，50℃反应3h。加入30mL水，乙酸乙酯萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝10:1)得3A(200mg,收率：39％)。1A (435 mg, 0.93 mmol) was added to a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (20 mL) and triethylamine (0.5 mL), and concentrate in vacuo. Add DMA (30mL), 1A-1 (371mg, 1.86mmol), 0.05mL acetic acid to this concentrate, stir at 50°C for 2h, add sodium triacetoxyborohydride (591mg, 2.79mmol), react at 50°C for 3h. Add 30mL of water, extract with ethyl acetate (3×50mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=10:1) to give 3A (200mg, yield rate: 39%).
LCMS m/z＝550.2[M+H]+ LCMS m/z=550.2[M+H] +
第二步：3B的制备Step 2: Preparation of 3B
参考第一步的反应条件，3A先脱Boc，再与进行还原胺化反应得到3B(302mg)Referring to the reaction conditions of the first step, 3A is de-Boc first, and then with Reductive amination gave 3B (302 mg)
LCMS m/z＝605.3[M+H]+ LCMS m/z=605.3[M+H] +
第三步：化合物3的制备The third step: the preparation of compound 3
参考实施例1第二步的合成方法，以3A先脱Boc，再与中间体1发生亲核取代反应得到化合物3粗品，粗品用prep-HPLC(制备方法2)化合物3(90mg，收率：24％)。Referring to the synthesis method in the second step of Example 1, 3A was used to remove Boc first, and then undergo a nucleophilic substitution reaction with Intermediate 1 to obtain the crude product of Compound 3. The crude product was prep-HPLC (Preparation Method 2) Compound 3 (90 mg, yield: twenty four%).
LCMS m/z＝761.3[M+H]+ LCMS m/z=761.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.07–12.80(m,1H),12.14(s,1H),11.05(s,1H),10.72–10.33(m,1H),8.19(s,1H),7.93–7.86(m,1H),7.69–7.59(m,2H),7.25–7.17(m,1H),7.14–7.02(m,1H),6.79(d,1H),6.65(dd,1H),5.05(dd,1H),4.10(t,2H),3.83(dd,2H),3.06–2.94(m,2H),2.94–2.81(m,3H),2.77–2.64(m,1H),2.64–2.52(m,1H),2.50–2.45(m,1H),2.37–2.20(m,3H),2.08–1.97(m,1H),1.95–1.70(m,7H),1.59–1.42(m,2H),1.30–1.10(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ13.07–12.80(m,1H),12.14(s,1H),11.05(s,1H),10.72–10.33(m,1H),8.19(s,1H) ),7.93–7.86(m,1H),7.69–7.59(m,2H),7.25–7.17(m,1H),7.14–7.02(m,1H),6.79(d,1H),6.65(dd,1H ),5.05(dd,1H),4.10(t,2H),3.83(dd,2H),3.06–2.94(m,2H),2.94–2.81(m,3H),2.77–2.64(m,1H), 2.64–2.52(m,1H),2.50–2.45(m,1H),2.37–2.20(m,3H),2.08–1.97(m,1H),1.95–1.70(m,7H),1.59–1.42(m ,2H),1.30–1.10(m,2H).
实施例4：制备化合物4
Embodiment 4: preparation compound 4
参考实施例1的合成方法，得到化合物4(73mg)，精制方法同化合物3。Referring to the synthetic method of Example 1, compound 4 (73 mg) was obtained, and the purification method was the same as that of compound 3.
LCMS m/z＝775.3[M+H]+ LCMS m/z=775.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.02–12.83(m,1H),12.13(s,1H),11.04(s,1H),10.72–10.31(m,1H),8.20(s,1H),7.90(d,1H),7.68–7.58(m,2H),7.25–7.16(m,1H),7.15–7.02(m,1H),6.77(d,1H),6.64(dd,1H),5.05(dd,1H),4.13(t,2H),3.74–3.63(m,2H),3.11–2.81(m,6H),2.76–2.52(m,5H),2.50–2.43(m,1H),2.39–2.17(m,3H),2.09–1.92(m,3H),1.91–1.67(m,5H),1.56–1.38(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ13.02–12.83(m,1H),12.13(s,1H),11.04(s,1H),10.72–10.31(m,1H),8.20(s,1H) ),7.90(d,1H),7.68–7.58(m,2H),7.25–7.16(m,1H),7.15–7.02(m,1H),6.77(d,1H),6.64(dd,1H), 5.05(dd,1H),4.13(t,2H),3.74–3.63(m,2H),3.11–2.81(m,6H),2.76–2.52(m,5H),2.50–2.43(m,1H), 2.39–2.17(m,3H),2.09–1.92(m,3H),1.91–1.67(m,5H),1.56–1.38(m,2H).
实施例5：制备化合物5的三氟乙酸盐
Embodiment 5: the trifluoroacetate salt of preparation compound 5
第一步：5A的制备Step 1: Preparation of 5A
将4-哌啶乙醇(500mg，3.87mmol)溶于DMSO(10mL)中，依次加入中间体1(500mg,1.81mmol)和DIPEA(500mg,3.87mmol)，85℃搅拌5h。冷却至室温，加入50mL水，乙酸乙酯萃取(3×30mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(石油醚：乙酸乙酯(V:V)＝1:1)得5A(540mg，收率：77％)。4-Piperidine ethanol (500mg, 3.87mmol) was dissolved in DMSO (10mL), intermediate 1 (500mg, 1.81mmol) and DIPEA (500mg, 3.87mmol) were added in turn, and stirred at 85°C for 5h. Cool to room temperature, add 50mL of water, extract with ethyl acetate (3×30mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain 5A (540 mg, yield: 77%).
LCMS m/z＝386.1[M+H]+ LCMS m/z=386.1[M+H] +
第二步：5B的制备Step 2: Preparation of 5B
将5A(540mg，1.4mmol)溶于二氯甲烷(20mL)中，加入戴斯马丁氧化剂(1.19g，2.8mmol)，室温反应1h。硅藻土抽滤，滤液浓缩，硅胶柱色谱纯化(石油醚：乙酸乙酯(V:V)＝1:1)得5B(500mg，收率：93％)。5A (540 mg, 1.4 mmol) was dissolved in dichloromethane (20 mL), and Dess Martin oxidant (1.19 g, 2.8 mmol) was added, and reacted at room temperature for 1 h. Suction filtration with celite, concentration of the filtrate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate (V:V) = 1:1) gave 5B (500 mg, yield: 93%).
LCMS m/z＝384.2[M+H]+ LCMS m/z=384.2[M+H] +
第三步：化合物5的三氟乙酸盐的制备The third step: the preparation of the trifluoroacetic acid salt of compound 5
1A(126mg，0.27mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)，室温反应1h。真空浓缩，加入1,4-二氧六环(20mL)和三乙胺(0.5mL)，真空浓缩。向此浓缩物中加入5B(124mg,0.32mmol)，0.05mL醋酸，50℃搅拌2h，冷却至室温，加入三乙酰氧基硼氢化钠(114mg,0.54mmol)，室温反应过夜。加入100mL水和20mL饱和碳酸氢钠溶液。用二氯甲烷萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，用prep-HPLC(制备方法1)得到化合物5的三氟乙酸盐(10mg)。1A (126 mg, 0.27 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (20 mL) and triethylamine (0.5 mL), and concentrate in vacuo. Add 5B (124mg, 0.32mmol) and 0.05mL acetic acid to this concentrate, stir at 50°C for 2h, cool to room temperature, add sodium triacetoxyborohydride (114mg, 0.54mmol), and react overnight at room temperature. Add 100 mL of water and 20 mL of saturated sodium bicarbonate solution. Extracted with dichloromethane (3×50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and used prep-HPLC (preparation method 1) to obtain the trifluoroacetic acid salt of compound 5 (10 mg).
LCMS m/z＝734.3[M+H]+ LCMS m/z=734.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),11.06(s,1H),10.51(s,1H),9.11(s,1H),8.24(s,1H),7.98(d,1H),7.68(d,1H),7.62(d,1H),7.37–7.31(m,1H),7.30–7.24(m,1H),7.24–7.20(m,1H),7.13(d,1H),5.06(dd,1H),4.08(d,2H),3.65(d,2H),3.22–3.14(m,2H),3.14–3.04(m,2H),2.99(t,2H),2.94–2.82(m,2H),2.70–2.54(m,2H),2.36–1.94(m,5H),1.87–1.58(m,4H),1.35–1.18(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ12.19(s,1H),11.06(s,1H),10.51(s,1H),9.11(s,1H),8.24(s,1H),7.98( d,1H),7.68(d,1H),7.62(d,1H),7.37–7.31(m,1H),7.30–7.24(m,1H),7.24–7.20(m,1H),7.13(d, 1H),5.06(dd,1H),4.08(d,2H),3.65(d,2H),3.22–3.14(m,2H),3.14–3.04(m,2H),2.99(t,2H),2.94 –2.82(m,2H),2.70–2.54(m,2H),2.36–1.94(m,5H),1.87–1.58(m,4H),1.35–1.18(m,3H).
实施例6：制备化合物6的三氟乙酸盐
Embodiment 6: the trifluoroacetate salt of preparation compound 6
以1A为起始原料，参考实施例1的合成方法，得到化合物6的三氟乙酸盐(100mg)。Using 1A as the starting material, referring to the synthesis method of Example 1, the trifluoroacetic acid salt of compound 6 (100 mg) was obtained.
LCMS m/z＝692.3[M+H]+ LCMS m/z=692.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.38–12.09(m,1H),11.06(s,1H),10.71–10.31(m,1H),9.83–9.40(m,1H),8.50–8.14(m,1H),8.19–7.90(m,1H),7.73–7.66(m,1H),7.66–7.60(m,1H),7.25–7.21(m,1H),7.19–7.14(m,1H),6.86–6.79(m,1H),6.73–6.66(m,1H),5.11–5.02(m,1H),4.32–4.23(m,2H),3.93–3.83(m,2H),3.69–3.48(m,4H),3.42–3.26(m,2H),3.23–3.05(m,3H),2.97–2.84(m,1H),2.65–2.54(m,1H),2.24–1.92(m,5H). 1 H NMR (400MHz, DMSO-d6) δ12.38–12.09(m,1H),11.06(s,1H),10.71–10.31(m,1H),9.83–9.40(m,1H),8.50–8.14( m,1H),8.19–7.90(m,1H),7.73–7.66(m,1H),7.66–7.60(m,1H),7.25–7.21(m,1H),7.19–7.14(m,1H), 6.86–6.79(m,1H),6.73–6.66(m,1H),5.11–5.02(m,1H),4.32–4.23(m,2H),3.93–3.83(m,2H),3.69–3.48(m ,4H),3.42–3.26(m,2H),3.23–3.05(m,3H),2.97–2.84(m,1H),2.65–2.54(m,1H),2.24–1.92(m,5H).
实施例7：制备化合物7
Embodiment 7: preparation compound 7
将6A(180mg,0.34mmol)加入氯化氢的1,4-二氧六环(8mL,4mol/L)溶液中，室温反应1h。真空浓缩，加入碳酸氢钠(0.11g,1.31mmol)，6B(0.14g,0.51mmol)和DMSO(10mL)，100℃搅拌4h。冷却至室温，加入20mL水，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤，浓缩，制备硅胶板纯化(二氯甲烷：甲醇(V:V)＝10:1)得化合物7(60mg，产率：26％)。Add 6A (180mg, 0.34mmol) into a solution of hydrogen chloride in 1,4-dioxane (8mL, 4mol/L) and react at room temperature for 1h. Concentrate in vacuo, add sodium bicarbonate (0.11g, 1.31mmol), 6B (0.14g, 0.51mmol) and DMSO (10mL), stir at 100°C for 4h. Cool to room temperature, add 20 mL of water, extract with ethyl acetate (30 mL×3), wash the organic phase with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, filter, concentrate, and prepare silica gel plate for purification (dichloromethane: Methanol (V:V)=10:1) to obtain compound 7 (60 mg, yield: 26%).
LCMS m/z＝692.0[M+H]+ LCMS m/z=692.0[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.09–12.82(m,1H),12.29–12.05(m,1H),11.06(s,1H),10.73–10.32(m,1H),8.35–8.07(m,1H),8.00–7.84(m,1H),7.71–7.47(m,2H),7.30–6.97(m,3H),6.90–6.72(m,1H),5.14–5.00(m,1H),4.52–4.23(m,2H),4.04–3.82(m,2H),3.26–2.93(m,4H),2.93–2.82(m,2H),2.80–2.51(m,5H),2.10–1.80(m,5H). 1 H NMR (400MHz, DMSO-d6) δ13.09–12.82(m,1H),12.29–12.05(m,1H),11.06(s,1H),10.73–10.32(m,1H),8.35–8.07( m,1H),8.00–7.84(m,1H),7.71–7.47(m,2H),7.30–6.97(m,3H),6.90–6.72(m,1H),5.14–5.00(m,1H), 4.52–4.23(m,2H),4.04–3.82(m,2H),3.26–2.93(m,4H),2.93–2.82(m,2H),2.80–2.51(m,5H),2.10–1.80(m ,5H).
实施例8：制备化合物8
Embodiment 8: preparation compound 8
将6A(180mg,0.34mmol)加入氯化氢的1,4-二氧六环(10mL,4mol/L)溶液中，室温反应1h，真空浓缩，加入碳酸氢钠(286mg,3.40mmol)，8A(150mg,0.51mmol)和DMSO(10mL)，80℃搅拌2h。冷却至室温，加入20mL水，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(20mL ×2)，无水硫酸钠干燥，过滤，浓缩，制备硅胶板纯化(二氯甲烷：甲醇(V:V)＝10:1)得化合物8(70mg，产率：29％)Add 6A (180mg, 0.34mmol) to a solution of hydrogen chloride in 1,4-dioxane (10mL, 4mol/L), react at room temperature for 1h, concentrate in vacuo, add sodium bicarbonate (286mg, 3.40mmol), 8A (150mg , 0.51mmol) and DMSO (10mL), stirred at 80°C for 2h. Cool to room temperature, add 20mL of water, extract with ethyl acetate (30mL×3), and wash the organic phase with saturated brine (20mL ×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel plate (dichloromethane:methanol (V:V)=10:1) to obtain compound 8 (70mg, yield: 29%)
LCMS m/z＝710.2[M+H]+ LCMS m/z=710.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.09–12.81(m,1H),12.35–12.07(m,1H),11.07(s,1H),10.72–10.31(m,1H),8.21(s,1H),7.92(d,1H),7.73–7.48(m,2H),7.26–7.02(m,2H),6.92(d,1H),5.07(dd,1H),4.43–4.18(m,2H),4.00–3.73(m,2H),3.15–2.94(m,2H),2.95–2.82(m,2H),2.79–2.53(m,4H),2.50–2.43(m,2H),2.20–1.98(m,3H),1.97–1.75(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ13.09–12.81(m,1H),12.35–12.07(m,1H),11.07(s,1H),10.72–10.31(m,1H),8.21(s ,1H),7.92(d,1H),7.73–7.48(m,2H),7.26–7.02(m,2H),6.92(d,1H),5.07(dd,1H),4.43–4.18(m,2H ),4.00–3.73(m,2H),3.15–2.94(m,2H),2.95–2.82(m,2H),2.79–2.53(m,4H),2.50–2.43(m,2H),2.20–1.98 (m,3H),1.97–1.75(m,3H).
实施例9：制备化合物9
Embodiment 9: preparation compound 9
以1A为起始原料，参考实施例1的合成方法，得到化合物9(18mg)，精制方法采用硅胶板(DCM:MeOH＝10:1)。Using 1A as the starting material, referring to the synthesis method of Example 1, compound 9 (18 mg) was obtained, and the purification method used a silica gel plate (DCM:MeOH=10:1).
LCMS m/z＝706.2[M+H]+ LCMS m/z=706.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.17–12.80(m,1H),12.38–12.03(m,1H),11.06(s,1H),10.72–10.33(m,1H),8.34–8.14(m,1H),7.94(d,1H),7.81–7.53(m,2H),7.32–7.05(m,2H),6.99–6.75(m,2H),5.06(dd,1H),3.92–3.49(m,4H),3.50–3.38(m,1H),3.13–2.99(m,1H),3.00–2.77(m,2H),2.72–2.54(m,3H),2.37–1.73(m,10H),1.19(t,1H). 1 H NMR (400MHz,DMSO-d 6 )δ13.17–12.80(m,1H),12.38–12.03(m,1H),11.06(s,1H),10.72–10.33(m,1H),8.34–8.14 (m,1H),7.94(d,1H),7.81–7.53(m,2H),7.32–7.05(m,2H),6.99–6.75(m,2H),5.06(dd,1H),3.92–3.49 (m,4H),3.50–3.38(m,1H),3.13–2.99(m,1H),3.00–2.77(m,2H),2.72–2.54(m,3H),2.37–1.73(m,10H) ,1.19(t,1H).
实施例10：制备化合物10
Embodiment 10: preparation compound 10
1A(200mg，0.43mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)中,室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和氨水(1mL)，浓缩，真空干燥，向此浓缩物中加入DMA(10mL)，10A(185mg,0.64mmol)(参照专利US20190192668合成所得)，醋酸(26mg,0.43mmol)和分子筛(500mg)，室温搅拌2h，加入三乙酰氧基硼氢化钠(182mg,0.86mmol)，室温反应过夜。加入饱和碳酸氢钠溶液(30mL)，用乙酸乙酯萃取(3×30mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝30:1)得化合物10(57mg,收率：21％)。1A (200 mg, 0.43 mmol) was added to a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10mL) and ammonia water (1mL), concentrate, dry in vacuo, add DMA (10mL) to this concentrate, 10A (185mg, 0.64mmol) (obtained by referring to the synthesis of patent US20190192668 ), acetic acid (26mg, 0.43mmol) and Molecular sieves (500 mg), stirred at room temperature for 2 h, added sodium triacetoxyborohydride (182 mg, 0.86 mmol), and reacted overnight at room temperature. Add saturated sodium bicarbonate solution (30mL), extract with ethyl acetate (3×30mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=30:1 ) to obtain compound 10 (57 mg, yield: 21%).
LCMS m/z＝638.2[M+H]+ LCMS m/z=638.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.02–12.81(m,1H),12.27–12.05(m,1H),11.08(s,1H),10.67–10.33(m,1H),8.19(s,1H),7.92–7.83(m,1H),7.69–7.55(m,1H),7.23–7.17(m,1H),7.15–7.04(m,2H),7.01–6.90(m,2H),5.39(dd,1H),3.77–3.67(m,5H),3.04–2.95(m,2H),2.95–2.84(m,1H),2.82–2.59(m,3H),2.21–2.08(m,2H),2.09–1.97(m,1H),1.94–1.69(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ13.02–12.81(m,1H),12.27–12.05(m,1H),11.08(s,1H),10.67–10.33(m,1H),8.19(s ,1H),7.92–7.83(m,1H),7.69–7.55(m,1H),7.23–7.17(m,1H),7.15–7.04(m,2H),7.01–6.90(m,2H),5.39 (dd,1H),3.77–3.67(m,5H),3.04–2.95(m,2H),2.95–2.84(m,1H),2.82–2.59(m,3H),2.21–2.08(m,2H) ,2.09–1.97(m,1H),1.94–1.69(m,4H).
实施例11：制备化合物11
Embodiment 11: Preparation of compound 11
第一步：11I的制备Step 1: Preparation of 11I
将11H(400mg,1.03mmol)(合成方法参考专利WO2016205942A1)和11G(194mg,1.13mmol)溶于无水THF(15mL)，氮气置换3次，加热至40℃，氮气保护逐滴滴加LiHMDS的THF溶液(10.3mL,1mol/L)，40℃反应2h，80℃反应2h。冷却至室温，加入饱和氯化铵溶液(30mL)淬灭，用乙酸乙酯(30mL x 3)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-5/1)得到11I(325mg，收率:61％)。Dissolve 11H (400mg, 1.03mmol) (refer to patent WO2016205942A1 for the synthesis method) and 11G (194mg, 1.13mmol) in anhydrous THF (15mL), replace with nitrogen three times, heat to 40°C, and add LiHMDS dropwise under nitrogen protection. THF solution (10.3mL, 1mol/L), reacted at 40°C for 2h and at 80°C for 2h. Cooled to room temperature, quenched by adding saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( Mobile phase: dichloromethane/methanol (V/V)=100/1-5/1) to obtain 11I (325 mg, yield: 61%).
LCMS m/z＝515.0[M+1]+ LCMS m/z=515.0[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),11.80(s,1H),10.55(br.s,1H),8.48–8.43(m,1H),7.76(br.s,1H),7.56–7.43(m,1H),7.31(d,1H),7.26–7.12(m,1H),6.95–6.88(m,1H),3.54–3.45(m,4H),3.11–2.99(m,4H),1.43(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ12.81(s,1H),11.80(s,1H),10.55(br.s,1H),8.48–8.43(m,1H),7.76(br.s ,1H),7.56–7.43(m,1H),7.31(d,1H),7.26–7.12(m,1H),6.95–6.88(m,1H),3.54–3.45(m,4H),3.11–2.99 (m,4H),1.43(s,9H).
第二步：11J的盐酸盐的制备Step 2: Preparation of the hydrochloride salt of 11J
将11I(325mg,0.63mmol)溶于1,4-二氧六环(5mL)中，加入氯化氢的二氧六环溶液(4M,15mL),室温反应3h。减压浓缩得到11J的盐酸盐粗品(320mg)。Dissolve 11I (325 mg, 0.63 mmol) in 1,4-dioxane (5 mL), add hydrogen chloride in dioxane (4 M, 15 mL), and react at room temperature for 3 h. Concentration under reduced pressure gave crude hydrochloride (320 mg) of 11J.
第三步：11L的制备Step 3: Preparation of 11L
将上步所得11J的盐酸盐粗品(320mg)和11K(286mg,1.54mmol)溶于DMA(10mL)中，加入冰乙酸(5mg,0.08mmol)，30℃反应1h，加入三乙酰氧基硼氢化钠(490mg,2.31mmol)，30℃反应过夜。加入饱和碳酸氢钠溶液(20mL)，用乙酸乙酯萃取(30mL x 3)，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-10/1)，得到11L(255mg，两步收率：69％)。Dissolve the crude hydrochloride product of 11J (320mg) and 11K (286mg, 1.54mmol) obtained in the previous step in DMA (10mL), add glacial acetic acid (5mg, 0.08mmol), react at 30°C for 1h, and add triacetoxyboron Sodium hydride (490mg, 2.31mmol), react at 30°C overnight. Add saturated sodium bicarbonate solution (20mL), extract with ethyl acetate (30mL x 3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (mobile phase: Dichloromethane/methanol (V/V)=100/1-10/1) to obtain 11 L (255 mg, two-step yield: 69%).
LCMS m/z＝584.2[M+1]+ LCMS m/z=584.2[M+1] +
第四步：11M的盐酸盐的制备Step 4: Preparation of 11M hydrochloride
将11L(250mg,0.43mmol)溶于1,4-二氧六环(15mL)中，加入氯化氢的二氧六环溶液(4M,15mL)，室温反应过夜。减压浓缩得到11M的盐酸盐粗品(250mg)。Dissolve 11L (250mg, 0.43mmol) in 1,4-dioxane (15mL), add hydrogen chloride in dioxane (4M, 15mL), and react overnight at room temperature. Concentration under reduced pressure gave 11M crude hydrochloride (250mg).
第五步：化合物11的制备Step 5: Preparation of Compound 11
将11M的盐酸盐粗品(250mg)和中间体1(266mg,0.96mmol)溶于DMSO(10mL)中，加入DIPEA(187mg，1.45mmol)，80℃反应3h。反应完后冷却至室温，加入水(20mL)，用乙酸乙酯(20mL x 3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩物用prep-HPLC(制备方法2)得到化合物11(55mg，两步收率:17％)。11M crude hydrochloride (250mg) and intermediate 1 (266mg, 0.96mmol) were dissolved in DMSO (10mL), DIPEA (187mg, 1.45mmol) was added, and reacted at 80°C for 3h. After the reaction, cool to room temperature, add water (20mL), extract with ethyl acetate (20mL x 3), wash the organic phase with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use the concentrate prep-HPLC (preparation method 2) gave compound 11 (55 mg, two-step yield: 17%).
LCMS m/z＝740.2[M+1]+ LCMS m/z=740.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),11.80(s,1H),11.05(s,1H),10.56(br.s,1H),8.53–8.39(m,1H),8.00–7.57(m,2H),7.55–7.40(m,1H),7.31(d,1H),7.24–7.07(m,1H),6.95–6.85(m,1H),6.82–6.74(m,1H),6.69–6.60(m,1H),5.05(dd,1H),4.21–4.11(m,2H),3.78–3.68(m,2H),3.20–2.98(m,5H),2.95–2.81(m,1H),2.75–2.53(m,8H),2.06–1.96(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.78(s,1H),11.80(s,1H),11.05(s,1H),10.56(br.s,1H),8.53–8.39(m,1H ),8.00–7.57(m,2H),7.55–7.40(m,1H),7.31(d,1H),7.24–7.07(m,1H),6.95–6.85(m,1H),6.82–6.74(m ,1H),6.69–6.60(m,1H),5.05(dd,1H),4.21–4.11(m,2H),3.78–3.68(m,2H),3.20–2.98(m,5H),2.95–2.81 (m,1H),2.75–2.53(m,8H),2.06–1.96(m,1H).
实施例12：制备化合物12
Embodiment 12: Preparation of compound 12
第一步：12B的制备Step 1: Preparation of 12B
将11G(308mg，1.80mmol)和12A(700mg,1.80mmol)(参照专利CN109721620合成所得)溶于无水THF(20mL)，氮气置换3次，加热反应液到40℃，在氮气的保护下，加入LiHMDS的THF溶液(18mL,1mol/L)，40℃反应2h，80℃反应2h。冷却至室温，加入饱和氯化铵溶液(40mL)淬灭，用二氯甲烷(50mL×3)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，硅胶柱色谱纯化(洗脱剂：乙酸乙酯)得12B(222mg,产率:24％)Dissolve 11G (308mg, 1.80mmol) and 12A (700mg, 1.80mmol) (synthesized with reference to patent CN109721620) in anhydrous THF (20mL), replace with nitrogen three times, heat the reaction solution to 40°C, and under the protection of nitrogen, Add LiHMDS solution in THF (18mL, 1mol/L), react at 40°C for 2h, and react at 80°C for 2h. Cool to room temperature, quench by adding saturated ammonium chloride solution (40mL), extract with dichloromethane (50mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: ethyl acetate) to 12B (222mg, yield: 24%)
LCMS m/z＝515.1[M+H]+ LCMS m/z=515.1[M+H] +
第二步：12C的制备Step 2: Preparation of 12C
参考实施例3第一步反应条件，12B先脱Boc，进一步与进行还原胺化反应得到12C(130mg)。With reference to the first step reaction conditions of Example 3, 12B takes off Boc earlier, and further with Reductive amination was performed to give 12C (130 mg).
LCMS m/z＝584.2[M+H]+ LCMS m/z=584.2[M+H] +
第三步：化合物12的制备The third step: the preparation of compound 12
参考实施例7反应条件，12C先脱Boc，进一步与中间体1进行亲核取代反应得到化合物12(30mg)。Referring to the reaction conditions of Example 7, 12C was de-Boc first, and further performed a nucleophilic substitution reaction with intermediate 1 to obtain compound 12 (30 mg).
LCMS m/z＝739.8[M+H]+ LCMS m/z=739.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.27–12.96(m,1H),12.05–11.78(m,1H),11.06(s,1H),10.70–10.15(m,1H),8.62–8.40(m,1H),8.21–7.81(m,2H),7.63(d,1H),7.44–7.24(m,1H),7.22–6.97(m,1H),6.78(s,1H),6.65(d,1H),5.05(dd,1H),4.31–4.04(m,2H),3.89–3.60(m,2H),3.11–2.81(m,4H),2.81–2.53(m,5H),2.29–1.94(m,3H),1.94–1.70(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ13.27–12.96(m,1H),12.05–11.78(m,1H),11.06(s,1H),10.70–10.15(m,1H),8.62–8.40 (m,1H),8.21–7.81(m,2H),7.63(d,1H),7.44–7.24(m,1H),7.22–6.97(m,1H),6.78(s,1H),6.65(d ,1H),5.05(dd,1H),4.31–4.04(m,2H),3.89–3.60(m,2H),3.11–2.81(m,4H),2.81–2.53(m,5H),2.29–1.94 (m,3H),1.94–1.70(m,4H).
实施例13：
Example 13:
第一步：13A的制备Step 1: Preparation of 13A
将2,6-双(苄氧基)-3-溴吡啶(5.0g,13.50mmol)、联硼酸频那醇酯(5.14g,20.24mmol)和醋酸钾(2.65g,27.0mmol)加入干燥1,4-二氧六环(20mL)中，加入Pd(dppf)Cl2·DCM(1.10g,1.35mmol)，氮气保护100℃反应过夜。冷却至室温，硅藻土抽滤，乙酸乙酯(50mL×3)萃取，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(乙酸乙酯/石油醚(V/V)＝1/20)得13A(4g，收率：71％)。2,6-Bis(benzyloxy)-3-bromopyridine (5.0 g, 13.50 mmol), pinacol diboronate (5.14 g, 20.24 mmol) and potassium acetate (2.65 g, 27.0 mmol) were added to dry 1 , Pd(dppf)Cl 2 ·DCM (1.10 g, 1.35 mmol) was added to 4-dioxane (20 mL), and reacted overnight at 100° C. under nitrogen protection. Cool to room temperature, filter with diatomaceous earth, extract with ethyl acetate (50mL×3), dry over anhydrous sodium sulfate, filter, concentrate, purify by silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/20 ) to give 13A (4 g, yield: 71%).
LCMS m/z＝418.2[M+H]+ LCMS m/z=418.2[M+H] +
第二步：13C的制备Step 2: Preparation of 13C
氮气保护下将13B(1.5g,4.75mmol)(参照专利CN113512025合成)、13A(2.97g,7.12mmol)、Pd(dppf)Cl2·DCM(0.78g,0.96mmol)，碳酸铯(3.10g,9.5mmol)加入1,4-二氧六环(45mL)和水(10mL)中，105℃反应3h。冷却至室温，加入水(50mL)，乙酸乙酯萃取(30mL×3)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(乙酸乙酯/石油醚(V/V)＝1/5)得13C(1.06g，收率：46.5％)。Under nitrogen protection, 13B (1.5g, 4.75mmol) (synthesized with reference to patent CN113512025), 13A (2.97g, 7.12mmol), Pd(dppf)Cl 2 ·DCM (0.78g, 0.96mmol), cesium carbonate (3.10g, 9.5mmol) was added to 1,4-dioxane (45mL) and water (10mL), and reacted at 105°C for 3h. Cool to room temperature, add water (50mL), extract with ethyl acetate (30mL×3), dry over anhydrous sodium sulfate, filter, concentrate, purify by silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/5 ) to give 13C (1.06 g, yield: 46.5%).
LCMS m/z＝480.1[M+H]+ LCMS m/z=480.1[M+H] +
第三步：13D的制备Step 3: Preparation of 13D
将13C(700mg,1.46mmol)溶于无水THF(20mL)中，加入四氢铝锂(166mg,4.37mmol)，室温反应1h。加入水(2mL)，硅藻土抽滤，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(乙酸乙酯/石油醚(V/V)＝1/1)，得到13D(580mg，收率：88％)13C (700mg, 1.46mmol) was dissolved in anhydrous THF (20mL), lithium aluminum hydride (166mg, 4.37mmol) was added, and reacted at room temperature for 1h. Add water (2mL), suction filter with celite, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/1) to give 13D (580 mg, harvested Rate: 88%)
LCMS m/z＝452.2[M+H]+ LCMS m/z=452.2[M+H] +
第四步：13E的制备Step 4: Preparation of 13E
将13D(600mg,1.33mmol)溶于THF(30mL)中，加入三乙胺(673mg,6.65mmol)，室温搅拌10min，加入叔丁基二甲硅基三氟甲磺酸酯(879mg,3.33mmol)，室温反应1h。浓缩，硅胶柱色谱纯化(乙酸乙酯/石油醚(V/V)＝1/5)得13E(630mg，收率：84％)。Dissolve 13D (600mg, 1.33mmol) in THF (30mL), add triethylamine (673mg, 6.65mmol), stir at room temperature for 10min, add tert-butyldimethylsilyl trifluoromethanesulfonate (879mg, 3.33mmol ), react at room temperature for 1h. Concentrate and purify by silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/5) to give 13E (630 mg, yield: 84%).
1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.1Hz,1H),7.59(d,J＝8.1Hz,1H),7.40(s,1H),7.38(s,1H),7.32(t,J＝7.2Hz,2H),7.29-7.23(m,2H),7.22–7.14(m,5H),6.90(dd,J＝8.1,7.1Hz,1H),6.47(d,J＝8.1Hz,1H),5.40(s,2H),5.35(s,2H),5.01(s,2H),4.37(s,3H),0.84(s,9H),0.01(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.84(d, J=8.1Hz, 1H), 7.59(d, J=8.1Hz, 1H), 7.40(s, 1H), 7.38(s, 1H), 7.32 (t,J=7.2Hz,2H),7.29-7.23(m,2H),7.22–7.14(m,5H),6.90(dd,J=8.1,7.1Hz,1H),6.47(d,J=8.1 Hz,1H),5.40(s,2H),5.35(s,2H),5.01(s,2H),4.37(s,3H),0.84(s,9H),0.01(s,6H).
第五步：13F的制备Step 5: Preparation of 13F
将13E(630mg,1.11mmol)溶于乙醇(30mL)中，加入10％钯碳(55％水)(1g)，氢气置换三次，室温反应过夜。硅藻土抽滤，浓缩，硅胶柱色谱纯化(乙酸乙酯/石油醚(V/V)＝1/1)得13F(197mg， 收率：46％)。Dissolve 13E (630 mg, 1.11 mmol) in ethanol (30 mL), add 10% palladium carbon (55% water) (1 g), replace with hydrogen three times, and react overnight at room temperature. Diatomaceous earth suction filtration, concentrated, silica gel column chromatography (ethyl acetate/petroleum ether (V/V) = 1/1) to give 13F (197mg, Yield: 46%).
LCMS m/z＝388.2[M+H]+ LCMS m/z=388.2[M+H] +
第六步：13G的制备Step 6: Preparation of 13G
将13F(197mg,0.51mmol)溶于THF(5mL)中，加入四丁基氟化铵的THF溶液(2.55mL，1mol/L)，室温反应1h。加入水(20mL)，乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥，过滤，浓缩得13G。Dissolve 13F (197 mg, 0.51 mmol) in THF (5 mL), add tetrabutylammonium fluoride in THF (2.55 mL, 1 mol/L), and react at room temperature for 1 h. Water (20 mL) was added, extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 13G.
LCMS m/z＝274.1[M+H]+ LCMS m/z=274.1[M+H] +
第七步：13H的制备Step 7: Preparation of 13H
将上一步13G溶于二氯甲烷(5mL)中，加入戴斯-马丁氧化剂(432mg，1.02mmol)，室温反应1h。硅藻土抽滤，浓缩，硅胶柱色谱纯化(甲醇/二氯甲烷(V/V)＝1/20)得13H(100mg，两步收率：72％)。Dissolve 13G from the previous step in dichloromethane (5 mL), add Dess-Martin oxidant (432 mg, 1.02 mmol), and react at room temperature for 1 h. Suction filtration with celite, concentration, and purification by silica gel column chromatography (methanol/dichloromethane (V/V)=1/20) to give 13H (100 mg, two-step yield: 72%).
LCMS m/z＝272.1[M+H]+ LCMS m/z=272.1[M+H] +
第八步：化合物13的制备Step 8: Preparation of Compound 13
以1A+13H为起始原料，参考实施例10的合成方法，得到化合物13(85mg)。Using 1A+13H as the starting material, referring to the synthesis method of Example 10, compound 13 (85 mg) was obtained.
LCMS m/z＝622.2[M+H]+ LCMS m/z=622.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.04–12.82(m,1H),12.30–12.09(m,1H),10.88(s,1H),10.65–10.31(m,1H),8.19(s,1H),7.88(d,1H),7.74–7.52(m,2H),7.32–7.11(m,2H),7.10–6.96(m,2H),4.44–4.30(m,4H),3.82(s,2H),3.08–2.91(m,2H),2.85–2.71(m,1H),2.71–2.59(m,2H),2.36(ddd,1H),2.26–2.08(m,3H),1.93–1.69(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ13.04–12.82(m,1H),12.30–12.09(m,1H),10.88(s,1H),10.65–10.31(m,1H),8.19(s ,1H),7.88(d,1H),7.74–7.52(m,2H),7.32–7.11(m,2H),7.10–6.96(m,2H),4.44–4.30(m,4H),3.82(s ,2H),3.08–2.91(m,2H),2.85–2.71(m,1H),2.71–2.59(m,2H),2.36(ddd,1H),2.26–2.08(m,3H),1.93–1.69 (m,4H).
实施例14：制备化合物14
Embodiment 14: Preparation of compound 14
以14A为起始原料，参考实施例1的合成方法，得到化合物14(20mg)，采用prep-HPLC制备(制备方法2)精制。Using 14A as the starting material, refer to the synthetic method of Example 1 to obtain compound 14 (20 mg), which was prepared by prep-HPLC (preparation method 2) and refined.
LCMS m/z＝691.2[M+H]+ LCMS m/z=691.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),12.09(s,1H),11.04(s,1H),10.80–10.59(m,1H),7.98(s,1H),7.70–7.42(m,4H),7.18(d,1H),7.08–7.01(m,1H),6.83–6.74(m,1H),6.69–6.59(m,1H),5.11–5.01(m,1H),4.23–4.12(m,2H),3.75–3.67(m,2H),3.08–2.84(m,4H),2.68–2.55(m,4H),2.18–1.93(m,4H),1.83–1.68(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ12.71(s,1H),12.09(s,1H),11.04(s,1H),10.80–10.59(m,1H),7.98(s,1H), 7.70–7.42(m,4H),7.18(d,1H),7.08–7.01(m,1H),6.83–6.74(m,1H),6.69–6.59(m,1H),5.11–5.01(m,1H ),4.23–4.12(m,2H),3.75–3.67(m,2H),3.08–2.84(m,4H),2.68–2.55(m,4H),2.18–1.93(m,4H),1.83–1.68 (m,4H).
实施例15：化合物15的制备
Embodiment 15: Preparation of compound 15
以6A为起始原料，参考实施例10的合成方法，得到化合物15(28mg)。Using 6A as the starting material, referring to the synthesis method of Example 10, Compound 15 (28 mg) was obtained.
LCMS m/z＝707.3[M+H]+ LCMS m/z=707.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.63–8.49(m,1H),7.74–7.58(m,1H),7.57–7.21(m,5H),5.83–5.43(m,1H),5.20–4.90(m,2H),4.86–4.37(m,4H),4.11–3.65(m,8H),3.63–3.43(m,2H),3.24–3.10(m,2H),3.07–2.92(m,1H),2.73–2.33(m,4H),1.36–1.22(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.63–8.49(m,1H),7.74–7.58(m,1H),7.57–7.21(m,5H),5.83–5.43(m,1H),5.20– 4.90(m,2H),4.86–4.37(m,4H),4.11–3.65(m,8H),3.63–3.43(m,2H),3.24–3.10(m,2H),3.07–2.92(m,1H ),2.73–2.33(m,4H),1.36–1.22(m,2H).
实施例16：制备化合物16
Embodiment 16: Preparation of compound 16
第一步：16B的制备Step 1: Preparation of 16B
将16A(3g,17.35mmol)，2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(4.71g,20.82mmol)和碳酸钾(7.19g,52.05mmol)加入DMF(20mL)中，氮气保护110℃反应过夜。冷却至室温，倒入100mL冰水中，抽滤，滤饼用硅胶柱色谱纯化(二氯甲烷：甲醇＝20:1)得16B(4.2g,产率:67％)。16A (3 g, 17.35 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (4.71 g, 20.82 mmol) and potassium carbonate (7.19 g, 52.05 mmol) were added to DMF ( 20 mL), under nitrogen protection at 110°C overnight. Cool to room temperature, pour into 100mL ice water, filter with suction, and purify the filter cake by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 16B (4.2g, yield: 67%).
LCMS m/z＝363.2[M+H]+ LCMS m/z=363.2[M+H] +
第二步：16C的制备Step 2: Preparation of 16C
将16B(4.2g,11.59mmol)加入无水乙醇(100mL)中，加入10％钯碳(6g)，氢气置换三次，40℃反应3h。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(5.67g,28.98mmol)，氮气保护85℃反应过夜。冷却至室温，硅藻土抽滤，浓缩滤液，将浓缩物用硅胶柱色谱纯化(流动相：二氯甲烷：甲醇＝20:1)得16C(3.42g,产率:69％)。16B (4.2 g, 11.59 mmol) was added into absolute ethanol (100 mL), 10% palladium on carbon (6 g) was added, hydrogen was replaced three times, and reacted at 40° C. for 3 h. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (5.67g, 28.98mmol), and react overnight at 85°C under nitrogen protection. Cool to room temperature, suction filter with diatomaceous earth, concentrate the filtrate, and purify the concentrate by silica gel column chromatography (mobile phase: dichloromethane:methanol=20:1) to obtain 16C (3.42g, yield: 69%).
LCMS m/z＝429.3[M+H]+ LCMS m/z=429.3[M+H] +
第三步：16D的制备Step 3: Preparation of 16D
将2-氨基噻吩-3-腈(0.41g，3.31mmol)和16C(1.42g,3.31mmol)溶于无水THF(15mL)，氮气置换3次，加热至40℃，氮气保护加入LiHMDS的THF溶液(16.55mL,1mol/L)，40℃反应2h，80℃反应2h。冷却至室温，加入饱和氯化铵溶液(20mL)淬灭，分离有机层，水层用二氯甲烷(40mL×3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，加入甲醇(20mL)和甲基叔丁基醚(20mL)打浆，抽滤收集固体，干燥得16D(1.5g,产率:89％)。Dissolve 2-aminothiophene-3-carbonitrile (0.41g, 3.31mmol) and 16C (1.42g, 3.31mmol) in anhydrous THF (15mL), replace with nitrogen three times, heat to 40°C, and add LiHMDS THF under nitrogen protection solution (16.55mL, 1mol/L), react at 40°C for 2h, and react at 80°C for 2h. Cool to room temperature, add saturated ammonium chloride solution (20mL) to quench, separate the organic layer, extract the aqueous layer with dichloromethane (40mL×3), combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, add methanol ( 20 mL) and methyl tert-butyl ether (20 mL), the solid was collected by suction filtration and dried to obtain 16D (1.5 g, yield: 89%).
LCMS m/z＝507.2[M+H]+ LCMS m/z=507.2[M+H] +
第四步：化合物16的制备The fourth step: the preparation of compound 16
以16D为起始原料，参考实施例8的合成方法，得到化合物16(120mg)。Using 16D as the starting material, referring to the synthesis method of Example 8, compound 16 (120 mg) was obtained.
LCMS m/z＝663.2[M+H]+ LCMS m/z=663.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.72–12.53(m,1H),12.03(s,1H),11.05(s,1H),10.82–10.46(m,1H),7.96(s,1H),7.65(d,1H),7.59(d,1H),7.54–7.41(m,1H),7.27–7.10(m,2H),6.92(d,1H),6.81(s,1H),6.68(d,1H),5.05(dd,1H),3.84(s,4H),3.22–3.02(m,4H),2.98–2.80(m,1H),2.68–2.53(m,2H),2.12–1.80(m,5H). 1 H NMR (400MHz,DMSO-d 6 )δ12.72–12.53(m,1H),12.03(s,1H),11.05(s,1H),10.82–10.46(m,1H),7.96(s,1H ),7.65(d,1H),7.59(d,1H),7.54–7.41(m,1H),7.27–7.10(m,2H),6.92(d,1H),6.81(s,1H),6.68( d,1H),5.05(dd,1H),3.84(s,4H),3.22–3.02(m,4H),2.98–2.80(m,1H),2.68–2.53(m,2H),2.12–1.80( m,5H).
实施例17：制备化合物17
Embodiment 17: Preparation of compound 17
第一步：17A的制备Step 1: Preparation of 17A
将12A(1000mg,2.57mmol)和2-氨基-5,6-二氢-4H-环戊烯并噻吩-3-甲腈(420mg,2.56mmol)加入无水THF(5mL)，氮气置换3次，40℃搅拌12分钟，氮气保护逐滴滴加LiHMDS的THF溶液(25mL,1mol/L)，80℃反应2h。冷却至室温，加入饱和氯化铵溶液(50mL)淬灭，用二氯甲烷(50mL x 2)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-10/1)得到17A(1000mg，收率:77％)。Add 12A (1000mg, 2.57mmol) and 2-amino-5,6-dihydro-4H-cyclopentenothiophene-3-carbonitrile (420mg, 2.56mmol) into anhydrous THF (5mL), nitrogen replacement 3 times , stirred at 40°C for 12 minutes, added LiHMDS solution in THF (25mL, 1mol/L) dropwise under nitrogen protection, and reacted at 80°C for 2h. Cooled to room temperature, quenched by adding saturated ammonium chloride solution (50mL), extracted with dichloromethane (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( Mobile phase: dichloromethane/methanol (V/V)=100/1-10/1) to obtain 17A (1000 mg, yield: 77%).
LCMS m/z＝507.3[M+1]+ LCMS m/z=507.3[M+1] +
第二步：17B的制备Step 2: Preparation of 17B
将17A(1000mg,1.97mmol)溶于甲醇(2mL)中，加入氯化氢的二氧六环溶液(4mol/L,10mL)，室温反应2h，减压浓缩。向浓缩物中加入甲醇(10mL)和三乙胺(1mL)，再次减压浓缩。向此浓缩物中依次加入DMA(10mL)，3-甲酰基氮杂环丁烷-1-羧酸叔丁酯(730mg,3.94mmol)，醋酸(60mg,1.00mmol)，40℃搅拌2h，加入三乙酰氧基硼氢化钠(1260mg,5.94mmol)，继续在40℃反应4h。冷却至室温，加入饱和碳酸氢钠水溶液(30mL)和乙酸乙酯(20mL)，分离有机相并减压浓缩，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-10/1)得到17B(380mg,收率：33％)。Dissolve 17A (1000 mg, 1.97 mmol) in methanol (2 mL), add hydrogen chloride in dioxane (4 mol/L, 10 mL), react at room temperature for 2 h, and concentrate under reduced pressure. Methanol (10 mL) and triethylamine (1 mL) were added to the concentrate, and concentrated again under reduced pressure. To this concentrate, add DMA (10mL), tert-butyl 3-formylazetidine-1-carboxylate (730mg, 3.94mmol), acetic acid (60mg, 1.00mmol), stir at 40°C for 2h, add Sodium triacetoxyborohydride (1260mg, 5.94mmol) continued to react at 40°C for 4h. Cool to room temperature, add saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL), separate the organic phase and concentrate under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (V/V )=100/1−10/1) to obtain 17B (380 mg, yield: 33%).
LCMS m/z＝576.3[M+H]+ LCMS m/z=576.3[M+H] +
第三步：化合物17的制备The third step: the preparation of compound 17
17B(300mg，0.52mmol)加入氯化氢的二氧六环溶液(4mol/L,5mL),室温反应2h。真空浓缩，向此浓缩物中依次加入DMSO(10mL)，DIPEA(340mg,2.64mmol)，中间体1(180mg,0.65mmol)，100℃搅拌2h。冷却至室温，将反应混合物缓慢倒入冰水(20mL)中，抽滤并收集固体。滤饼继续用制备HPLC(制备方法2)得到化合物17(20mg,收率：5％)。17B (300mg, 0.52mmol) was added to a solution of hydrogen chloride in dioxane (4mol/L, 5mL), and reacted at room temperature for 2h. Concentrate in vacuo, add DMSO (10mL), DIPEA (340mg, 2.64mmol), intermediate 1 (180mg, 0.65mmol) to this concentrate successively, and stir at 100°C for 2h. After cooling to room temperature, the reaction mixture was slowly poured into ice water (20 mL), and the solid was collected by suction filtration. The filter cake was further subjected to preparative HPLC (preparative method 2) to obtain compound 17 (20 mg, yield: 5%).
LCMS m/z＝732.2[M+H]+ LCMS m/z=732.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.09–12.85(m,1H),12.28–12.03(m,1H),11.05(s,1H),10.68–10.37(m,1H),7.97–7.81(m,1H),7.64(d,1H),7.18–7.04(m,1H),6.96–6.83(m,1H),6.83–6.72(m,1H),6.65(d,1H),5.09–5.01(m,1H),4.22–4.06(m,2H),3.79–3.68(m,2H),3.17–2.93(m,5H),2.92–2.53(m,8H),2.48–2.41(m,2H),2.23–1.76(m,7H). 1 H NMR (400MHz,DMSO-d 6 )δ13.09–12.85(m,1H),12.28–12.03(m,1H),11.05(s,1H),10.68–10.37(m,1H),7.97–7.81 (m,1H),7.64(d,1H),7.18–7.04(m,1H),6.96–6.83(m,1H),6.83–6.72(m,1H),6.65(d,1H),5.09–5.01 (m,1H),4.22–4.06(m,2H),3.79–3.68(m,2H),3.17–2.93(m,5H),2.92–2.53(m,8H),2.48–2.41(m,2H) ,2.23–1.76(m,7H).
实施例18：制备化合物18
Embodiment 18: Preparation of compound 18
16D(250mg，0.49mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)中,室温反应1h。真空浓缩，向此浓缩物中加入DMF(10mL)、18A(258mg,0.73mmol)(参照WO2021170109合成)和碳酸氢钠(412mg,4.9mmol)，50℃反应过夜。后冷却至室温，加入水(30mL)稀释，乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇＝10:1)，粗品进一步用制备HPLC(制备方法2)化合物18(14mg，产率：4％)。16D (250 mg, 0.49 mmol) was added into a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add DMF (10 mL), 18A (258 mg, 0.73 mmol) (synthesized with reference to WO2021170109) and sodium bicarbonate (412 mg, 4.9 mmol) to the concentrate, and react overnight at 50°C. After cooling to room temperature, dilute with water (30 mL), extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol=10:1), the crude product is further Compound 18 (14 mg, yield: 4%) was prepared by preparative HPLC (Preparation Method 2).
LCMS m/z＝339.2[(M+2H)/2]+ LCMS m/z=339.2[(M+2H)/2] +
1H NMR(400MHz,DMSO-d6)δ12.66–12.50(m,1H),12.06(s,1H),11.10(s,1H),10.82–10.49(m,1H),7.95(s,1H),7.90–7.84(m,1H),7.84–7.77(m,2H),7.58(d,1H),7.51–7.37(m,1H),7.23–7.07(m,2H),6.92–6.83(m,1H),5.14(dd,1H),3.83(s,2H),3.15–2.98(m,8H),2.95–2.82(m,1H),2.69–2.53(m,2H),2.12–1.99(m,1H),1.86(t,4H). 1 H NMR (400MHz,DMSO-d 6 )δ12.66–12.50(m,1H),12.06(s,1H),11.10(s,1H),10.82–10.49(m,1H),7.95(s,1H ),7.90–7.84(m,1H),7.84–7.77(m,2H),7.58(d,1H),7.51–7.37(m,1H),7.23–7.07(m,2H),6.92–6.83(m ,1H),5.14(dd,1H),3.83(s,2H),3.15–2.98(m,8H),2.95–2.82(m,1H),2.69–2.53(m,2H),2.12–1.99(m ,1H),1.86(t,4H).
实施例19：制备化合物19
Embodiment 19: Preparation of compound 19
参考化合物16的合成方法，以16A为起始原料得到化合物19(100mg)，终产物采用prep-HPLC制备(制备方法2)精制。Referring to the synthesis method of compound 16, compound 19 (100 mg) was obtained from 16A as the starting material, and the final product was prepared by prep-HPLC (preparation method 2) and refined.
LCMS m/z＝691.2[M+H]+ LCMS m/z=691.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.59(d,1H),12.18–11.95(m,1H),11.05(s,1H),10.80–10.48(m,1H),8.04–7.85(m,1H),7.66(d,1H),7.58(d,1H),7.52–7.41(m,1H),7.35–7.30(m,1H),7.27–7.11(m,3H),6.94–6.87(m,1H),5.06(dd,1H),3.60–3.42(m,4H),3.21–3.08(m,4H),2.96–2.81(m,1H),2.72–2.53(m,2H),2.06–1.96(m,1H),1.71–1.56(m,8H). 1 H NMR (400MHz,DMSO-d 6 )δ12.59(d,1H),12.18–11.95(m,1H),11.05(s,1H),10.80–10.48(m,1H),8.04–7.85(m ,1H),7.66(d,1H),7.58(d,1H),7.52–7.41(m,1H),7.35–7.30(m,1H),7.27–7.11(m,3H),6.94–6.87(m ,1H),5.06(dd,1H),3.60–3.42(m,4H),3.21–3.08(m,4H),2.96–2.81(m,1H),2.72–2.53(m,2H),2.06–1.96 (m,1H),1.71–1.56(m,8H).
实施例20：制备化合物20的三氟乙酸盐

Example 20: Preparation of Trifluoroacetate Salt of Compound 20

第一步：20A的制备Step 1: Preparation of 20A
24A(350mg，0.65mmol)加入氯化氢的二氧六环溶液(4mol/L,10.83mL),室温反应1h。真空浓缩，加入DMF(20mL)，1,2-二氟-4-硝基苯(207mg,1.3mmol)和碳酸氢钠(0.55g,6.5mmol)，80℃反应4h。冷却至室温，加水稀释，乙酸乙酯(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，真空浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇＝20:1)得20A(250mg，产率：68％)。24A (350 mg, 0.65 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 10.83 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add DMF (20mL), 1,2-difluoro-4-nitrobenzene (207mg, 1.3mmol) and sodium bicarbonate (0.55g, 6.5mmol), react at 80°C for 4h. Cool to room temperature, dilute with water, extract with ethyl acetate (30mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate in vacuo, and purify by silica gel column chromatography (dichloromethane:methanol=20:1) to give 20A (250mg , yield: 68%).
LCMS m/z＝575.2[M+H]+ LCMS m/z=575.2[M+H] +
第二步：20B的制备Step 2: Preparation of 20B
20A(140mg，0.24mmol)溶于THF(5mL)和甲醇(5mL)中，加入钯碳(10％)(300mg)，氢气置换三次，氢气氛围下室温反应过夜，硅藻土抽滤，浓缩得20B(120mg，产率：92％)。20A (140 mg, 0.24 mmol) was dissolved in THF (5 mL) and methanol (5 mL), added palladium carbon (10%) (300 mg), replaced by hydrogen three times, reacted overnight at room temperature under hydrogen atmosphere, filtered with diatomaceous earth, and concentrated to obtain 20B (120 mg, yield: 92%).
LCMS m/z＝273.2[(M+2H)/2]+ LCMS m/z=273.2[(M+2H)/2] +
第三步：化合物20的三氟乙酸盐的制备The third step: the preparation of the trifluoroacetic acid salt of compound 20
将20B(120mg，0.22mmol)，3-溴哌啶-2,6-二酮(63mg，0.33mmol)和碳酸氢钠(55mg，0.66mmol)加入无水DMF(2mL)中，80℃反应20h。加入水(5mL)，乙酸乙酯(10mL×3)萃取，无水硫酸钠干燥，过滤，浓缩，硅胶制备板纯化(二氯甲烷：甲醇＝8：1)，粗品继续用制备HPLC(制备方法1)纯化得化合物20的三氟乙酸盐(5mg)。Add 20B (120mg, 0.22mmol), 3-bromopiperidine-2,6-dione (63mg, 0.33mmol) and sodium bicarbonate (55mg, 0.66mmol) into anhydrous DMF (2mL), react at 80°C for 20h . Add water (5mL), extract with ethyl acetate (10mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and purify on a silica gel preparative plate (dichloromethane:methanol=8:1), the crude product continues to be prepared by preparative HPLC (preparative method 1) Trifluoroacetic acid salt of compound 20 (5 mg) was purified.
LCMS m/z＝656.2[M+H]+ LCMS m/z=656.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.75(s,1H),9.59(s,1H),7.59(d,1H),7.55(d,1H),7.32–7.23(m,1H),7.24–6.91(m,3H),6.52(d,1H),6.48–6.35(m,2H),4.21(dd,1H),3.99(t,2H),3.89–3.70(m,2H),3.31–3.20(m,4H),3.21–3.10(m,3H),3.09–2.91(m,2H),2.80–2.53(m,3H),2.15–2.05(m,1H),2.04–1.94(m,1H),1.91–1.75(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.11(s,1H),10.75(s,1H),9.59(s,1H),7.59(d,1H),7.55(d,1H),7.32– 7.23(m,1H),7.24–6.91(m,3H),6.52(d,1H),6.48–6.35(m,2H),4.21(dd,1H),3.99(t,2H),3.89–3.70( m,2H),3.31–3.20(m,4H),3.21–3.10(m,3H),3.09–2.91(m,2H),2.80–2.53(m,3H),2.15–2.05(m,1H), 2.04–1.94(m,1H),1.91–1.75(m,1H).
实施例21：化合物21的制备
Embodiment 21: Preparation of compound 21
第一步：21C的制备Step 1: Preparation of 21C
将21A(399mg，2.02mmol)加入醋酸/水(13mL，(V/V)＝10/3)中，125℃微波反应2h。冷却 至室温，加入21B(768mg，2.63mmol)(合成方法参考专利WO2016205942A1)，室温反应2h。加饱和碳酸氢钠溶液(50mL)，用乙酸乙酯(200mL)萃取，有机相减压浓缩，残留物通过柱层析分离纯化(流动相：甲醇/二氯甲烷(V/V)＝0-6％)得到21C(400mg，产率：44％)。21A (399mg, 2.02mmol) was added into acetic acid/water (13mL, (V/V)=10/3), and microwaved at 125°C for 2h. cool down After reaching room temperature, 21B (768mg, 2.63mmol) was added (refer to patent WO2016205942A1 for the synthesis method), and reacted at room temperature for 2h. Add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (200 mL), concentrate the organic phase under reduced pressure, and separate and purify the residue by column chromatography (mobile phase: methanol/dichloromethane (V/V)=0- 6%) to give 21C (400 mg, yield: 44%).
LCMS m/z＝452.4[M+H]+ LCMS m/z=452.4[M+H] +
第二步：化合物21E的制备The second step: the preparation of compound 21E
将21C(400mg,0.89mmol)加入到氯化氢的二氧六环溶液(4mol/L,10mL)中，室温下反应1h，减压浓缩。向浓缩物中加入甲醇(10mL)和三乙胺(1mL)，然后再次减压浓缩。向此浓缩物中加入DMA(10mL)、醋酸(11mg,0.18mmol)、21D(330mg,1.78mmol)。室温搅拌2h，再加入三乙酰氧基硼氢化钠(380mg,1.79mmol)，室温反应12h。加入水(100mL)，用乙酸乙酯(100mL×2)萃取，有机相减压浓缩，残留物通过柱层析分离纯化(流动相：甲醇/二氯甲烷(V/V)＝0-6％)得到21E(150mg,收率：33％)。21C (400 mg, 0.89 mmol) was added to a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), reacted at room temperature for 1 h, and concentrated under reduced pressure. Methanol (10 mL) and triethylamine (1 mL) were added to the concentrate, followed by concentration under reduced pressure again. To this concentrate was added DMA (10 mL), acetic acid (11 mg, 0.18 mmol), 21D (330 mg, 1.78 mmol). Stir at room temperature for 2 h, then add sodium triacetoxyborohydride (380 mg, 1.79 mmol), and react at room temperature for 12 h. Water (100 mL) was added, extracted with ethyl acetate (100 mL×2), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol/dichloromethane (V/V)=0-6% ) to give 21E (150 mg, yield: 33%).
LCMS m/z＝521.6[M+H]+ LCMS m/z=521.6[M+H] +
第三步：化合物21的制备The third step: the preparation of compound 21
将21E(150mg，0.29mmol)加入到氯化氢的二氧六环溶液(4mol/L,10mL)中，室温下反应1h，减压浓缩，将浓缩物加入到DMSO(8mL)中，加入21F(104mg，0.38mmol)和DIPEA(225mg,1.74mmol)，90℃反应2h。冷却至室温，加入水(20mL)，抽滤，将滤饼干燥，通过薄层色谱制备板纯化(甲醇/二氯甲烷(V/V)＝1/10)，得到化合物21(30mg,收率：15％)。21E (150mg, 0.29mmol) was added to a solution of hydrogen chloride in dioxane (4mol/L, 10mL), reacted at room temperature for 1h, concentrated under reduced pressure, the concentrate was added to DMSO (8mL), and 21F (104mg , 0.38mmol) and DIPEA (225mg, 1.74mmol), reacted at 90°C for 2h. Cool to room temperature, add water (20mL), filter with suction, dry the filter cake, and purify by thin-layer chromatography (methanol/dichloromethane (V/V)=1/10) to obtain compound 21 (30mg, yield : 15%).
LCMS m/z＝677.8[M+H]+ LCMS m/z=677.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.06–12.77(m,1H),12.52–12.29(m,1H),11.07(s,1H),9.06(d,1H),8.05(d,1H),7.63(d,1H),7.56–7.39(m,1H),7.24–7.03(m,2H),6.99–6.88(m,1H),6.84–6.74(m,1H),6.71–6.59(m,1H),5.06(dd,1H),4.23–4.09(m,2H),3.79–3.61(m,2H),3.17–3.00(m,5H),2.93–2.82(m,1H),2.71–2.64(m,2H),2.63–2.51(m,6H),2.11–1.92(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ13.06–12.77(m,1H),12.52–12.29(m,1H),11.07(s,1H),9.06(d,1H),8.05(d,1H ),7.63(d,1H),7.56–7.39(m,1H),7.24–7.03(m,2H),6.99–6.88(m,1H),6.84–6.74(m,1H),6.71–6.59(m ,1H),5.06(dd,1H),4.23–4.09(m,2H),3.79–3.61(m,2H),3.17–3.00(m,5H),2.93–2.82(m,1H),2.71–2.64 (m,2H),2.63–2.51(m,6H),2.11–1.92(m,1H).
实施例22：化合物22的制备
Embodiment 22: Preparation of compound 22
第一步：22B的制备Step 1: Preparation of 22B
23F(300mg，0.64mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,20mL)，室温反应2h。真空浓缩，向浓缩物中加入1,4-二氧六环(20mL)和三乙胺(1mL)，再次减压浓缩。向此浓缩物中加入DMA(10mL)，22A(306mg,1.28mmol)和乙酸(38mg,0.63mmol)，80℃反应1h，冷却至室温，加入三乙酰氧基硼氢化钠(407mg,1.92mmol)，室温反应过夜。加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥，过滤，真空浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝10:1)得22B(200mg,收率：53％)。23F (300mg, 0.64mmol) was added with a solution of hydrogen chloride in 1,4-dioxane (4mol/L, 20mL), and reacted at room temperature for 2h. Concentrate in vacuo, add 1,4-dioxane (20 mL) and triethylamine (1 mL) to the concentrate, and concentrate again under reduced pressure. Add DMA (10mL), 22A (306mg, 1.28mmol) and acetic acid (38mg, 0.63mmol) to this concentrate, react at 80°C for 1h, cool to room temperature, add sodium triacetoxyborohydride (407mg, 1.92mmol) , react overnight at room temperature. Add 20 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, filter, concentrate in vacuo, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=10:1) 22B (200 mg, yield: 53%) was obtained.
LCMS m/z＝590.7[M+H]+ LCMS m/z=590.7[M+H] +
第二步：化合物22的制备The second step: the preparation of compound 22
参考化合物7反应条件，22B先脱Boc，进一步与中间体1进行亲核取代反应得到化合物22(50mg)，采用prep-HPLC制备(制备方法2)精制。Referring to the reaction conditions of compound 7, 22B was de-Boc first, and then underwent nucleophilic substitution reaction with intermediate 1 to obtain compound 22 (50 mg), which was prepared by prep-HPLC (preparation method 2).
LCMS m/z＝746.8[M+H]+ LCMS m/z=746.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.69–12.52(m,1H),12.07(s,1H),11.05(s,1H),10.82–10.48(m,1H),8.16–7.78(m,1H),7.70–7.61(m,1H),7.61–7.55(m,1H),7.55–7.39(m,1H),7.38–7.29(m,1H),7.28–7.06(m,3H),6.95–6.82(m,1H),5.06(dd,1H),3.53–3.34(m,4H),3.21–2.99(m,4H),2.97–2.71(m,2H),2.65–2.53(m,2H),2.47–2.30(m,4H),2.13–1.94(m,3H),1.75–1.47(m,6H). 1 H NMR (400MHz,DMSO-d 6 )δ12.69–12.52(m,1H),12.07(s,1H),11.05(s,1H),10.82–10.48(m,1H),8.16–7.78(m ,1H),7.70–7.61(m,1H),7.61–7.55(m,1H),7.55–7.39(m,1H),7.38–7.29(m,1H),7.28–7.06(m,3H),6.95 –6.82(m,1H),5.06(dd,1H),3.53–3.34(m,4H),3.21–2.99(m,4H),2.97–2.71(m,2H),2.65–2.53(m,2H) ,2.47–2.30(m,4H),2.13–1.94(m,3H),1.75–1.47(m,6H).
实施例23：化合物23的制备
Embodiment 23: Preparation of compound 23
第一步：23A的三氟乙酸盐的制备The first step: the preparation of the trifluoroacetate salt of 23A
将3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(0.5g，2.67mmol)溶于二氯甲烷(10mL)中,再缓慢加入三氟乙酸(10mL)。室温反应1h。真空浓缩，得到23A的三氟乙酸盐(0.5g)。3-(Hydroxymethyl)azetidine-1-carboxylate tert-butyl ester (0.5 g, 2.67 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added slowly. Reaction at room temperature for 1h. Concentration in vacuo afforded the trifluoroacetate salt of 23A (0.5 g).
第二步：23B的制备Step 2: Preparation of 23B
氮气保护下，在茄型瓶中加入23A的三氟乙酸盐和碳酸钾(1.73g，12.5mmol)，室温搅拌0.5h，再加入1-溴-4-碘苯(0.71g，2.5mmol)、L-脯氨酸(0.12g，1.0mmol)、碘化亚铜(0.095g，0.5mmol)和DMSO(10mL)，氮气置换三次，90℃过夜反应。加入20mL水，并用乙酸乙酯萃取(3×30mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(石油醚：乙酸乙酯(V:V)＝5:1)得化合物23B(0.41g，两步产率：63％)。Under nitrogen protection, add 23A trifluoroacetate and potassium carbonate (1.73g, 12.5mmol) into an eggplant-shaped bottle, stir at room temperature for 0.5h, then add 1-bromo-4-iodobenzene (0.71g, 2.5mmol) , L-proline (0.12g, 1.0mmol), cuprous iodide (0.095g, 0.5mmol) and DMSO (10mL), replaced with nitrogen three times, reacted overnight at 90°C. Add 20 mL of water, and extract with ethyl acetate (3×30 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate (V:V)=5:1) to obtain compound 23B ( 0.41 g, two-step yield: 63%).
LCMS m/z＝242.1[M+H]+ LCMS m/z=242.1[M+H] +
第三步：23C的制备Step 3: Preparation of 23C
氮气保护下，将23B(0.1g,0.41mmol)、23B-1(0.26g，0.61mmol)溶于4mL二氧六环和2mL水中，加入Pd(dppf)Cl2·DCM(0.033g，0.041mmol)和碳酸铯(0.4g，1.23mmol)，氮气置换三次，100℃反应过夜。冷却至室温，加入10mL水，并用二氯甲烷(3×20mL)萃取，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝20:1)得23C(0.064g,收率：34％)。Under nitrogen protection, 23B (0.1g, 0.41mmol), 23B-1 (0.26g, 0.61mmol) were dissolved in 4mL of dioxane and 2mL of water, and Pd(dppf)Cl 2 ·DCM (0.033g, 0.041mmol) was added ) and cesium carbonate (0.4g, 1.23mmol), replaced with nitrogen three times, and reacted overnight at 100°C. Cool to room temperature, add 10 mL of water, and extract with dichloromethane (3×20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=20:1) to obtain 23C (0.064g, yield: 34%).
LCMS m/z＝453.2[M+H]+ LCMS m/z=453.2[M+H] +
第四步：23D的制备Step 4: Preparation of 23D
将23C(0.064g,0.14mmol)、10％钯碳(0.09g)加入到5mL甲醇中，氢气置换三次，30℃过夜反应。冷却至室温，用硅藻土过滤，滤饼用甲醇洗涤三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到23D。Add 23C (0.064g, 0.14mmol) and 10% palladium carbon (0.09g) into 5mL of methanol, replace with hydrogen three times, and react overnight at 30°C. Cool to room temperature, filter with celite, wash the filter cake three times with methanol, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 23D.
LCMS m/z＝275.1[M+H]+ LCMS m/z=275.1[M+H] +
第五步：23E的制备Step 5: Preparation of 23E
将上一步得到的23D溶于二氯甲烷(3mL)中，加入戴斯-马丁氧化剂(66mg，0.16mmol)，室温反应1h。硅藻土抽滤，浓缩，薄层色谱板纯化(甲醇/二氯甲烷(V/V)＝1/20)得23E(27mg，两步 收率：71％)。23D obtained in the previous step was dissolved in dichloromethane (3 mL), added Dess-Martin oxidant (66 mg, 0.16 mmol), and reacted at room temperature for 1 h. Diatomaceous earth suction filtration, concentration, thin-layer chromatography purification (methanol/dichloromethane (V/V) = 1/20) to give 23E (27mg, two steps Yield: 71%).
LCMS m/z＝273.1[M+H]+ LCMS m/z=273.1[M+H] +
第六步：化合物23的制备Step 6: Preparation of compound 23
23F(56mg，0.13mmol)(参照专利WO2016205942合成所得)加入氯化氢的二氧六环溶液(4mol/L,5mL),室温反应1h。后真空浓缩，加入1,4-二氧六环(10mL)和三乙胺(0.5mL)，真空浓缩。向此浓缩物中加入DMA(5mL)，23E(33mg,0.12mmol)，醋酸(72mg,0.12mmol)，室温搅拌2h后，加入三乙酰氧基硼氢化钠(33mg,0.16mmol)，室温反应过夜。加入10mL水，并用乙酸乙酯萃取(3×10mL)，无水硫酸钠干燥，过滤，浓缩，薄层色谱硅胶板纯化(二氯甲烷：甲醇(V:V)＝15:1)，得到的产品进一步制备液相纯化(仪器：waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：流动相A：乙腈，流动相B：水(含0.05％氨水))，将所得制备液加入饱和碳酸氢钠水溶液(10mL)中并用二氯甲烷(30mL x 3)萃取，合并有机相，无水硫酸钠干燥、过滤、减压浓缩得到化合物23(6mg,收率：8％)。23F (56mg, 0.13mmol) (synthesized with reference to patent WO2016205942) was added with hydrogen chloride in dioxane solution (4mol/L, 5mL), and reacted at room temperature for 1h. After concentrated in vacuo, 1,4-dioxane (10 mL) and triethylamine (0.5 mL) were added and concentrated in vacuo. Add DMA (5mL), 23E (33mg, 0.12mmol), acetic acid (72mg, 0.12mmol) to this concentrate, stir at room temperature for 2h, add sodium triacetoxyborohydride (33mg, 0.16mmol), react overnight at room temperature . Add 10mL of water, and extract with ethyl acetate (3×10mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by thin-layer chromatography on silica gel plate (dichloromethane:methanol (V:V)=15:1) to obtain The product is further prepared for liquid phase purification (instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm × 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammoniacal liquor)), the gained The preparation solution was added to saturated aqueous sodium bicarbonate solution (10mL) and extracted with dichloromethane (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23 (6mg, yield: 8%) .
LCMS m/z＝623.3[M+H]+ LCMS m/z=623.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.68–12.54(m,1H),12.08(s,1H),10.80–10.55(m,2H),8.08–7.89(m,1H),7.62–7.56(m,1H),7.54–7.40(m,1H),7.23–7.08(m,2H),7.04–6.96(m,2H),6.93–6.86(m,1H),6.46–6.35(m,2H),4.00–3.89(m,2H),3.69(dd,1H),3.51–3.42(m,2H),3.17–3.05(m,4H),3.02–2.91(m,1H),2.71–2.54(m,7H),2.48–2.40(m,1H),2.17–2.08(m,1H),2.05–1.96(m,1H). 1 H NMR (400MHz, DMSO-d6) δ12.68–12.54(m,1H),12.08(s,1H),10.80–10.55(m,2H),8.08–7.89(m,1H),7.62–7.56( m,1H),7.54–7.40(m,1H),7.23–7.08(m,2H),7.04–6.96(m,2H),6.93–6.86(m,1H),6.46–6.35(m,2H), 4.00–3.89(m,2H),3.69(dd,1H),3.51–3.42(m,2H),3.17–3.05(m,4H),3.02–2.91(m,1H),2.71–2.54(m,7H ),2.48–2.40(m,1H),2.17–2.08(m,1H),2.05–1.96(m,1H).
实施例24：制备化合物24
Example 24: Preparation of compound 24
参考实施例3第一步反应条件，23F先脱Boc，进一步与进行还原胺化反应得到24A(230mg)。With reference to the first step reaction conditions of Example 3, 23F is first removed from Boc, and further combined with Reductive amination gave 24A (230 mg).
LCMS m/z＝536.3[M+H]+ LCMS m/z=536.3[M+H] +
参考化合物7的制备方法，24A先脱Boc，进一步与中间体1进行亲核取代反应得到化合物24(60mg)，采用prep-HPLC制备(制备方法2)精制。Referring to the preparation method of compound 7, 24A was first de-Boc, and then subjected to nucleophilic substitution reaction with intermediate 1 to obtain compound 24 (60 mg), which was prepared by prep-HPLC (preparation method 2) and refined.
LCMS m/z＝692.2[M+H]+ LCMS m/z=692.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.68–12.53(m,1H),12.08(s,1H),11.05(s,1H),10.79–10.52(m,1H),8.08–7.87(m,1H),7.70–7.55(m,2H),7.55–7.38(m,1H),7.26–7.07(m,2H),6.97–6.84(m,1H),6.81–6.72(m,1H),6.70–6.59(m,1H),5.05(dd,1H),4.26–4.06(m,2H),3.81–3.62(m,2H),3.21–2.98(m,5H),2.97–2.79(m,1H),2.78–2.52(m,8H),2.07–1.94(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.68–12.53(m,1H),12.08(s,1H),11.05(s,1H),10.79–10.52(m,1H),8.08–7.87(m ,1H),7.70–7.55(m,2H),7.55–7.38(m,1H),7.26–7.07(m,2H),6.97–6.84(m,1H),6.81–6.72(m,1H),6.70 –6.59(m,1H),5.05(dd,1H),4.26–4.06(m,2H),3.81–3.62(m,2H),3.21–2.98(m,5H),2.97–2.79(m,1H) ,2.78–2.52(m,8H),2.07–1.94(m,1H).
实施例25：制备化合物25
Example 25: Preparation of compound 25
第一步：25B的制备Step 1: Preparation of 25B
将25A(340mg,0.88mmol)(参照专利CN109721620合成所得)和11G(150mg,0.88mmol)溶于无水THF(5mL)中，氮气置换3次，40搅拌12分钟，在氮气保护下逐滴滴加LiHMDS的THF溶液(8.8mL,1mol/L)，60℃反应5h。冷却至室温，加入水(50mL)淬灭，用乙酸乙酯(50mL x 2)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，向残留物加入乙酸乙酯(10mL)打浆并抽滤，将抽滤所得固体旋干，得到25B(350mg，收率:78％)。Dissolve 25A (340 mg, 0.88 mmol) (synthesized with reference to patent CN109721620) and 11G (150 mg, 0.88 mmol) in anhydrous THF (5 mL), replace with nitrogen three times, stir at 40 for 12 minutes, drop by drop under nitrogen protection Add a THF solution of LiHMDS (8.8 mL, 1 mol/L), and react at 60° C. for 5 h. Cool to room temperature, quench with water (50mL), extract with ethyl acetate (50mL x 2), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, add ethyl acetate (10mL) to the residue and extract After filtration, the solid obtained by suction filtration was spin-dried to obtain 25B (350 mg, yield: 78%).
LCMS m/z＝514.2[M+1]+ LCMS m/z=514.2[M+1] +
第二步：25C的制备Step 2: Preparation of 25C
参考17B的制备方法，25B先脱Boc，进一步与进行还原胺化反应得到25C(230mg)。Referring to the preparation method of 17B, 25B is de-Boc first, and further combined with Reductive amination was performed to give 25C (230 mg).
LCMS m/z＝583.1[M+H]+ LCMS m/z=583.1[M+H] +
第三步：化合物25的制备The third step: the preparation of compound 25
参考化合物17的制备方法，25C先脱Boc，进一步与中间体1发生亲核取代反应的到化合物25(40mg)。Referring to the preparation method of compound 17, 25C was de-Boc first, and further reacted with intermediate 1 to obtain compound 25 (40 mg).
LCMS m/z＝739.8[M+H]+ LCMS m/z=739.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),11.62–10.19(m,2H),8.55–8.37(m,1H),7.63(d,1H),7.57–7.40(m,2H),7.35–7.25(m,1H),7.12–6.95(m,1H),6.83–6.74(m,1H),6.71–6.60(m,1H),5.12–4.99(dd,1H),4.21–4.08(m,2H),3.74–3.63(m,2H),3.07–2.84(m,4H),2.69–2.52(m,5H),2.16–2.00(m,3H),1.86–1.66(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ12.94(s,1H),11.62–10.19(m,2H),8.55–8.37(m,1H),7.63(d,1H),7.57–7.40(m ,2H),7.35–7.25(m,1H),7.12–6.95(m,1H),6.83–6.74(m,1H),6.71–6.60(m,1H),5.12–4.99(dd,1H),4.21 –4.08(m,2H),3.74–3.63(m,2H),3.07–2.84(m,4H),2.69–2.52(m,5H),2.16–2.00(m,3H),1.86–1.66(m, 4H).
实施例26：制备化合物26
Example 26: Preparation of compound 26
第一步：化合物26的制备The first step: preparation of compound 26
将23F(313mg,0.67mmol)溶于甲醇(5mL)中，加入盐酸-1,4-二氧六环溶液(5mL,4M)，室温搅拌2h。减压浓缩，加入二氯甲烷(10mL)和三乙胺(3mL)搅拌3分钟，减压浓缩后加入26A(合成方法见WO 2022012622A1)(150mg,0.56mmol)、DMA(10mL)、醋酸(33.63mg，0.56mmol)和 分子筛(100mg)，室温搅拌2h，加入三乙酰氧基硼氢化钠(178.03mg,0.84mmol)，室温搅拌过夜。加入乙酸乙酯(30mL)和水(50mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩后用制备液相纯化制备方法7)，得到化合物26(7mg，收率：2％)。23F (313mg, 0.67mmol) was dissolved in methanol (5mL), hydrochloric acid-1,4-dioxane solution (5mL, 4M) was added, and stirred at room temperature for 2h. Concentrate under reduced pressure, add dichloromethane (10mL) and triethylamine (3mL) and stir for 3 minutes, concentrate under reduced pressure and add 26A (see WO 2022012622A1 for the synthesis method) (150mg, 0.56mmol), DMA (10mL), acetic acid (33.63 mg, 0.56mmol) and Molecular sieves (100mg), stirred at room temperature for 2h, added sodium triacetoxyborohydride (178.03mg, 0.84mmol), stirred at room temperature overnight. Add ethyl acetate (30mL) and water (50mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified by preparative liquid phase Preparation method 7) to obtain compound 26 (7mg, yield: 2%) .
LCMS m/z＝618.4[M+1]+ LCMS m/z=618.4[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),11.94(s,1H),11.05–10.46(s,2H),7.96(s,1H),7.59(d,1H),7.47(dd,1H),7.23–7.01(m,4H),6.94–6.86(m,1H),4.20(dd,1H),3.16–3.08(m,4H),2.88–2.74(m,3H),2.69–2.57(m,6H),2.19–2.06(m,1H),2.05–1.96(m,1H),1.32–1.18(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.61(s,1H),11.94(s,1H),11.05–10.46(s,2H),7.96(s,1H),7.59(d,1H), 7.47(dd,1H),7.23–7.01(m,4H),6.94–6.86(m,1H),4.20(dd,1H),3.16–3.08(m,4H),2.88–2.74(m,3H), 2.69–2.57(m,6H),2.19–2.06(m,1H),2.05–1.96(m,1H),1.32–1.18(m,1H).
实施例27：制备化合物27
Example 27: Preparation of compound 27
第一步：27B的制备Step 1: Preparation of 27B
将27A(1g,4.80mmol)、碳酸氢钠(1.21g,14.40mmol)和哌嗪-1-甲酸叔丁酯(2.68g,14.40mmol)溶于DMSO(20mL)中，140℃反应5h。冷却至室温，加入水(30mL)，用乙酸乙酯(30mL*3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(流动相：石油醚/乙酸乙酯(V/V)＝100/1-10/1)，得到27B(1.24g，收率：72％)。27A (1g, 4.80mmol), sodium bicarbonate (1.21g, 14.40mmol) and tert-butyl piperazine-1-carboxylate (2.68g, 14.40mmol) were dissolved in DMSO (20mL), and reacted at 140°C for 5h. Cool to room temperature, add water (30mL), extract with ethyl acetate (30mL*3), wash the organic phase with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is purified by silica gel column layer Analysis and purification (mobile phase: petroleum ether/ethyl acetate (V/V)=100/1-10/1) gave 27B (1.24 g, yield: 72%).
LCMS m/z＝303.1[M+1-isobutene]+ LCMS m/z=303.1[M+1-isobutene] +
第二步至第五步的合成方法参考化合物19和化合物11的制备得化合物27(37mg)。The synthesis method of the second step to the fifth step refers to the preparation of compound 19 and compound 11 to obtain compound 27 (37 mg).
LCMS m/z＝728.2[M+1]+ LCMS m/z=728.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ13.13–12.92(m,1H),12.30–12.10(m,1H),11.07(s,1H),10.51–10.17(m,1H),8.30–8.05(m,1H),7.74–7.51(m,2H),7.42–7.28(m,1H),7.27–7.12(m,1H),6.90–6.72(m,1H),6.72–6.59(m,1H),5.16–4.96(m,1H),4.27–4.08(m,2H),3.83–3.64(m,2H),3.23–3.10(m,4H),3.10–2.99(m,1H),2.95–2.79(m,1H),2.73–2.64(m,2H),2.64–2.51(m,6H),2.07–1.96(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ13.13–12.92(m,1H),12.30–12.10(m,1H),11.07(s,1H),10.51–10.17(m,1H),8.30–8.05 (m,1H),7.74–7.51(m,2H),7.42–7.28(m,1H),7.27–7.12(m,1H),6.90–6.72(m,1H),6.72–6.59(m,1H) ,5.16–4.96(m,1H),4.27–4.08(m,2H),3.83–3.64(m,2H),3.23–3.10(m,4H),3.10–2.99(m,1H),2.95–2.79( m,1H),2.73–2.64(m,2H),2.64–2.51(m,6H),2.07–1.96(m,1H).
实施例28：制备化合物28
Example 28: Preparation of compound 28
第一步：28B的制备Step 1: Preparation of 28B
将28A(5.53g,29.01mmol)，哌嗪-1-羧酸叔丁酯(10.81g,58.02mmol)和碳酸氢钠(7.31g,87.03mmol)加入DMSO(300mL)中，140℃反应6h。冷却至室温，倒入500mL冰水中，抽滤收集固体，水洗涤，二氯甲烷(200mL)复溶，分去水层，有机层用无水硫酸钠干燥，过滤，浓缩，二氯甲烷/正己烷(v/v＝1/1)(100mL)打浆，抽滤收集固体得28B(7.18g,产率:73％)。28A (5.53g, 29.01mmol), tert-butyl piperazine-1-carboxylate (10.81g, 58.02mmol) and sodium bicarbonate (7.31g, 87.03mmol) were added into DMSO (300mL), and reacted at 140°C for 6h. Cool to room temperature, pour into 500mL ice water, collect the solid by suction filtration, wash with water, redissolve in dichloromethane (200mL), separate the water layer, dry the organic layer with anhydrous sodium sulfate, filter, concentrate, dichloromethane/n-hexane Alkanes (v/v=1/1) (100mL) was beaten, and the solid was collected by suction filtration to obtain 28B (7.18g, yield: 73%).
LCMS m/z＝341.20[M+H]+ LCMS m/z=341.20[M+H] +
第二步至第五步的合成方法参考化合物19和化合物11制备得到化合物28(23mg)。Compound 28 (23 mg) was prepared by referring to compound 19 and compound 11 in the synthesis method of the second step to the fifth step.
终产物后处理方法：反应液倒入甲基叔丁基醚/甲醇(50mL/10mL)中，抽滤收集固体，固体进一步用制备HPLC(制备方法2)。Final product post-treatment method: the reaction solution was poured into methyl tert-butyl ether/methanol (50mL/10mL), the solid was collected by suction filtration, and the solid was further subjected to preparative HPLC (preparation method 2).
LCMS m/z＝758.1[M+H]+ LCMS m/z=758.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.98–12.85(m,1H),11.82(s,1H),11.05(s,1H),10.43(br.s,1H),8.47(d,1H),8.00–7.56(m,2H),7.53–7.22(m,3H),6.78(s,1H),6.71–6.60(m,1H),5.05(dd,1H),4.25–4.08(m,2H),3.82–3.66(m,2H),3.12–2.95(m,5H),2.94–2.81(m,1H),2.78–2.53(m,8H),2.05–1.98(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.98–12.85(m,1H),11.82(s,1H),11.05(s,1H),10.43(br.s,1H),8.47(d,1H ),8.00–7.56(m,2H),7.53–7.22(m,3H),6.78(s,1H),6.71–6.60(m,1H),5.05(dd,1H),4.25–4.08(m,2H ),3.82–3.66(m,2H),3.12–2.95(m,5H),2.94–2.81(m,1H),2.78–2.53(m,8H),2.05–1.98(m,1H).
实施例29：制备化合物29
Example 29: Preparation of compound 29
以1A为起始原料，参考实施例3的合成方法，得到化合物29(8mg)。Using 1A as the starting material, referring to the synthesis method of Example 3, compound 29 (8 mg) was obtained.
LCMS m/z＝678.2[M+1]+ LCMS m/z=678.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ13.12–12.85(m,1H),12.38–12.03(m,1H),11.20–10.96(m,1H),10.73–10.52(m,1H),8.27–8.06(m,1H),7.92–7.86(m,1H),7.70–7.64(m,1H),7.63–7.56(m,1H),7.23–7.15(m,1H),7.10–7.04(m,1H),6.83–6.79(m,1H),6.71–6.65(m,1H),5.13–5.03(m,1H),4.22–4.11(m,2H),3.98–3.86(m,2H),3.03–2.95(m,2H),2.92–2.83(m,1H),2.78–2.72(m,1H),2.64–2.53(m,3H),2.09–1.98(m,3H),1.95–1.76(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ13.12–12.85(m,1H),12.38–12.03(m,1H),11.20–10.96(m,1H),10.73–10.52(m,1H),8.27 –8.06(m,1H),7.92–7.86(m,1H),7.70–7.64(m,1H),7.63–7.56(m,1H),7.23–7.15(m,1H),7.10–7.04(m, 1H),6.83–6.79(m,1H),6.71–6.65(m,1H),5.13–5.03(m,1H),4.22–4.11(m,2H),3.98–3.86(m,2H),3.03– 2.95(m,2H),2.92–2.83(m,1H),2.78–2.72(m,1H),2.64–2.53(m,3H),2.09–1.98(m,3H),1.95–1.76(m,4H ).
实施例30：制备化合物30
Example 30: Preparation of compound 30
将1A(150mg，0.32mmol)溶于甲醇(5mL)，加入盐酸-二氧六环溶液(3mL,4M)，室温反应1h。减压浓缩，依次加入DMSO(15mL)、DIPEA(3mL)和6B(265.17mg,0.96mmol)，100℃反应3h。冷却至室温，加入水(20mL)，搅拌10分钟，抽滤，滤饼用制备液相纯化(仪器：waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm)；流动相组成：乙腈/水(含0.05％的氨水))，得到化合物30(17mg，收率：9％)。 Dissolve 1A (150 mg, 0.32 mmol) in methanol (5 mL), add hydrochloric acid-dioxane solution (3 mL, 4M), and react at room temperature for 1 h. Concentrate under reduced pressure, add DMSO (15 mL), DIPEA (3 mL) and 6B (265.17 mg, 0.96 mmol) successively, and react at 100° C. for 3 h. Cool to room temperature, add water (20mL), stir for 10 minutes, suction filter, filter cake is purified with preparative liquid phase (instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19mm * 150mm); Mobile phase composition: acetonitrile/water (containing 0.05% ammonia water)) to obtain compound 30 (17 mg, yield: 9%).
LCMS m/z＝623.2[M+1]+ LCMS m/z=623.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ13.11–12.84(m,1H),12.16(s,1H),11.07(s,1H),10.69–10.34(m,1H),8.20(br.s,1H),7.98–7.88(m,1H),7.76–7.59(m,2H),7.45–7.31(m,2H),7.24–7.09(m,2H),5.11(dd,1H),3.96–3.79(m,2H),3.17–2.80(m,4H),2.69–2.53(m,2H),2.17–1.92(m,5H). 1 H NMR (400MHz,DMSO-d 6 )δ13.11–12.84(m,1H),12.16(s,1H),11.07(s,1H),10.69–10.34(m,1H),8.20(br.s ,1H),7.98–7.88(m,1H),7.76–7.59(m,2H),7.45–7.31(m,2H),7.24–7.09(m,2H),5.11(dd,1H),3.96–3.79 (m,2H),3.17–2.80(m,4H),2.69–2.53(m,2H),2.17–1.92(m,5H).
实施例31：制备化合物31的三氟乙酸盐
Example 31: Preparation of Trifluoroacetate Salt of Compound 31
1A(103mg，0.22mmol)加入氯化氢的二氧六环溶液(4mol/L,5mL),室温反应1h。真空浓缩，加入1,4-二氧六环(5mL)和氨水(0.2mL)，真空浓缩。向此浓缩物中加入DMSO(5mL)，中间体1(73mg,0.26mmol)和DIPEA(142mg,1.1mmol)，90℃反应3h。冷却至室温，缓慢倒入20mL冰水中，抽滤，滤饼用制备HPLC(制备方法1)纯化得化合物31的三氟乙酸盐(15mg)。1A (103 mg, 0.22 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 5 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (5 mL) and ammonia (0.2 mL), and concentrate in vacuo. To this concentrate was added DMSO (5 mL), Intermediate 1 (73 mg, 0.26 mmol) and DIPEA (142 mg, 1.1 mmol), and reacted at 90° C. for 3 h. Cool to room temperature, slowly pour into 20 mL of ice water, filter with suction, and purify the filter cake by preparative HPLC (Preparation Method 1) to obtain trifluoroacetic acid salt of compound 31 (15 mg).
LCMS m/z＝623.2[M+H]+ LCMS m/z=623.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),12.29(s,1H),11.07(s,1H),10.28(s,1H),8.41(s,1H),8.17(s,1H),7.70(d,1H),7.62(d,1H),7.45–7.38(m,1H)7.37–7.27(m,2H),7.23(d,1H),5.08(dd,1H),4.26(d,2H),3.29–3.08(m,3H),2.98–2.84(m,1H),2.71–2.53(m,2H),2.15–1.82(m,5H). 1 H NMR (400MHz,DMSO-d 6 )δ13.31(s,1H),12.29(s,1H),11.07(s,1H),10.28(s,1H),8.41(s,1H),8.17( s,1H),7.70(d,1H),7.62(d,1H),7.45–7.38(m,1H),7.37–7.27(m,2H),7.23(d,1H),5.08(dd,1H), 4.26(d,2H),3.29–3.08(m,3H),2.98–2.84(m,1H),2.71–2.53(m,2H),2.15–1.82(m,5H).
实施例32：制备化合物32
Example 32: Preparation of compound 32
第一步：32A的制备Step 1: Preparation of 32A
将11H(0.5g,1.29mmol)(合成方法参考专利WO2016/205942A1)和3-氨基噻吩-2-甲腈(0.19g,1.53mmol)溶于无水THF(15mL)，氮气置换3次，加热到40℃，氮气的保护下逐滴滴加LiHMDS的THF溶液(13mL,1mol/L)，40℃反应2h，80℃反应2h。冷却至室温，加入饱和氯化铵溶液(30mL)淬灭，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-5/1)得到32A(0.4g，收率:67％)。Dissolve 11H (0.5g, 1.29mmol) (refer to patent WO2016/205942A1 for the synthesis method) and 3-aminothiophene-2-carbonitrile (0.19g, 1.53mmol) in anhydrous THF (15mL), replace nitrogen three times, and heat To 40°C, LiHMDS solution in THF (13mL, 1mol/L) was added dropwise under the protection of nitrogen, reacted at 40°C for 2h, and at 80°C for 2h. Cool to room temperature, add saturated ammonium chloride solution (30mL) to quench, extract with ethyl acetate (30mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is subjected to silica gel column layer Analysis and purification (mobile phase: dichloromethane/methanol (V/V) = 100/1-5/1) gave 32A (0.4 g, yield: 67%).
LCMS m/z＝467.2[M+1]+ LCMS m/z=467.2[M+1] +
第二步：32B的制备Step 2: Preparation of 32B
32A(0.4g，0.86mmol)加入氯化氢的二氧六环溶液(4mol/L,9mL),室温反应1h。真空浓缩， 加入二氯甲烷(10mL)和三乙胺(1mL)，真空浓缩。向此浓缩物中加入DMA(10mL)，3-甲酰基氮杂环丁烷-1-羧酸叔丁酯(0.21g,1.13mmol)，室温搅拌1h，加入三乙酰氧基硼氢化钠(0.27g,1.27mmol)，室温反应过夜。加入20mL水，并用乙酸乙酯(3×30mL)萃取，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝30:1)得32B(0.24g,收率：52％)。32A (0.4 g, 0.86 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 9 mL), and reacted at room temperature for 1 h. concentrated in vacuo, Dichloromethane (10 mL) and triethylamine (1 mL) were added and concentrated in vacuo. To this concentrate was added DMA (10 mL), tert-butyl 3-formylazetidine-1-carboxylate (0.21 g, 1.13 mmol), stirred at room temperature for 1 h, added sodium triacetoxyborohydride (0.27 g, 1.27mmol), react overnight at room temperature. Add 20mL of water and extract with ethyl acetate (3×30mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=30:1) to give 32B (0.24g , yield: 52%).
LCMS m/z＝536.2[M+H]+ LCMS m/z=536.2[M+H] +
第三步：化合物32的制备The third step: the preparation of compound 32
32B(0.24g，0.45mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)，室温反应1h。真空浓缩。向此浓缩物中加入DMSO(4mL)，中间体1(0.16g,0.58mmol)，碳酸氢钠(0.15g,1.79mmol)，100℃搅拌4h。冷却至室温，将反应混合物缓慢倒入20mL冰水中，抽滤并收集固体。滤饼继续用制备HPLC(制备方法2)得到化合物32(90mg，收率：29％)。32B (0.24g, 0.45mmol) was added with a solution of hydrogen chloride in dioxane (4mol/L, 10mL), and reacted at room temperature for 1h. Concentrate in vacuo. To this concentrate were added DMSO (4 mL), Intermediate 1 (0.16 g, 0.58 mmol), sodium bicarbonate (0.15 g, 1.79 mmol), and stirred at 100° C. for 4 h. After cooling to room temperature, the reaction mixture was slowly poured into 20 mL of ice water, and the solid was collected by suction filtration. The filter cake was further subjected to preparative HPLC (preparative method 2) to obtain compound 32 (90 mg, yield: 29%).
LCMS m/z＝692.2[M+H]+ LCMS m/z=692.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.82–12.67(m,1H),11.79(s,1H),11.05(s,1H),10.60(br.s,1H),7.97–7.90(m,1H),7.82(br.s,1H),7.67–7.60(m,1H),7.56–7.41(m,1H),7.26–7.08(m,1H),7.00(d,1H),6.96–6.86(m,1H),6.82–6.74(m,1H),6.71–6.59(m,1H),5.05(dd,1H),4.23–4.09(m,2H),3.84–3.65(m,2H),3.19–2.97(m,5H),2.97–2.81(m,1H),2.75–2.53(m,8H),2.05–1.95(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.82–12.67(m,1H),11.79(s,1H),11.05(s,1H),10.60(br.s,1H),7.97–7.90(m ,1H),7.82(br.s,1H),7.67–7.60(m,1H),7.56–7.41(m,1H),7.26–7.08(m,1H),7.00(d,1H),6.96–6.86 (m,1H),6.82–6.74(m,1H),6.71–6.59(m,1H),5.05(dd,1H),4.23–4.09(m,2H),3.84–3.65(m,2H),3.19 –2.97(m,5H),2.97–2.81(m,1H),2.75–2.53(m,8H),2.05–1.95(m,1H).
实施例33：制备化合物33
Example 33: Preparation of Compound 33
第一步：33A的制备Step 1: Preparation of 33A
参考1B的制备方法，11I先脱Boc，进一步与进行还原胺化反应得到33A(320mg)。Referring to the preparation method of 1B, 11I is de-Boc first, and further combined with Reductive amination gave 33A (320 mg).
LCMS m/z＝612.2[M+H]+ LCMS m/z=612.2[M+H] +
第二步：化合物33的制备The second step: the preparation of compound 33
参考化合物11第四步和第五步合成方法，33A先Boc，进一步与中间体1发生亲核取代反应得到化合物33(50mg)。Referring to the synthesis method of the fourth and fifth steps of compound 11, 33A was first Boc, and further reacted with intermediate 1 to obtain compound 33 (50 mg).
LCMS m/z＝384.7[(M+2H)/2]+ LCMS m/z=384.7[(M+2H)/2] +
1H NMR(400MHz,DMSO-d6)δ12.82–12.72(m,1H),11.85–11.74(m,1H),11.06(s,1H),10.54(br.s,1H),8.54–8.38(m,1H),7.95–7.56(m,2H),7.54–7.40(m,1H),7.34–7.28(m,2H),7.27–7.07(m,2H),6.94–6.85(m,1H),5.06(dd,1H),4.11–3.98(m,2H),3.18–3.06(m,4H),3.05–2.82(m,3H),2.70–2.53(m,6H),2.28–2.16(m,2H),2.09–1.76(m,4H),1.22–1.11(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.82–12.72(m,1H),11.85–11.74(m,1H),11.06(s,1H),10.54(br.s,1H),8.54–8.38 (m,1H),7.95–7.56(m,2H),7.54–7.40(m,1H),7.34–7.28(m,2H),7.27–7.07(m,2H),6.94–6.85(m,1H) ,5.06(dd,1H),4.11–3.98(m,2H),3.18–3.06(m,4H),3.05–2.82(m,3H),2.70–2.53(m,6H),2.28–2.16(m, 2H),2.09–1.76(m,4H),1.22–1.11(m,2H).
实施例34：制备化合物34
Example 34: Preparation of compound 34
第一步：34A的制备Step 1: Preparation of 34A
将23F(800mg,1.71mmol)溶于甲醇(10mL)，加入盐酸-二氧六环溶液(6mL,4M)，室温反应1h。减压浓缩，向浓缩物中加入甲醇(10mL)和氨水(3mL)，减压浓缩。向浓缩物中加入4-甲酰基哌啶-1-羧酸叔丁酯(729mg,3.42mmol)、DMA(20mL)和醋酸(103mg，1.72mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(725mg,3.42mmol)，室温搅拌过夜。加入乙酸乙酯(50mL)和水(50mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)，得到34A(630mg，收率：65％)。Dissolve 23F (800mg, 1.71mmol) in methanol (10mL), add hydrochloric acid-dioxane solution (6mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add methanol (10 mL) and aqueous ammonia (3 mL) to the concentrate, and concentrate under reduced pressure. Add tert-butyl 4-formylpiperidine-1-carboxylate (729 mg, 3.42 mmol), DMA (20 mL) and acetic acid (103 mg, 1.72 mmol) to the concentrate, stir at room temperature for 2 h, add triacetoxy borohydrogenate Sodium (725mg, 3.42mmol), stirred overnight at room temperature. Add ethyl acetate (50mL) and water (50mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (V/V) =100/1-20/1), to obtain 34A (630 mg, yield: 65%).
LCMS m/z＝564.7[M+1]+ LCMS m/z=564.7[M+1] +
第二步：化合物34的制备The second step: the preparation of compound 34
将34A(250mg,0.44mmol)溶于甲醇(5mL)，加入盐酸-二氧六环溶液(5mL,4M)，室温反应1h。减压浓缩，向此浓缩物中加入DMSO(20mL)、DIPEA(5mL)和中间体1(243mg,0.88mmol)，100℃反应3h。冷却到室温，加入水(20mL)，搅拌5分钟，抽滤，滤饼用制备液相纯化(制备方法7)得到化合物34(50mg，收率：16％)。Dissolve 34A (250mg, 0.44mmol) in methanol (5mL), add hydrochloric acid-dioxane solution (5mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add DMSO (20 mL), DIPEA (5 mL) and intermediate 1 (243 mg, 0.88 mmol) to the concentrate, and react at 100 ° C for 3 h. Cool to room temperature, add water (20 mL), stir for 5 minutes, filter with suction, and purify the filter cake with preparative liquid phase (preparative method 7) to obtain compound 34 (50 mg, yield: 16%).
LCMS m/z＝720.2[M+1]+ LCMS m/z=720.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),11.98(br.s,1H),11.06(s,1H),10.83–10.43(m,1H),7.96(br.s,1H),7.69–7.55(m,2H),7.54–7.39(m,1H),7.36–7.28(m,1H),7.26–7.06(m,3H),6.93–6.84(m,1H),5.06(dd,1H),4.13–3.96(m,2H),3.17–3.05(m,4H),3.04–2.82(m,3H),2.63–2.52(m,6H),2.27–2.15(m,2H),2.07–1.96(m,1H),1.87–1.76(m,3H),1.22–1.10(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.62(s,1H),11.98(br.s,1H),11.06(s,1H),10.83–10.43(m,1H),7.96(br.s ,1H),7.69–7.55(m,2H),7.54–7.39(m,1H),7.36–7.28(m,1H),7.26–7.06(m,3H),6.93–6.84(m,1H),5.06 (dd,1H),4.13–3.96(m,2H),3.17–3.05(m,4H),3.04–2.82(m,3H),2.63–2.52(m,6H),2.27–2.15(m,2H) ,2.07–1.96(m,1H),1.87–1.76(m,3H),1.22–1.10(m,2H).
实施例35：制备化合物35
Example 35: Preparation of Compound 35
24A(100mg，0.19mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL),室温反应2h，减压浓缩，向此浓缩物中依次加入DMSO(8mL)，35A(参照专利WO2021249534A1合成所得)(52mg,0.19mmol)，碳酸氢钠(80mg,0.95mmol)，100℃搅拌12h。冷却至室温，加入水(50mL)，抽滤并收集滤饼，将滤饼干燥，用制备HPLC(制备方法2)得到化合物35(5mg，收率：4％)。24A (100mg, 0.19mmol) was added with 1,4-dioxane solution of hydrogen chloride (4mol/L, 10mL), reacted at room temperature for 2h, concentrated under reduced pressure, and added DMSO (8mL) to this concentrate successively, 35A (refer to Patent WO2021249534A1 synthesized) (52mg, 0.19mmol), sodium bicarbonate (80mg, 0.95mmol), stirred at 100°C for 12h. Cool to room temperature, add water (50 mL), filter with suction and collect the filter cake, dry the filter cake, and use preparative HPLC (preparative method 2) to obtain compound 35 (5 mg, yield: 4%).
LCMS m/z＝691.3[M+H]+ LCMS m/z=691.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),12.03(br.s,1H),10.95(s,1H),10.79–10.50(m,1H),8.21(s,1H),8.02(d,1H),7.93(br.s,1H),7.63–7.40(m,2H),7.23–7.08(m,2H),6.95–6.84(m,2H),6.72–6.64(m,1H),5.73(dd,1H),4.22–4.07(m,2H),3.76–3.63(m,2H),3.16–3.05(m,5H),2.94–2.86(m,1H),2.75–2.56(m,8H),2.14–2.05(m,1H). 1 H NMR(400MHz,DMSO-d6)δ12.68(s,1H),12.03(br.s,1H),10.95(s,1H),10.79–10.50(m,1H),8.21(s,1H) ,8.02(d,1H),7.93(br.s,1H),7.63–7.40(m,2H),7.23–7.08(m,2H),6.95–6.84(m,2H),6.72–6.64(m, 1H),5.73(dd,1H),4.22–4.07(m,2H),3.76–3.63(m,2H),3.16–3.05(m,5H),2.94–2.86(m,1H),2.75–2.56( m,8H),2.14–2.05(m,1H).
实施例36：制备化合物36
Example 36: Preparation of compound 36
参考化合物25的制备方法，得到化合物36(15mg)。Referring to the preparation method of compound 25, compound 36 (15 mg) was obtained.
LCMS m/z＝710.2[M+H]+ LCMS m/z=710.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ13.16–12.68(m,1H),12.07(s,1H),11.05(s,1H),10.72–10.14(m,1H),7.94(br.s,1H),7.63(d,1H),7.61–7.54(m,1H),7.49–7.23(m,2H),7.18–7.11(m,1H),6.83–6.75(m,1H),6.68–6.60(m,1H),5.05(dd,1H),4.21–4.10(m,2H),3.79–3.65(m,2H),3.10–2.95(m,5H),2.93–2.82(m,1H),2.73–2.65(m,2H),2.65–2.52(m,6H),2.06–1.99(m,1H). 1 H NMR (400MHz, DMSO-d6) δ13.16–12.68(m,1H),12.07(s,1H),11.05(s,1H),10.72–10.14(m,1H),7.94(br.s, 1H),7.63(d,1H),7.61–7.54(m,1H),7.49–7.23(m,2H),7.18–7.11(m,1H),6.83–6.75(m,1H),6.68–6.60( m,1H),5.05(dd,1H),4.21–4.10(m,2H),3.79–3.65(m,2H),3.10–2.95(m,5H),2.93–2.82(m,1H),2.73– 2.65(m,2H),2.65–2.52(m,6H),2.06–1.99(m,1H).
实施例37：制备化合物37的三氟乙酸盐
Example 37: Preparation of Trifluoroacetate Salt of Compound 37
第一步：37B的制备Step 1: Preparation of 37B
将37A(1000mg，7.09mmol)和3-氨基哌啶-2,6-二酮盐酸盐(1506mg,9.15mmol)溶于DMF(10mL)中，依次加入HATU(CAS:148893-10-1)(5354mg,14.08mmol)和DIPEA(4549mg,35.2mmol)，25℃反应12h。加入20mL水，乙酸乙酯萃取(3×20mL)，有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得37B粗品(900mg)。37A (1000 mg, 7.09 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (1506 mg, 9.15 mmol) were dissolved in DMF (10 mL), and HATU (CAS: 148893-10-1) was added in sequence (5354mg, 14.08mmol) and DIPEA (4549mg, 35.2mmol), react at 25°C for 12h. 20 mL of water was added, extracted with ethyl acetate (3×20 mL), the organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 37B (900 mg).
LCMS m/z＝252.1[M+H]+ LCMS m/z=252.1[M+H] +
第二步：化合物37的三氟乙酸盐的制备The second step: the preparation of the trifluoroacetic acid salt of compound 37
24A(800mg，1.49mmol)加入氯化氢的二氧六环溶液(4mol/L,20mL)和1,4-二氧六环(5mL)中,室温反应5h。真空浓缩，向此浓缩物中加入DMSO(5mL)，37B(374mg)，碳酸氢钠(626mg,7.45mmol)，80℃搅拌4h。冷却至室温，将反应混合物过滤，滤液直接用制备HPLC(制备方法1)纯化得到化合物37的三氟乙酸盐(100mg)。24A (800 mg, 1.49 mmol) was added to a solution of hydrogen chloride in dioxane (4 mol/L, 20 mL) and 1,4-dioxane (5 mL), and reacted at room temperature for 5 h. Concentrate in vacuo, add DMSO (5 mL), 37B (374 mg), sodium bicarbonate (626 mg, 7.45 mmol) to the concentrate, and stir at 80° C. for 4 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was directly purified by preparative HPLC (preparation method 1) to obtain the trifluoroacetate salt of compound 37 (100 mg).
LCMS m/z＝667.8[M+H]+ LCMS m/z=667.8[M+H] +
1H NMR(400MHz,Methanol-d4)δ7.94(d,1H),7.85(d,1H),7.63(d,1H),7.49(d,1H),7.30–7.27(m,1H),7.24–7.20(m,1H),7.16(d,1H),6.93(dd,1H),4.80–4.75(m,2H),4.32(t,2H),3.92–3.88(m,2H),3.70–3.37(m,10H),2.87–2.78(m,1H),2.75–2.67(m,1H),2.35–2.28(m,1H),2.22–2.10(m,1H). 1 H NMR (400MHz, Methanol-d4) δ7.94(d,1H),7.85(d,1H),7.63(d,1H),7.49(d,1H),7.30–7.27(m,1H),7.24 –7.20(m,1H),7.16(d,1H),6.93(dd,1H),4.80–4.75(m,2H),4.32(t,2H),3.92–3.88(m,2H),3.70–3.37 (m,10H),2.87–2.78(m,1H),2.75–2.67(m,1H),2.35–2.28(m,1H),2.22–2.10(m,1H).
实施例38：制备化合物38
Example 38: Preparation of Compound 38
第一步：38A的制备Step 1: Preparation of 38A
氮气保护下，在茄型瓶中加入氮杂环丁-3-基甲醇盐酸盐(3.45g，27.92mmol)、DMSO(80mL)和碳酸钾(16.07g，116.28mmol)，室温搅拌0.5h，加入4-溴-2-氟-1-碘苯(7.0g，23.26mmol)、L-脯氨酸(1.07g，9.29mmol)、碘化亚铜(0.89g，4.67mmol)，加入DMSO(80mL)，氮气置换三次。氮气保护90℃反应12h。加入100mL水，并用乙酸乙酯萃取(3×60mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(石油醚：乙酸乙酯(V:V)＝5:1)得38A(2.7g，产率：45％)。Under nitrogen protection, add azetidin-3-ylmethanol hydrochloride (3.45g, 27.92mmol), DMSO (80mL) and potassium carbonate (16.07g, 116.28mmol) into an eggplant-shaped flask, stir at room temperature for 0.5h, Add 4-bromo-2-fluoro-1-iodobenzene (7.0g, 23.26mmol), L-proline (1.07g, 9.29mmol), cuprous iodide (0.89g, 4.67mmol), add DMSO (80mL ), replaced with nitrogen three times. The reaction was carried out under nitrogen protection at 90°C for 12h. Add 100mL of water, and extract with ethyl acetate (3×60mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to give 38A (2.7 g, yield: 45%).
LCMS m/z＝260.2[M+H]+ LCMS m/z=260.2[M+H] +
第二步：38B的制备Step 2: Preparation of 38B
氮气保护下，将38A(2.5g,9.61mmol)、23B-1(6.01g，14.40mmol)加入40mL二氧六环和10mL水中，加入Pd(dppf)Cl2·DCM(0.78g，0.94mmol)和碳酸铯(9.39g，28.82mmol)，氮气置换三次，氮气保护100℃反应6h。冷却至室温，加入30mL水，用二氯甲烷(3×20mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝20:1)得38B(1.6g,收率：35％)。Under nitrogen protection, add 38A (2.5g, 9.61mmol), 23B-1 (6.01g, 14.40mmol) into 40mL dioxane and 10mL water, add Pd(dppf)Cl 2 ·DCM (0.78g, 0.94mmol) Replaced with cesium carbonate (9.39g, 28.82mmol) three times with nitrogen, and reacted at 100°C under nitrogen protection for 6h. Cool to room temperature, add 30mL of water, extract with dichloromethane (3×20mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=20: 1) Obtain 38B (1.6g, yield: 35%).
LCMS m/z＝471.1[M+H]+ LCMS m/z=471.1[M+H] +
第三步：38C的制备Step 3: Preparation of 38C
将38B(1.67g,3.55mmol)、10％钯碳(1.6g)加入30mL甲醇中，氢气置换三次，30℃反应4h。硅藻土过滤，滤饼用甲醇洗涤三次，合并有机相，无水硫酸钠干燥，过滤，减压旋干，得38C(0.7g,收率：67％)。Add 38B (1.67g, 3.55mmol) and 10% palladium on carbon (1.6g) into 30mL of methanol, replace with hydrogen three times, and react at 30°C for 4h. Filter through celite, wash the filter cake three times with methanol, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry under reduced pressure to obtain 38C (0.7 g, yield: 67%).
LCMS m/z＝293.2[M+H]+ LCMS m/z=293.2[M+H] +
第四步：38D的制备Step 4: Preparation of 38D
将38C(400mg，1.37mmol)溶于DMSO(5mL)中，加入2-碘酰基苯甲酸(0.46g，1.64mmol)，50℃反应1h。加入水(20mL)，用二氯甲烷(3×20mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝20:1)得38D(0.22g，收率：55％)。38C (400mg, 1.37mmol) was dissolved in DMSO (5mL), 2-iodobenzoic acid (0.46g, 1.64mmol) was added, and reacted at 50°C for 1h. Add water (20mL), extract with dichloromethane (3×20mL), dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=20:1) 38D was obtained (0.22 g, yield: 55%).
LCMS m/z＝291.3[M+H]+ LCMS m/z=291.3[M+H] +
第五步：化合物38的制备Step 5: Preparation of compound 38
23F(220mg，0.47mmol)加入氯化氢的二氧六环溶液(4mol/L,5mL)，室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和三乙胺(0.5mL)，真空浓缩。向此浓缩物中加入DMA(5mL)，38D(136mg,0.47mmol)，醋酸(28mg,0.47mmol)，室温搅拌1h，加入三乙酰氧基硼氢化钠(129mg,0.61mmol)，室温反应4h。精制方法同化合物3，得到化合物38(43mg,收率：14％)。 23F (220 mg, 0.47 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 5 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and triethylamine (0.5 mL), and concentrate in vacuo. To this concentrate was added DMA (5 mL), 38D (136 mg, 0.47 mmol), acetic acid (28 mg, 0.47 mmol), stirred at room temperature for 1 h, added sodium triacetoxyborohydride (129 mg, 0.61 mmol), and reacted at room temperature for 4 h. The purification method was the same as that of compound 3 to obtain compound 38 (43 mg, yield: 14%).
LCMS m/z＝641.7[M+H]+ LCMS m/z=641.7[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.68–12.54(m,1H),12.08(s,1H),10.89–10.53(m,2H),8.07–7.84(m,1H),7.65–7.55(m,1H),7.54–7.40(m,1H),7.26–7.07(m,2H),6.99–6.82(m,3H),6.57–6.42(m,1H),4.11–3.96(m,2H),3.74(dd,1H),3.66–3.51(m,2H),3.19–3.03(m,4H),3.02–2.90(m,1H),2.74–2.52(m,7H),2.48–2.42(m,1H),2.24–2.08(m,1H),2.05–1.92(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.68–12.54(m,1H),12.08(s,1H),10.89–10.53(m,2H),8.07–7.84(m,1H),7.65–7.55 (m,1H),7.54–7.40(m,1H),7.26–7.07(m,2H),6.99–6.82(m,3H),6.57–6.42(m,1H),4.11–3.96(m,2H) ,3.74(dd,1H),3.66–3.51(m,2H),3.19–3.03(m,4H),3.02–2.90(m,1H),2.74–2.52(m,7H),2.48–2.42(m, 1H),2.24–2.08(m,1H),2.05–1.92(m,1H).
实施例39：制备化合物39
Example 39: Preparation of compound 39
第一步：39B的制备Step 1: Preparation of 39B
11I(400mg，0.78mmol)加入氯化氢的二氧六环溶液(4mol/L,10mL)中，室温反应2h。真空浓缩，加入1,4-二氧六环(10mL)和氨水(1mL)，真空浓缩。向此浓缩物中加入DMA(10mL)，4-氟-4-甲酰基哌啶-1-羧酸叔丁酯(217mg,0.94mmol)(参照专利WO2004005255合成所得)，室温搅拌1h，加入三乙酰氧基硼氢化钠(231mg,1.09mmol)，室温反应4h。加入饱和碳酸氢钠溶液(30mL)，并用乙酸乙酯萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝10:1)得39B(200mg,收率：41％)。11I (400 mg, 0.78 mmol) was added to a solution of hydrogen chloride in dioxane (4 mol/L, 10 mL), and reacted at room temperature for 2 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and ammonia (1 mL), and concentrate in vacuo. Add DMA (10mL) and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (217mg, 0.94mmol) to this concentrate (synthesized with reference to patent WO2004005255), stir at room temperature for 1h, and add triacetyl Sodium oxyborohydride (231mg, 1.09mmol), react at room temperature for 4h. Add saturated sodium bicarbonate solution (30mL), and extract with ethyl acetate (3×50mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=10:1 ) to give 39B (200 mg, yield: 41%).
LCMS m/z＝630.7[M+H]+ LCMS m/z=630.7[M+H] +
第二步：化合物39的制备The second step: the preparation of compound 39
将39B(200mg，0.32mmol)和氯化氢的二氧六环溶液(5mL,4M)依次加入甲醇(5mL)中，室温搅拌2小时。减压浓缩，向残余物中加入DMSO(10mL)、中间体1(116mg,0.42mmol)、碳酸氢钠(134mg，1.60mmol)，100℃反应4h。冷却至室温，将滤液减压抽滤，将滤液缓慢加入到甲基叔丁基醚(50mL)和甲醇(10mL)中打浆，得到产品进一步制备液相纯化(制备方法6)得到化合物39(46mg，收率:18％)。39B (200 mg, 0.32 mmol) and hydrogen chloride in dioxane (5 mL, 4M) were sequentially added to methanol (5 mL), and stirred at room temperature for 2 hours. Concentrate under reduced pressure, add DMSO (10 mL), intermediate 1 (116 mg, 0.42 mmol), sodium bicarbonate (134 mg, 1.60 mmol) to the residue, and react at 100 ° C for 4 h. After cooling to room temperature, the filtrate was filtered under reduced pressure, and the filtrate was slowly added to methyl tert-butyl ether (50mL) and methanol (10mL) to make a slurry, and the product was further purified by liquid phase (preparation method 6) to obtain compound 39 (46mg , yield: 18%).
LCMS m/z＝393.9[(M+2H)/2]+ LCMS m/z=393.9[(M+2H)/2] +
1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),11.80(s,1H),11.06(s,1H),10.76–10.34(m,1H),8.51–8.40(m,1H),7.92–7.58(m,2H),7.55–7.41(m,1H),7.41–7.34(m,1H),7.34–7.30(m,1H),7.29–7.10(m,2H),6.94–6.85(m,1H),5.07(dd,1H),4.02–3.78(m,2H),3.29–3.24(m,1H),3.18–3.05(m,4H),2.96–2.83(m,1H),2.73–2.65(m,4H),2.67–2.52(m,5H),2.08–1.93(m,3H),1.89–1.67(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.77(s,1H),11.80(s,1H),11.06(s,1H),10.76–10.34(m,1H),8.51–8.40(m,1H ),7.92–7.58(m,2H),7.55–7.41(m,1H),7.41–7.34(m,1H),7.34–7.30(m,1H),7.29–7.10(m,2H),6.94–6.85 (m,1H),5.07(dd,1H),4.02–3.78(m,2H),3.29–3.24(m,1H),3.18–3.05(m,4H),2.96–2.83(m,1H),2.73 –2.65(m,4H),2.67–2.52(m,5H),2.08–1.93(m,3H),1.89–1.67(m,2H).
实施例40：制备化合物40
Example 40: Preparation of Compound 40
第一步：40B的制备Step 1: Preparation of 40B
将40A(2g,11.52mmol)，哌嗪-1-羧酸叔丁酯(4.29g,23.03mmol)和碳酸钾(7.44g,53.84mmol)加入DMF(50mL)中，100℃反应过夜。冷却至室温，倒入300mL冰水中，抽滤，将滤饼用水(50mL)洗涤，干燥得40B(3.4g,产率:91％)。40A (2g, 11.52mmol), tert-butyl piperazine-1-carboxylate (4.29g, 23.03mmol) and potassium carbonate (7.44g, 53.84mmol) were added into DMF (50mL) and reacted overnight at 100°C. Cool to room temperature, pour into 300 mL of ice water, filter with suction, wash the filter cake with water (50 mL), and dry to obtain 40B (3.4 g, yield: 91%).
LCMS m/z＝324.20[M+H]+ LCMS m/z=324.20[M+H] +
第二步：40C的制备Step 2: Preparation of 40C
将40B(1.7g,5.26mmol)加入无水乙醇(100mL)中，加入10％钯碳(2g)，氢气置换三次，室温反应过夜。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.57g,13.14mmol)，氮气保护回流反应5h。冷却至室温，硅藻土抽滤，浓缩滤液，将浓缩物用硅胶柱色谱纯化(流动相：二氯甲烷/甲醇＝20/1)得40C(1.86g,产率:91％)。Add 40B (1.7g, 5.26mmol) into absolute ethanol (100mL), add 10% palladium carbon (2g), replace with hydrogen three times, and react overnight at room temperature. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (2.57g, 13.14mmol), and react under reflux under nitrogen protection for 5h. Cool to room temperature, suction filter with diatomaceous earth, concentrate the filtrate, and purify the concentrate by silica gel column chromatography (mobile phase: dichloromethane/methanol=20/1) to obtain 40C (1.86 g, yield: 91%).
LCMS m/z＝390.2[M+H]+ LCMS m/z=390.2[M+H] +
第三步：40D的制备Step 3: Preparation of 40D
将2-氨基噻吩-3-甲腈(593mg，4.78mmol)和40C(1.86g,4.78mmol)加入无水THF(50mL)，氮气置换3次，氮气保护加入LiHMDS的THF溶液(47.8mL,1mol/L)，40℃反应2h，60℃反应过夜。冷却至室温，加入饱和氯化铵溶液(30mL)淬灭，分离有机层，水层用乙酸乙酯(20mL×3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，加入石油醚(40mL)和乙酸乙酯(20mL)打浆，抽滤收集固体，干燥得40D(600mg,产率:27％)。Add 2-aminothiophene-3-carbonitrile (593mg, 4.78mmol) and 40C (1.86g, 4.78mmol) into anhydrous THF (50mL), nitrogen replacement 3 times, and add a THF solution of LiHMDS (47.8mL, 1mol /L), react at 40°C for 2h, and react overnight at 60°C. Cool to room temperature, add saturated ammonium chloride solution (30mL) to quench, separate the organic layer, extract the aqueous layer with ethyl acetate (20mL×3), combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, add petroleum ether (40 mL) and ethyl acetate (20 mL), the solid was collected by suction filtration and dried to give 40D (600 mg, yield: 27%).
LCMS m/z＝468.2[M+H]+ LCMS m/z=468.2[M+H] +
第四步：40E的制备Step 4: Preparation of 40E
40D(350mg，0.75mmol)加入氯化氢的二氧六环溶液(4mol/L,30mL)和1,4-二氧六环(10mL)中，室温反应3h。真空浓缩，向浓缩物中加入二氯甲烷(5mL)、甲醇(5mL)和三乙胺(2mL)，减压浓缩。向此浓缩物中加入DMA(10mL)，3-甲酰基氮杂环丁烷-1-羧酸叔丁酯(139mg,0.75mmol)。室温搅拌1h后加入三乙酰氧基硼氢化钠(238mg,1.12mmol)，室温反应3h。加入20mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯(20mL×3)萃取，无水硫酸镁干燥，过滤，真空浓缩，硅胶柱色谱纯化(二氯甲烷：甲醇(V:V)＝10:1)得40E(120mg,收率：30％)。40D (350mg, 0.75mmol) was added to a solution of hydrogen chloride in dioxane (4mol/L, 30mL) and 1,4-dioxane (10mL), and reacted at room temperature for 3h. Concentrate in vacuo, add dichloromethane (5 mL), methanol (5 mL) and triethylamine (2 mL) to the concentrate, and concentrate under reduced pressure. To this concentrate was added DMA (10 mL), tert-butyl 3-formylazetidine-1-carboxylate (139 mg, 0.75 mmol). After stirring at room temperature for 1 h, sodium triacetoxyborohydride (238 mg, 1.12 mmol) was added and reacted at room temperature for 3 h. Add 20 mL of saturated sodium bicarbonate solution to quench the reaction, extract with ethyl acetate (20 mL×3), dry over anhydrous magnesium sulfate, filter, concentrate in vacuo, and purify by silica gel column chromatography (dichloromethane:methanol (V:V)=10 : 1) 40E (120 mg, yield: 30%) was obtained.
LCMS m/z＝537.3[M+H]+ LCMS m/z=537.3[M+H] +
第五步：化合物40的制备The fifth step: the preparation of compound 40
40E(120mg，0.22mmol)加入氯化氢的二氧六环溶液(4mol/L,20mL)和1,4-二氧六环(5mL)，室温反应5h。真空浓缩，向此浓缩物中加入DMSO(5mL)，中间体1(61mg，0.22mmol)，碳酸氢钠(56mg,0.67mmol)，80℃搅拌4h。冷却至室温，加入水(20mL)，并用二氯甲烷/甲醇混合溶剂(v/v＝10/1，3×30mL)萃取，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品用制备HPLC(制备方法2)得化合物40(10mg，收率：7％)。 40E (120 mg, 0.22 mmol) was added with hydrogen chloride in dioxane (4 mol/L, 20 mL) and 1,4-dioxane (5 mL), and reacted at room temperature for 5 h. Concentrate in vacuo, add DMSO (5 mL), Intermediate 1 (61 mg, 0.22 mmol), sodium bicarbonate (56 mg, 0.67 mmol) to the concentrate, and stir at 80°C for 4 h. Cool to room temperature, add water (20 mL), and extract with dichloromethane/methanol mixed solvent (v/v=10/1, 3×30 mL), and the organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, After filtration and concentration, the crude product was subjected to preparative HPLC (preparation method 2) to obtain compound 40 (10 mg, yield: 7%).
LCMS m/z＝693.2[M+H]+ LCMS m/z=693.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.77–12.70(m,1H),12.14(s,1H),11.05(s,1H),10.69–10.38(m,1H),8.55–8.47(m,1H),8.25–8.12(m,1H),7.65–7.60(m,2H),7.21–7.17(m,1H),7.02–6.97(m,1H),6.80–6.77(m,1H),6.67–6.63(m,1H),5.09–5.01(m,1H),4.20–4.13(m,2H),3.76–3.70(m,2H),3.45–3.39(m,4H),3.09–3.03(m,1H),2.93–2.83(m,1H),2.70–2.66(m,2H),2.57–2.53(m,6H),2.02–1.99(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.77–12.70(m,1H),12.14(s,1H),11.05(s,1H),10.69–10.38(m,1H),8.55–8.47(m ,1H),8.25–8.12(m,1H),7.65–7.60(m,2H),7.21–7.17(m,1H),7.02–6.97(m,1H),6.80–6.77(m,1H),6.67 –6.63(m,1H),5.09–5.01(m,1H),4.20–4.13(m,2H),3.76–3.70(m,2H),3.45–3.39(m,4H),3.09–3.03(m, 1H),2.93–2.83(m,1H),2.70–2.66(m,2H),2.57–2.53(m,6H),2.02–1.99(m,1H).
实施例41：制备化合物41
Example 41: Preparation of Compound 41
第一步：41B的制备Step 1: Preparation of 41B
将41A(3.0g,24.28mmol)溶于DMSO(50mL)中，加入碳酸钾(16.77g,121.35mmol)，室温搅拌30分钟，依次加入2-溴-1,3-二氟-5-碘苯(8.51g,26.69mmol)、L-脯氨酸(1.12g,9.73mmol)和碘化亚铜(0.92g,4.83mmol)，90℃反应12h。冷却到室温，加入乙酸乙酯(50mL)和水(50mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物用硅胶柱层析纯化(流动相：石油醚/乙酸乙酯(V/V)＝100/1-4/1)，得41B(2.844g,收率：42％)。Dissolve 41A (3.0g, 24.28mmol) in DMSO (50mL), add potassium carbonate (16.77g, 121.35mmol), stir at room temperature for 30 minutes, then add 2-bromo-1,3-difluoro-5-iodobenzene (8.51g, 26.69mmol), L-proline (1.12g, 9.73mmol) and cuprous iodide (0.92g, 4.83mmol), react at 90°C for 12h. Cooled to room temperature, added ethyl acetate (50mL) and water (50mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V)=100/1-4/1), to obtain 41B (2.844g, yield: 42%).
LCMS m/z＝278.2[M+1]+ LCMS m/z=278.2[M+1] +
第二步：41C的制备Step 2: Preparation of 41C
将41B(2.844g,10.23mmol)、23B-1(5.98g,14.33mmol)、Pd(dppf)Cl2·DCM(0.84g,1.03mmol)和碳酸铯(10.0g,30.69mmol)加入二氧六环(40mL)和水(10mL)中，用氮气置换三次，100℃反应过夜。冷却到室温，加水(50mL)和二氯甲烷(100mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)，得41C(2.375g，收率：48％)。41B (2.844g, 10.23mmol), 23B-1 (5.98g, 14.33mmol), Pd(dppf)Cl 2 ·DCM (0.84g, 1.03mmol) and cesium carbonate (10.0g, 30.69mmol) were added to dioxane ring (40 mL) and water (10 mL), replaced with nitrogen three times, and reacted overnight at 100°C. Cooled to room temperature, added water (50mL) and dichloromethane (100mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (V /V)=100/1-20/1), to obtain 41C (2.375g, yield: 48%).
LCMS m/z＝489.2[M+1]+ LCMS m/z=489.2[M+1] +
第三步：41D的制备Step 3: Preparation of 41D
将41C(900mg,1.84mmol)、钯碳(10％,1.0g)加入甲醇(30mL)中，氢气置换三次，在氢气条件下，30℃反应4h。抽滤，滤液减压浓缩，得41D粗品(430mg)。Add 41C (900mg, 1.84mmol) and palladium on carbon (10%, 1.0g) into methanol (30mL), replace with hydrogen three times, and react at 30°C for 4h under hydrogen. Suction filtration, and the filtrate was concentrated under reduced pressure to obtain 41D crude product (430 mg).
LCMS m/z＝311.3[M+1]+ LCMS m/z=311.3[M+1] +
第四步：41E的制备Step 4: Preparation of 41E
将41D的粗品(430mg)和2-碘酰基苯甲酸(467mg,1.67mmol)溶于DMSO(10mL)中，70℃反应6h。加入饱和碳酸氢钠溶液(10mL)和乙酸乙酯(50mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物用硅胶柱层析纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-20/1)，得41E(222mg， 两步收率：39％)。The crude product of 41D (430mg) and 2-iodobenzoic acid (467mg, 1.67mmol) were dissolved in DMSO (10mL), and reacted at 70°C for 6h. Add saturated sodium bicarbonate solution (10mL) and ethyl acetate (50mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol ( V/V)=100/1-20/1), get 41E (222mg, Two-step yield: 39%).
LCMS m/z＝341.1[M+MeOH+1]+ LCMS m/z=341.1[M+MeOH+1] +
第五步：化合物41的制备Step 5: Preparation of Compound 41
将23F(160mg,0.34mmol)溶于二氯甲烷(5mL)中，加入盐酸-二氧六环溶液(5mL,4M)，室温反应1h。减压浓缩，向浓缩物中加入二氯甲烷(10mL)和氨水(3mL)，减压浓缩。向此浓缩物中加入41E(105mg,0.34mmol)、DMA(5mL)和醋酸(20mg，0.33mmol)，室温搅拌2h，加入三乙酰氧基硼氢化钠(108mg,0.51mmol)，室温搅拌过夜。加入乙酸乙酯(50mL)和饱和碳酸氢钠溶液(50mL)萃取，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物用制备液相纯化(制备方法7)得到化合物41(13mg，收率：6％)。Dissolve 23F (160mg, 0.34mmol) in dichloromethane (5mL), add hydrochloric acid-dioxane solution (5mL, 4M), and react at room temperature for 1h. Concentrate under reduced pressure, add dichloromethane (10 mL) and aqueous ammonia (3 mL) to the concentrate, and concentrate under reduced pressure. Add 41E (105mg, 0.34mmol), DMA (5mL) and acetic acid (20mg, 0.33mmol) to this concentrate, stir at room temperature for 2h, add sodium triacetoxyborohydride (108mg, 0.51mmol), and stir overnight at room temperature. Ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the concentrate was purified by preparative liquid phase (preparative method 7) to obtain compound 41 (13 mg, Yield: 6%).
LCMS m/z＝659.3[M+1]+ LCMS m/z=659.3[M+1] +
1H NMR(400MHz,CF3COOD)δ8.48(s,1H),8.06(d,1H),7.93(d,1H),7.44(d,1H),7.36–7.20(m,3H),5.22–5.06(m,2H),5.00–4.83(m,2H),4.69–3.95(m,12H),3.09–2.85(m,2H),2.57–2.20(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.48(s,1H),8.06(d,1H),7.93(d,1H),7.44(d,1H),7.36–7.20(m,3H),5.22 –5.06(m,2H),5.00–4.83(m,2H),4.69–3.95(m,12H),3.09–2.85(m,2H),2.57–2.20(m,2H).
实施例42：制备化合物42
Example 42: Preparation of compound 42
将24A(0.24g,0.45mmol)溶于甲醇(5mL)中，缓慢加入盐酸二氧六环溶液(10mL，4M)，室温反应1h，减压浓缩。向此浓缩物中加入DIPEA(0.29g，2.24mmol)、42A(合成参照专利WO2021143822Al)(0.19g，0.59mmol)和二甲亚砜(10mL)，80℃反应过夜。反应液直接通过制备液相分离纯化(制备方法7)得化合物42(17mg，收率：5％)。24A (0.24g, 0.45mmol) was dissolved in methanol (5mL), slowly added dioxane hydrochloride solution (10mL, 4M), reacted at room temperature for 1h, and concentrated under reduced pressure. Add DIPEA (0.29g, 2.24mmol), 42A (refer to patent WO2021143822Al for synthesis) (0.19g, 0.59mmol) and dimethyl sulfoxide (10mL) to this concentrate, and react overnight at 80°C. The reaction solution was directly separated and purified by preparative liquid phase (preparative method 7) to obtain compound 42 (17 mg, yield: 5%).
LCMS m/z＝736.2[M+H]+ LCMS m/z=736.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),12.10(s,1H),11.06(s,1H),10.67(d,1H),8.00(s,1H),7.59(d,1H),7.48(dd,1H),7.31–7.03(m,2H),6.88(d,2H),6.13(s,2H),5.00(dd,1H),4.47(s,2H),4.04(s,2H),3.09(s,4H),2.98–2.77(m,2H),2.74–2.51(m,7H),2.47(s,1H),2.05–1.93(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.62(s,1H),12.10(s,1H),11.06(s,1H),10.67(d,1H),8.00(s,1H),7.59( d,1H),7.48(dd,1H),7.31–7.03(m,2H),6.88(d,2H),6.13(s,2H),5.00(dd,1H),4.47(s,2H),4.04 (s,2H),3.09(s,4H),2.98–2.77(m,2H),2.74–2.51(m,7H),2.47(s,1H),2.05–1.93(m,1H).
实施例43：化合物43的制备
Embodiment 43: Preparation of compound 43
以23F为起始原料，参考实施例22的合成方法，得到化合物43(100mg)。Using 23F as the starting material, referring to the synthesis method of Example 22, compound 43 (100 mg) was obtained.
LCMS m/z＝706.2[M+H]+ LCMS m/z=706.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.66–12.54(m,1H),12.07(s,1H),11.06(s,1H),10.79–10.49(m,1H),7.95(s,1H),7.71–7.55(m,2H),7.54–7.41(m,1H),7.38–7.31(m,1H),7.32–7.05(m,3H),6.94–6.84(m,1H),5.07(dd,1H),4.18–4.00(m,2H),3.20–3.05(m,4H),3.07–2.79(m,4H),2.77–2.63(m,4H),2.64–2.53(m,2H),2.12–1.97(m,1H),1.98–1.84(m,2H),1.60–1.41(m, 2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.66–12.54(m,1H),12.07(s,1H),11.06(s,1H),10.79–10.49(m,1H),7.95(s,1H) ),7.71–7.55(m,2H),7.54–7.41(m,1H),7.38–7.31(m,1H),7.32–7.05(m,3H),6.94–6.84(m,1H),5.07(dd ,1H),4.18–4.00(m,2H),3.20–3.05(m,4H),3.07–2.79(m,4H),2.77–2.63(m,4H),2.64–2.53(m,2H),2.12 –1.97(m,1H),1.98–1.84(m,2H),1.60–1.41(m, 2H).
实施例44：化合物44的制备
Embodiment 44: Preparation of Compound 44
以23F为起始原料，参考实施例22的合成方法，得到化合物44(110mg)。Using 23F as the starting material, referring to the synthesis method of Example 22, compound 44 (110 mg) was obtained.
LCMS m/z＝692.8[M+H]+ LCMS m/z=692.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.70–12.56(m,1H),12.07(s,1H),11.05(s,1H),10.79–10.50(m,1H),7.95(s,1H),7.69–7.61(m,1H),7.61–7.55(m,1H),7.56–7.40(m,1H),7.27–7.08(m,2H),6.99(s,1H),6.97–6.89(m,1H),6.86(d,1H),5.06(dd,1H),3.74(t,1H),3.60(t,1H),3.49–3.37(m,1H),3.21–3.09(m,4H),3.09–2.98(m,1H),2.95–2.81(m,1H),2.79–2.65(m,4H),2.64–2.52(m,3H),2.36–2.23(m,1H),2.08–1.85(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.70–12.56(m,1H),12.07(s,1H),11.05(s,1H),10.79–10.50(m,1H),7.95(s,1H ),7.69–7.61(m,1H),7.61–7.55(m,1H),7.56–7.40(m,1H),7.27–7.08(m,2H),6.99(s,1H),6.97–6.89(m ,1H),6.86(d,1H),5.06(dd,1H),3.74(t,1H),3.60(t,1H),3.49–3.37(m,1H),3.21–3.09(m,4H), 3.09–2.98(m,1H),2.95–2.81(m,1H),2.79–2.65(m,4H),2.64–2.52(m,3H),2.36–2.23(m,1H),2.08–1.85(m ,2H).
实施例45：化合物45的制备
Embodiment 45: Preparation of compound 45
以23F为起始原料，参考实施例22的合成方法，得到化合物45(50mg)。Using 23F as the starting material, referring to the synthesis method of Example 22, compound 45 (50 mg) was obtained.
LCMS m/z＝718.80[M+H]+ LCMS m/z=718.80[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),12.18–11.86(m,1H),11.06(s,1H),10.72–10.37(m,1H),8.04–7.69(m,1H),7.63(d,1H),7.56(d,1H),7.52–7.41(m,1H),7.21–7.09(m,2H),6.91–6.85(m,1H),6.78–6.73(m,1H),6.65–6.58(m,1H),5.05(dd,1H),4.08(s,2H),3.96(s,2H),3.15–3.05(m,4H),2.93–2.83(m,1H),2.73–2.66(m,1H),2.62–2.52(m,2H),2.47–2.35(m,6H),2.13–2.06(m,2H),2.04–1.98(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.85(s,1H),12.18–11.86(m,1H),11.06(s,1H),10.72–10.37(m,1H),8.04–7.69(m ,1H),7.63(d,1H),7.56(d,1H),7.52–7.41(m,1H),7.21–7.09(m,2H),6.91–6.85(m,1H),6.78–6.73(m ,1H),6.65–6.58(m,1H),5.05(dd,1H),4.08(s,2H),3.96(s,2H),3.15–3.05(m,4H),2.93–2.83(m,1H ),2.73–2.66(m,1H),2.62–2.52(m,2H),2.47–2.35(m,6H),2.13–2.06(m,2H),2.04–1.98(m,1H).
实施例46：化合物46的制备
Embodiment 46: Preparation of compound 46
以23F为起始原料，参考实施例22的合成方法，得到化合物46(50mg)。Using 23F as the starting material, referring to the synthesis method of Example 22, compound 46 (50 mg) was obtained.
LCMS m/z＝746.90[M+H]+ LCMS m/z=746.90[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),12.08(s,1H),11.05(s,1H),10.77–10.56(m,1H),8.05–7.82(m,1H),7.66–7.55(m,2H),7.53–7.41(m,1H),7.21–7.07(m,2H),6.92–6.82(m,1H),6.79–6.72(m,1H),6.67–6.59(m,1H),5.05(dd,1H),3.75(s,2H),3.69(s,2H),3.19–3.00(m,4H),2.92–2.82(m,1H),2.69–2.55(m,5H),2.32–2.21(m,1H),2.05–1.92(m,3H),1.81–1.71(m,2H), 1.56–1.47(m,2H),1.39–1.28(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ12.61(s,1H),12.08(s,1H),11.05(s,1H),10.77–10.56(m,1H),8.05–7.82(m,1H ),7.66–7.55(m,2H),7.53–7.41(m,1H),7.21–7.07(m,2H),6.92–6.82(m,1H),6.79–6.72(m,1H),6.67–6.59 (m,1H),5.05(dd,1H),3.75(s,2H),3.69(s,2H),3.19–3.00(m,4H),2.92–2.82(m,1H),2.69–2.55(m ,5H),2.32–2.21(m,1H),2.05–1.92(m,3H),1.81–1.71(m,2H), 1.56–1.47(m,2H),1.39–1.28(m,3H).
实施例47：化合物47的制备
Embodiment 47: Preparation of compound 47
以23F为起始原料，参考实施例22的合成方法，得到化合物47(40mg)。Using 23F as the starting material, referring to the synthesis method of Example 22, compound 47 (40 mg) was obtained.
LCMS m/z＝732.2[M+H]+ LCMS m/z=732.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),12.08(s,1H),11.05(s,1H),10.78–10.51(m,1H),8.04–7.87(m,1H),7.61(dd,2H),7.46(dd,1H),7.22–7.05(m,2H),6.98–6.81(m,3H),5.05(dd,1H),3.60–3.51(m,2H),3.38–3.32(m,2H),3.15–3.00(m,4H),2.92–2.52(m,10H),2.23–2.12(m,2H),2.06–1.98(m,1H),1.42–1.35(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.60(s,1H),12.08(s,1H),11.05(s,1H),10.78–10.51(m,1H),8.04–7.87(m,1H ),7.61(dd,2H),7.46(dd,1H),7.22–7.05(m,2H),6.98–6.81(m,3H),5.05(dd,1H),3.60–3.51(m,2H), 3.38–3.32(m,2H),3.15–3.00(m,4H),2.92–2.52(m,10H),2.23–2.12(m,2H),2.06–1.98(m,1H),1.42–1.35(m ,2H).
实施例48：化合物48的制备
Embodiment 48: Preparation of compound 48
第一步：48C的制备Step 1: Preparation of 48C
氮气保护下，在茄型瓶中加入48B(2g，19.77mmol)，二甲基亚砜(20mL)和碳酸钾(13.66g，5.62mmol)，室温搅拌0.5h，加入48A(5.59g，19.77mmol)、L-脯氨酸(0.91g，7.91mmol)、碘化亚铜(0.75g，3.95mmol)。在氮气保护90℃反应12h。加入50mL水，并用乙酸乙酯萃取(3×50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱纯化(石油醚：乙酸乙酯(V:V)＝5:1)得48C(2.52g，产率：50％)。Under nitrogen protection, add 48B (2g, 19.77mmol), dimethyl sulfoxide (20mL) and potassium carbonate (13.66g, 5.62mmol) into an eggplant-shaped bottle, stir at room temperature for 0.5h, add 48A (5.59g, 19.77mmol ), L-proline (0.91g, 7.91mmol), cuprous iodide (0.75g, 3.95mmol). The reaction was carried out at 90°C under nitrogen protection for 12h. Add 50mL of water, and extract with ethyl acetate (3×50mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to give 48C (2.52 g, yield: 50%).
第二步至第五步参考化合物38的合成方法，得到化合物48(53mg)。From the second step to the fifth step, refer to the synthesis method of compound 38 to obtain compound 48 (53 mg).
LCMS m/z＝637.9[M+H]+ LCMS m/z=637.9[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.69–12.54(m,1H),11.08–10.20(m,3H),7.96(br.s,1H),7.62–7.54(m,1H),7.53–7.41(m,1H),7.23–7.07(m,2H),7.07–7.00(m,2H),6.95–6.85(m,3H),3.79–3.65(m,3H),3.17–3.05(m,4H),2.78–2.55(m,7H),2.48–2.29(m,2H),2.22–1.97(m,2H),1.95–1.87(m,2H),1.63–1.45(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.69–12.54(m,1H),11.08–10.20(m,3H),7.96(br.s,1H),7.62–7.54(m,1H),7.53 –7.41(m,1H),7.23–7.07(m,2H),7.07–7.00(m,2H),6.95–6.85(m,3H),3.79–3.65(m,3H),3.17–3.05(m, 4H),2.78–2.55(m,7H),2.48–2.29(m,2H),2.22–1.97(m,2H),1.95–1.87(m,2H),1.63–1.45(m,2H).
实施例49：化合物49的制备
Embodiment 49: Preparation of compound 49
以49A为起始原料，参考实施例48的合成方法，得到化合物49(5mg)。Using 49A as the starting material, referring to the synthesis method of Example 48, compound 49 (5 mg) was obtained.
LCMS m/z＝649.2[M+1]+ LCMS m/z=649.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.65–12.56(m,1H),12.07(s,1H),10.79–10.57(m,2H),8.02–7.85(m,1H),7.59(d,1H),7.53–7.40(m,1H),7.23–7.06(m,2H),6.99(d,2H),6.93–6.85(m,1H),6.36(d,2H),3.82(s,2H),3.74–3.62(m,3H),3.16–3.03(m,4H),2.74–2.56(m,2H),2.47–2.39(m,5H),2.37–2.26(m,2H),2.16–1.94(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ12.65–12.56(m,1H),12.07(s,1H),10.79–10.57(m,2H),8.02–7.85(m,1H),7.59(d ,1H),7.53–7.40(m,1H),7.23–7.06(m,2H),6.99(d,2H),6.93–6.85(m,1H),6.36(d,2H),3.82(s,2H ),3.74–3.62(m,3H),3.16–3.03(m,4H),2.74–2.56(m,2H),2.47–2.39(m,5H),2.37–2.26(m,2H),2.16–1.94 (m,4H).
实施例50：化合物50的制备
Embodiment 50: the preparation of compound 50
以50B为起始原料，参考实施例48的合成方法，得到化合物50的三氟乙酸盐(35mg)。Using 50B as the starting material, referring to the synthesis method of Example 48, the trifluoroacetic acid salt of compound 50 (35 mg) was obtained.
LCMS m/z＝677.90[M+1]+ LCMS m/z=677.90[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.74(s,1H),9.46(s,1H),7.62–7.54(m,2H),7.28–7.25(m,1H),7.21–7.17(m,1H),7.04–6.98(m,3H),6.43–6.36(m,2H),3.85–3.59(m,6H),3.58(s,2H),3.51(s,2H),3.33–3.22(m,3H),3.08–2.99(m,2H),2.67–2.58(m,1H),2.14–1.98(m,6H),1.64–1.49(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ12.11(s,1H),10.74(s,1H),9.46(s,1H),7.62–7.54(m,2H),7.28–7.25(m,1H ),7.21–7.17(m,1H),7.04–6.98(m,3H),6.43–6.36(m,2H),3.85–3.59(m,6H),3.58(s,2H),3.51(s,2H ),3.33–3.22(m,3H),3.08–2.99(m,2H),2.67–2.58(m,1H),2.14–1.98(m,6H),1.64–1.49(m,4H).
实施例51：化合物51的制备
Embodiment 51: Preparation of compound 51
第一步：51A的制备 Step 1: Preparation of 51A
将23F(1.50g,3.22mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,50mL)中，室温反应2h，减压浓缩。向此浓缩物中依次加入DMA(20mL)、醋酸钠(1.40g,17.07mmol)、醋酸(1.5mL)、3,3-二氟-4-氧代哌啶-1-羧酸叔丁酯(1.14g,4.85mmol)，110℃反应12h。冷却至室温，倒入200mL水中，用乙酸乙酯(100mL×2)萃取，合并有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-12/1)得到51A(1.40g,产率:74％)。23F (1.50g, 3.22mmol) was added into a solution of hydrogen chloride in 1,4-dioxane (4mol/L, 50mL), reacted at room temperature for 2h, and concentrated under reduced pressure. To this concentrate was added sequentially DMA (20 mL), sodium acetate (1.40 g, 17.07 mmol), acetic acid (1.5 mL), tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate ( 1.14g, 4.85mmol), reacted at 110°C for 12h. Cool to room temperature, pour into 200mL water, extract with ethyl acetate (100mL×2), combine the organic layers and dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by column chromatography (mobile phase: two Chloromethane/methanol (V/V)=100/1-12/1) gave 51A (1.40 g, yield: 74%).
LCMS m/z＝584.6[M+H]+ LCMS m/z=584.6[M+H] +
第二步：51B的制备Step 2: Preparation of 51B
51A(1.40g，2.40mmol)溶于1,2-二氯乙烷/甲醇(v/v＝1/1，20mL)，依次加入醋酸(0.7mL)、氰基硼氢化钠(0.60g，9.55mmol)，室温反应12h。加入三乙胺(1mL)和硅胶并旋干，残留物通过柱层析分离纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-12/1)得到51B(0.80g，收率：57％)。51A (1.40g, 2.40mmol) was dissolved in 1,2-dichloroethane/methanol (v/v=1/1, 20mL), and acetic acid (0.7mL) and sodium cyanoborohydride (0.60g, 9.55 mmol), react at room temperature for 12h. Triethylamine (1 mL) and silica gel were added and spin-dried, and the residue was separated and purified by column chromatography (mobile phase: dichloromethane/methanol (V/V)=100/1-12/1) to obtain 51B (0.80 g, Yield: 57%).
LCMS m/z＝586.2[M+H]+ LCMS m/z=586.2[M+H] +
第三步至第五步参考化合物20的制备方法，得到化合物51的三氟乙酸盐(6mg)。The third step to the fifth step refer to the preparation method of compound 20 to obtain the trifluoroacetic acid salt of compound 51 (6 mg).
LCMS m/z＝706.8[M+H]+ LCMS m/z=706.8[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.77(s,1H),7.67–7.54(m,2H),7.46(br.s,1H),7.26–7.06(m,2H),6.89(t,1H),6.54(dd,1H),6.44(dd,1H),4.29(dd,1H),3.60–3.12(m,11H),3.12–2.96(m,1H),2.86–2.68(m,2H),2.62–2.53(m,1H),2.15–1.96(m,3H),1.93–1.80(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.14(s,1H),10.77(s,1H),7.67–7.54(m,2H),7.46(br.s,1H),7.26–7.06(m ,2H),6.89(t,1H),6.54(dd,1H),6.44(dd,1H),4.29(dd,1H),3.60–3.12(m,11H),3.12–2.96(m,1H), 2.86–2.68(m,2H),2.62–2.53(m,1H),2.15–1.96(m,3H),1.93–1.80(m,1H).
实施例52：化合物52的制备
Embodiment 52: Preparation of compound 52
第一步：52A的制备Step 1: Preparation of 52A
将23F(600mg,1.29mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)中，室温反应2小时，减压浓缩。向此浓缩物中依次加入DMA(15mL)、醋酸(0.5mL)、1A-1(260mg,1.30mmol)，80℃反应2h。降至室温，加入氰基硼氢化钠(405mg，6.44mmol)，室温反应12h。将反应液倒入100mL饱和碳酸氢钠水溶液中，用乙酸乙酯(500mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-12/1)得到52A(500mg,产率:71％)。23F (600 mg, 1.29 mmol) was added into a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL), reacted at room temperature for 2 hours, and concentrated under reduced pressure. To this concentrate, DMA (15 mL), acetic acid (0.5 mL), 1A-1 (260 mg, 1.30 mmol) were sequentially added, and reacted at 80° C. for 2 h. Cool down to room temperature, add sodium cyanoborohydride (405mg, 6.44mmol), and react at room temperature for 12h. The reaction solution was poured into 100 mL saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (500 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography ( Mobile phase: dichloromethane/methanol (V/V) = 100/1-12/1) to obtain 52A (500 mg, yield: 71%).
LCMS m/z＝550.3[M+H]+ LCMS m/z=550.3[M+H] +
第二步：52B的制备Step 2: Preparation of 52B
将52A(400mg,0.73mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)中，室温反应2h，减压浓缩。向此浓缩物中依次加入DMSO(50mL)、1,2-二氟-4-硝基苯(174mg,1.09mmol)、DIPEA(380mg,2.94mmol)，80℃反应12h。冷却至室温，倒入150mL水中，抽滤，滤饼用石油醚/乙酸乙酯(v/v＝1/1，20mL)打浆，再次抽滤，将滤饼干燥得到52B(300mg,产率:70％)。52A (400 mg, 0.73 mmol) was added into a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL), reacted at room temperature for 2 h, and concentrated under reduced pressure. DMSO (50 mL), 1,2-difluoro-4-nitrobenzene (174 mg, 1.09 mmol), and DIPEA (380 mg, 2.94 mmol) were sequentially added to the concentrate, and reacted at 80° C. for 12 h. Cooled to room temperature, poured into 150mL water, suction filtered, the filter cake was slurried with petroleum ether/ethyl acetate (v/v=1/1, 20mL), suction filtered again, and the filter cake was dried to obtain 52B (300mg, yield: 70%).
LCMS m/z＝589.2[M+H]+ LCMS m/z=589.2[M+H] +
第三步：52C的制备Step 3: Preparation of 52C
将52B(240mg,0.41mmol)溶于二氯甲烷/甲醇(v/v＝1/1，20mL)中，加入钯碳(231mg, wt％＝10％)，氢气氛围室温反应2h。抽滤，将滤液减压浓缩，得到52C(100mg,收率：44％)。Dissolve 52B (240mg, 0.41mmol) in dichloromethane/methanol (v/v=1/1, 20mL), add palladium on carbon (231mg, wt%=10%), hydrogen atmosphere room temperature reaction 2h. After suction filtration, the filtrate was concentrated under reduced pressure to obtain 52C (100 mg, yield: 44%).
LCMS m/z＝280.1[M/2+H]+ LCMS m/z＝280.1[M/2+H] +
第四步：化合物52的制备The fourth step: the preparation of compound 52
52C(100mg，0.18mmol)溶于DMF(10mL)，加入3-溴哌啶-2,6-二酮(311mg,1.62mmol)和碳酸氢钠(76mg,0.90mmol)，80℃搅拌12h。冷却至室温，倒入150mL水中，抽滤，将滤饼干燥并进一步用制备HPLC(制备方法1)纯化得到化合物52的三氟乙酸盐(4mg，产率：3％)。52C (100mg, 0.18mmol) was dissolved in DMF (10mL), 3-bromopiperidine-2,6-dione (311mg, 1.62mmol) and sodium bicarbonate (76mg, 0.90mmol) were added, and stirred at 80°C for 12h. Cool to room temperature, pour into 150 mL of water, filter with suction, dry the filter cake and further purify by preparative HPLC (Preparation Method 1) to obtain the trifluoroacetate salt of compound 52 (4 mg, yield: 3%).
LCMS m/z＝670.7[M+H]+ LCMS m/z=670.7[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.24–11.93(m,1H),10.77(s,1H),9.72–9.51(m,1H),7.66–7.49(m,2H),7.27(s,1H),7.24–6.96(m,3H),6.88(t,1H),6.57–6.28(m,2H),4.29–4.25(m,1H),3.85–3.75(m,2H),3.75–3.65(m,2H),3.43–3.20(m,5H),3.14–2.98(m,2H),2.77–2.53(m,4H),2.25–2.05(m,3H),1.93–1.75(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ12.24–11.93(m,1H),10.77(s,1H),9.72–9.51(m,1H),7.66–7.49(m,2H),7.27(s ,1H),7.24–6.96(m,3H),6.88(t,1H),6.57–6.28(m,2H),4.29–4.25(m,1H),3.85–3.75(m,2H),3.75–3.65 (m,2H),3.43–3.20(m,5H),3.14–2.98(m,2H),2.77–2.53(m,4H),2.25–2.05(m,3H),1.93–1.75(m,3H) .
实施例53：化合物53的制备
Embodiment 53: Preparation of compound 53
参考化合物52的合成方法，得到化合物53的三氟乙酸盐(5mg)。Referring to the synthesis method of compound 52, the trifluoroacetate salt of compound 53 (5 mg) was obtained.
LCMS m/z＝642.2[M+H]+ LCMS m/z=642.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.20–11.98(m,1H),10.75(s,1H),10.61–10.17(m,1H),7.62–7.52(m,2H),7.27(s,1H),7.22–7.16(m,1H),7.03–6.95(m,1H),6.59–6.42(m,3H),4.25–4.22(m,1H),4.12–4.05(m,2H),4.03–3.97(m,2H),3.87–3.36(m,5H),3.33–2.90(m,4H),2.77–2.55(m,2H),2.15–2.03(m,1H),1.91–1.78(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.20–11.98(m,1H),10.75(s,1H),10.61–10.17(m,1H),7.62–7.52(m,2H),7.27(s ,1H),7.22–7.16(m,1H),7.03–6.95(m,1H),6.59–6.42(m,3H),4.25–4.22(m,1H),4.12–4.05(m,2H),4.03 –3.97(m,2H),3.87–3.36(m,5H),3.33–2.90(m,4H),2.77–2.55(m,2H),2.15–2.03(m,1H),1.91–1.78(m, 1H).
实施例54：化合物54的制备
Embodiment 54: Preparation of compound 54
参考化合物68的合成方法，23F先脱Boc，再与54A进行还原胺化反应得到化合物54(150mg)。Referring to the synthesis method of compound 68, 23F was de-Boced first, and then reductively aminated with 54A to obtain compound 54 (150 mg).
LCMS m/z＝326.2[(M+2H)/2]+ LCMS m/z=326.2[(M+2H)/2] +
1H NMR(400MHz,CF3COOD)δ8.31–8.22(m,1H),8.07(d,1H),7.87(dd,1H),7.63(d,2H),7.54(d,2H),7.46(d,1H),7.30(d,1H),4.68–4.44(m,2H),4.44–4.25(m,4H),4.24–4.02(m,3H),4.00–3.88(m,2H),3.88–3.72(m,2H),3.69–3.51(m,2H),3.09–2.88(m,2H),2.78–2.63(m,1H),2.52–2.34(m,4H),2.29–2.06(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.31–8.22 (m, 1H), 8.07 (d, 1H), 7.87 (dd, 1H), 7.63 (d, 2H), 7.54 (d, 2H), 7.46 (d,1H),7.30(d,1H),4.68–4.44(m,2H),4.44–4.25(m,4H),4.24–4.02(m,3H),4.00–3.88(m,2H),3.88 –3.72(m,2H),3.69–3.51(m,2H),3.09–2.88(m,2H),2.78–2.63(m,1H),2.52–2.34(m,4H),2.29–2.06(m, 2H).
实施例55：化合物55的制备
Embodiment 55: Preparation of compound 55
参考化合物68的合成方法，32A先脱Boc，再与54A进行还原胺化反应得到化合物55(95mg)。Referring to the synthesis method of compound 68, 32A was de-Boced first, and then reductively aminated with 54A to obtain compound 55 (95 mg).
LCMS m/z＝651.3[M+H]+ LCMS m/z=651.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.29(s,1H),8.12–7.98(m,2H),7.93–7.81(m,1H),7.68–7.57(m,2H),7.57–7.47(m,2H),7.28(d,1H),4.71–4.43(m,2H),4.43–4.22(m,4H),4.22–4.01(m,3H),4.00–3.86(m,2H),3.86–3.70(m,2H),3.68–3.52(m,2H),3.06–2.87(m,2H),2.78–2.60(m,1H),2.52–2.33(m,4H),2.27–2.06(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.29(s,1H), 8.12–7.98(m,2H), 7.93–7.81(m,1H), 7.68–7.57(m,2H), 7.57–7.47( m,2H),7.28(d,1H),4.71–4.43(m,2H),4.43–4.22(m,4H),4.22–4.01(m,3H),4.00–3.86(m,2H),3.86– 3.70(m,2H),3.68–3.52(m,2H),3.06–2.87(m,2H),2.78–2.60(m,1H),2.52–2.33(m,4H),2.27–2.06(m,2H ).
实施例56：化合物56的制备
Embodiment 56: Preparation of compound 56
参考化合物38的合成方法，得到化合物56(70mg)。Referring to the synthetic method of compound 38, compound 56 (70 mg) was obtained.
LCMS m/z＝669.3[M+H]+ LCMS m/z=669.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.28–8.21(m,1H),8.09–8.01(m,1H),7.89–7.81(m,1H),7.60–7.51(m,1H),7.51–7.39(m,3H),7.29(d,1H),4.62–4.43(m,2H),4.43–4.25(m,4H),4.24–4.04(m,3H),4.01–3.89(m,2H),3.87–3.70(m,2H),3.65–3.51(m,2H),3.09–2.86(m,2H),2.77–2.61(m,1H),2.56–2.25(m,4H),2.27–2.06(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.28–8.21(m,1H),8.09–8.01(m,1H),7.89–7.81(m,1H),7.60–7.51(m,1H),7.51– 7.39(m,3H),7.29(d,1H),4.62–4.43(m,2H),4.43–4.25(m,4H),4.24–4.04(m,3H),4.01–3.89(m,2H), 3.87–3.70(m,2H),3.65–3.51(m,2H),3.09–2.86(m,2H),2.77–2.61(m,1H),2.56–2.25(m,4H),2.27–2.06(m ,2H).
实施例57：制备化合物57
Example 57: Preparation of Compound 57
参考由38C制备化合物38的合成方法，得到化合物57(97mg)。Referring to the synthesis method of compound 38 from 38C, compound 57 (97 mg) was obtained.
LCMS m/z＝652.3[M+H]+ LCMS m/z=652.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.64–12.55(m,1H),12.08(s,1H),10.78(s,1H),10.75–10.54(m,1H),8.03–7.89(m,2H),7.62–7.56(m,1H),7.53–7.40(m,1H),7.39–7.32(m,1H),7.23–7.06(m,2H),6.93–6.85(m,1H),6.79(d,1H),4.26(d,2H),3.72(dd,1H),3.19–3.03(m,4H),2.79(t,2H),2.74–2.61(m,1H),2.61–2.51(m,4H),2.30–2.09(m,3H),2.03–1.92(m,1H),1.90–1.73 (m,3H),1.30–1.19(m,1H),1.17–1.03(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.64–12.55(m,1H),12.08(s,1H),10.78(s,1H),10.75–10.54(m,1H),8.03–7.89(m ,2H),7.62–7.56(m,1H),7.53–7.40(m,1H),7.39–7.32(m,1H),7.23–7.06(m,2H),6.93–6.85(m,1H),6.79 (d,1H),4.26(d,2H),3.72(dd,1H),3.19–3.03(m,4H),2.79(t,2H),2.74–2.61(m,1H),2.61–2.51(m ,4H),2.30–2.09(m,3H),2.03–1.92(m,1H),1.90–1.73 (m,3H),1.30–1.19(m,1H),1.17–1.03(m,2H).
实施例58：制备化合物58
Example 58: Preparation of Compound 58
参考化合物68的合成方法，32A先脱Boc，再与23E进行还原胺化反应得到化合物58(35mg)Referring to the synthesis method of compound 68, 32A was first de-Boc, and then reductively aminated with 23E to obtain compound 58 (35mg)
LCMS m/z＝312.3[(M+2H)/2]+ LCMS m/z=312.3[(M+2H)/2] +
1H NMR(400MHz,DMSO-d6)δ12.77–12.68(m,1H),11.82–11.74(m,1H),10.76–10.36(m,2H),7.96–7.90(m,1H),7.81(br.s,1H),7.54–7.40(m,1H),7.23–7.08(m,1H),7.04–6.97(m,3H),6.93–6.87(m,1H),6.43–6.34(m,2H),3.99–3.91(m,2H),3.69(dd,1H),3.50–3.42(m,2H),3.17–3.04(m,4H),3.02–2.91(m,1H),2.68–2.54(m,6H),2.48–2.41(m,2H),2.16–2.06(m,1H),2.04–1.96(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.77–12.68(m,1H),11.82–11.74(m,1H),10.76–10.36(m,2H),7.96–7.90(m,1H),7.81 (br.s,1H),7.54–7.40(m,1H),7.23–7.08(m,1H),7.04–6.97(m,3H),6.93–6.87(m,1H),6.43–6.34(m, 2H),3.99–3.91(m,2H),3.69(dd,1H),3.50–3.42(m,2H),3.17–3.04(m,4H),3.02–2.91(m,1H),2.68–2.54( m,6H),2.48–2.41(m,2H),2.16–2.06(m,1H),2.04–1.96(m,1H).
实施例59：化合物59的制备
Embodiment 59: Preparation of compound 59
参考实施例38的合成方法，得到化合物59(165mg)。Referring to the synthesis method of Example 38, compound 59 (165 mg) was obtained.
LCMS m/z＝687.9[M+H]+ LCMS m/z=687.9[M+H] +
1H NMR(400MHz,CF3COOD)δ8.28–8.23(m,1H),8.08–8.02(m,1H),7.90–7.81(m,1H),7.44(d,1H),7.39–7.32(m,2H),7.28(d,1H),4.63–4.45(m,2H),4.45–4.22(m,5H),4.22–4.04(m,2H),4.03–3.90(m,2H),3.87–3.70(m,2H),3.65–3.51(m,2H),3.08–2.86(m,2H),2.76–2.60(m,1H),2.55–2.36(m,3H),2.35–2.24(m,1H),2.23–2.05(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.28–8.23(m,1H),8.08–8.02(m,1H),7.90–7.81(m,1H),7.44(d,1H),7.39–7.32( m,2H),7.28(d,1H),4.63–4.45(m,2H),4.45–4.22(m,5H),4.22–4.04(m,2H),4.03–3.90(m,2H),3.87– 3.70(m,2H),3.65–3.51(m,2H),3.08–2.86(m,2H),2.76–2.60(m,1H),2.55–2.36(m,3H),2.35–2.24(m,1H ),2.23–2.05(m,2H).
实施例60：化合物60的制备
Embodiment 60: the preparation of compound 60
参考化合物38的制备方法，得到化合物60(110mg)。Referring to the preparation method of compound 38, compound 60 (110 mg) was obtained.
LCMS m/z＝669.9[M+H]+ LCMS m/z=669.9[M+H] +
1H NMR(400MHz,CF3COOD)δ8.25(d,1H),8.05(d,1H),7.86(dd,1H),7.70(t,1H),7.44(d,1H),7.39–7.32(m,2H),7.28(d,1H),4.69–3.85(m,13H),3.68–3.52(m,2H),3.08–2.86(m,2H),2.77–2.61(m,1H),2.51–2.34(m,4H),2.29–2.12(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.25(d,1H),8.05(d,1H),7.86(dd,1H),7.70(t,1H),7.44(d,1H),7.39–7.32 (m,2H),7.28(d,1H),4.69–3.85(m,13H),3.68–3.52(m,2H),3.08–2.86(m,2H),2.77–2.61(m,1H),2.51 –2.34(m,4H),2.29–2.12(m,2H).
实施例61：化合物61的制备
Embodiment 61: the preparation of compound 61
参考化合物70的合成方法，23F先脱Boc，进一步与61A还原胺化反应得到化合物61(60mg)。Referring to the synthesis method of compound 70, 23F was first de-Boc, and further reductively aminated with 61A to obtain compound 61 (60 mg).
LCMS m/z＝652.3[M+H]+ LCMS m/z=652.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.69–12.54(m,1H),12.06(br.s,1H),10.81–10.53(m,1H),10.23(s,1H),7.96(br.s,1H),7.64–7.37(m,2H),7.23–7.07(m,4H),6.96–6.86(m,3H),3.75–3.60(m,4H),3.17–3.04(m,4H),2.73–2.60(m,4H),2.59–2.51(m,4H),2.29–2.15(m,2H),1.88–1.64(m,3H),1.32–1.15(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.69–12.54(m,1H),12.06(br.s,1H),10.81–10.53(m,1H),10.23(s,1H),7.96(br .s,1H),7.64–7.37(m,2H),7.23–7.07(m,4H),6.96–6.86(m,3H),3.75–3.60(m,4H),3.17–3.04(m,4H) ,2.73–2.60(m,4H),2.59–2.51(m,4H),2.29–2.15(m,2H),1.88–1.64(m,3H),1.32–1.15(m,2H).
实施例62：化合物62的制备
Embodiment 62: the preparation of compound 62
第一步：62B的制备Step 1: Preparation of 62B
将62A(10.00g，35.46mmol)、环丙基硼酸(5.48g，63.80mmol)、碳酸铯(27.73g，85.11mmol)、Pd(dppf)Cl2·DCM(1.74g，2.15mmol)加入二氧六环/水(v/v＝7/1，240mL)中，氮气保护100℃反应12h。冷却至室温，加入150mL水，用二氯甲烷(100mL×2)萃取，合并有机层并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(石油醚/乙酸乙酯＝100/1-1/1)得到62B(7.4g,产率:106％)。 62A (10.00 g, 35.46 mmol), cyclopropylboronic acid (5.48 g, 63.80 mmol), cesium carbonate (27.73 g, 85.11 mmol), Pd(dppf)Cl 2 ·DCM (1.74 g, 2.15 mmol) were added to dioxygen In Hexane/water (v/v=7/1, 240 mL), the reaction was carried out at 100° C. for 12 h under nitrogen protection. Cool to room temperature, add 150mL of water, extract with dichloromethane (100mL×2), combine the organic layers and dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by column chromatography (petroleum ether/ethyl acetate Ester = 100/1-1/1) afforded 62B (7.4 g, yield: 106%).
LCMS m/z＝197.1[M+H]+ LCMS m/z=197.1[M+H] +
参考化合物40和化合物70(第八步)的合成方法，以62B+哌嗪-1-羧酸叔丁酯为起始原料，得到化合物62(60mg)。Referring to the synthesis method of compound 40 and compound 70 (eighth step), using 62B+ piperazine-1-tert-butyl carboxylate as starting materials, compound 62 (60 mg) was obtained.
LCMS m/z＝663.3[M+H]+ LCMS m/z=663.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.66–12.54(m,1H),12.07(br.s,1H),10.73(s,1H),10.66(br.s,1H),7.97(br.s,1H),7.62–7.55(m,1H),7.42–7.25(m,1H),7.21–7.15(m,1H),7.14–6.96(m,3H),6.39(d,2H),3.94(t,2H),3.69(dd,1H),3.47(t,2H),3.08–2.86(m,5H),2.75–2.55(m,7H),2.48–2.30(m,2H),2.16–1.94(m,2H),1.04–0.92(m,2H),0.75–0.60(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.66–12.54(m,1H),12.07(br.s,1H),10.73(s,1H),10.66(br.s,1H),7.97(br .s,1H),7.62–7.55(m,1H),7.42–7.25(m,1H),7.21–7.15(m,1H),7.14–6.96(m,3H),6.39(d,2H),3.94 (t,2H),3.69(dd,1H),3.47(t,2H),3.08–2.86(m,5H),2.75–2.55(m,7H),2.48–2.30(m,2H),2.16–1.94 (m,2H),1.04–0.92(m,2H),0.75–0.60(m,2H).
实施例63：化合物63的制备
Embodiment 63: the preparation of compound 63
参考化合物68的制备方法，36A先脱Boc，进一步与54A进行还原胺化反应得到化合物63(30mg)。Referring to the preparation method of compound 68, 36A was de-Boced first, and then reductively aminated with 54A to obtain compound 63 (30 mg).
LCMS m/z＝669.3[M+H]+ LCMS m/z=669.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.81–12.71(m,1H),12.18–12.01(m,1H),10.75(s,1H),10.64–10.44(m,1H),8.08–7.90(m,1H),7.61–7.55(m,1H),7.49–7.22(m,2H),7.18(d,1H),7.07–7.00(m,2H),6.92–6.85(m,2H),3.78–3.60(m,3H),3.08–2.95(m,4H),2.67–2.54(m,6H),2.47–2.41(m,1H),2.30–2.21(m,2H),2.15–1.98(m,2H),1.89–1.78(m,2H),1.75–1.67(m,1H),1.28–1.21(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ12.81–12.71(m,1H),12.18–12.01(m,1H),10.75(s,1H),10.64–10.44(m,1H),8.08–7.90 (m,1H),7.61–7.55(m,1H),7.49–7.22(m,2H),7.18(d,1H),7.07–7.00(m,2H),6.92–6.85(m,2H),3.78 –3.60(m,3H),3.08–2.95(m,4H),2.67–2.54(m,6H),2.47–2.41(m,1H),2.30–2.21(m,2H),2.15–1.98(m, 2H),1.89–1.78(m,2H),1.75–1.67(m,1H),1.28–1.21(m,3H).
实施例64：化合物64的制备
Embodiment 64: the preparation of compound 64
参考化合物40的合成方法，得到化合物化合物64(90mg)。Referring to the synthetic method of compound 40, compound compound 64 (90 mg) was obtained.
LCMS m/z＝722.9[M+1]+ LCMS m/z=722.9[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.68–12.54(m,1H),12.06(s,1H),11.05(s,1H),10.72–10.51(m,1H),8.00–7.83(m,1H),7.66–7.61(m,1H),7.60–7.55(m,1H),7.30–7.24(m,1H),7.19–7.08(m,2H),6.81–6.75(m,1H),6.69–6.61(m,1H),5.05(dd,1H),4.24–4.05(m,2H),3.82(d,3H),3.77–3.66(m,2H),3.15–2.79(m,7H),2.76–2.64(m,2H),2.65–2.52(m,5H),2.05–1.95(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.68–12.54(m,1H),12.06(s,1H),11.05(s,1H),10.72–10.51(m,1H),8.00–7.83(m ,1H),7.66–7.61(m,1H),7.60–7.55(m,1H),7.30–7.24(m,1H),7.19–7.08(m,2H),6.81–6.75(m,1H),6.69 –6.61(m,1H),5.05(dd,1H),4.24–4.05(m,2H),3.82(d,3H),3.77–3.66(m,2H),3.15–2.79(m,7H),2.76 –2.64(m,2H),2.65–2.52(m,5H),2.05–1.95(m,1H).
实施例65：化合物65的制备
Embodiment 65: the preparation of compound 65
将23F(130mg，0.28mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)，室温反应1h。真空浓缩，加入1,4-二氧六环(10mL)和三乙胺(0.5mL)，真空浓缩。向此浓缩物中加入乙腈(8mL)，65A(参照专利WO2021170109A1合成所得)(131mg,0.28mmol)，碳酸钾(77mg,0.56mmol)和碘化钾(6mg,0.04mmol)，80℃反应过夜。真空浓缩，硅胶制备板纯化(制备方法1)得化合物65的三氟乙酸盐(5mg，产率：2％)。23F (130 mg, 0.28 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL), and reacted at room temperature for 1 h. Concentrate in vacuo, add 1,4-dioxane (10 mL) and triethylamine (0.5 mL), and concentrate in vacuo. Add acetonitrile (8mL), 65A (synthesized with reference to patent WO2021170109A1) (131mg, 0.28mmol), potassium carbonate (77mg, 0.56mmol) and potassium iodide (6mg, 0.04mmol) to this concentrate, react overnight at 80°C. Concentrated in vacuo, purified on silica gel preparative plate (preparative method 1) to obtain trifluoroacetic acid salt of compound 65 (5 mg, yield: 2%).
LCMS m/z＝661.7[M+H]+ LCMS m/z=661.7[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),11.15(s,1H),8.16(s,1H),8.11–7.89(m,2H),7.70–7.47(m,2H),7.42–6.89(m,3H),5.26–5.11(m,1H),4.50(s,2H),2.98–2.79(m,3H),2.72–2.53(m,4H),2.16–1.92(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.11(s,1H),11.15(s,1H),8.16(s,1H),8.11–7.89(m,2H),7.70–7.47(m,2H ),7.42–6.89(m,3H),5.26–5.11(m,1H),4.50(s,2H),2.98–2.79(m,3H),2.72–2.53(m,4H),2.16–1.92(m ,2H).
实施例66：化合物66的制备
Embodiment 66: the preparation of compound 66
参考化合物16的合成方法，得到化合物66(60mg)。Referring to the synthetic method of compound 16, compound 66 (60 mg) was obtained.
LCMS m/z＝746.3[M+H]+ LCMS m/z=746.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.62–12.53(m,1H),12.06(s,1H),11.04(s,1H),10.81–10.57(m,1H),8.05–7.85(m,1H),7.66–7.56(m,2H),7.51–7.39(m,1H),7.23–7.11(m,2H),6.92–6.84(m,1H),6.82–6.77(m,1H),6.68–6.62(m,1H),5.05(dd,1H),4.16–4.07(m,2H),3.85–3.76(m,2H),3.27–3.20(m,1H),3.19–3.10(m,2H),3.08–2.98(m,2H),2.92–2.82(m,1H),2.64–2.51(m,2H),2.35–2.06(m,4H),2.05–1.99(m,1H),1.72–1.64(m,2H),1.63–1.54(m,4H),1.39–1.33(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.62–12.53(m,1H),12.06(s,1H),11.04(s,1H),10.81–10.57(m,1H),8.05–7.85(m ,1H),7.66–7.56(m,2H),7.51–7.39(m,1H),7.23–7.11(m,2H),6.92–6.84(m,1H),6.82–6.77(m,1H),6.68 –6.62(m,1H),5.05(dd,1H),4.16–4.07(m,2H),3.85–3.76(m,2H),3.27–3.20(m,1H),3.19–3.10(m,2H) ,3.08–2.98(m,2H),2.92–2.82(m,1H),2.64–2.51(m,2H),2.35–2.06(m,4H),2.05–1.99(m,1H),1.72–1.64( m,2H),1.63–1.54(m,4H),1.39–1.33(m,2H).
实施例67：化合物67的制备
Embodiment 67: the preparation of compound 67
第一步：67A的制备Step 1: Preparation of 67A
将23F(500mg,1.07mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)，室温反应2h，减压浓缩，加入甲醇(10mL)复溶，加入三乙胺(1mL)，减压浓缩。向此浓缩物中依次加入DMF(15mL)、1-Boc-氮杂环丁烷-3-羧酸(237mg,1.18mmol)、N-甲基咪唑(270mg,3.29mmol)、N,N,N’,N’-四甲基氯甲脒六氟磷酸盐(390mg,1.39mmol)，室温反应2h，倒入100mL水中，用乙酸乙酯(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物通过柱层析分离纯化(流动相：二氯甲烷/甲醇(V/V)＝100/1-12/1)得到67A(500mg,产率:85％)。Add 23F (500mg, 1.07mmol) to 1,4-dioxane solution of hydrogen chloride (4mol/L, 10mL), react at room temperature for 2h, concentrate under reduced pressure, add methanol (10mL) to redissolve, add triethylamine (1mL ), concentrated under reduced pressure. To this concentrate was added successively DMF (15 mL), 1-Boc-azetidine-3-carboxylic acid (237 mg, 1.18 mmol), N-methylimidazole (270 mg, 3.29 mmol), N, N, N ', N'-Tetramethylchloroformamidine hexafluorophosphate (390mg, 1.39mmol), reacted at room temperature for 2h, poured into 100mL water, extracted with ethyl acetate (50mL×2), combined the organic phases, anhydrous sodium sulfate Dry, filter, concentrate under reduced pressure, and the residue is separated and purified by column chromatography (mobile phase: dichloromethane/methanol (V/V)=100/1-12/1) to obtain 67A (500mg, yield: 85%) .
LCMS m/z＝550.7[M+H]+ LCMS m/z=550.7[M+H] +
第二步：化合物67的制备The second step: the preparation of compound 67
将67A(250mg,0.45mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)，室温下反应2h，减压浓缩，向此浓缩物中加入DMSO(8mL)，中间体1(249mg,0.90mmol)，DIPEA(349mg,2.70mmol)，100℃搅拌2h。冷却至室温，倒入30mL冰水中，抽滤并收集固体。精制方法同化合物3，化合物67(50mg,产率:16％)。Add 67A (250mg, 0.45mmol) to 1,4-dioxane solution of hydrogen chloride (4mol/L, 10mL), react at room temperature for 2h, concentrate under reduced pressure, add DMSO (8mL) to this concentrate, intermediate 1 (249mg, 0.90mmol), DIPEA (349mg, 2.70mmol), stirred at 100°C for 2h. Cool to room temperature, pour into 30mL of ice water, filter with suction and collect the solid. The purification method was the same as that of compound 3 and compound 67 (50 mg, yield: 16%).
LCMS m/z＝706.2[M+H]+ LCMS m/z=706.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),12.19–11.96(m,1H),11.18–10.91(m,1H),10.77–10.55(m,1H),8.04–7.88(m,1H),7.72–7.43(m,3H),7.29–7.12(m,2H),7.00–6.91(m,1H),6.87–6.76(m,1H),6.76–6.64(m,1H),5.17–4.94(m,1H),4.34–4.13(m,4H),4.03–3.90(m,1H),3.76–3.61(m,2H),3.59–3.43(m,2H),3.18–3.03(m,4H),2.96–2.80(m,1H),2.61–2.52(m,2H),2.06–1.96(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.65(s,1H),12.19–11.96(m,1H),11.18–10.91(m,1H),10.77–10.55(m,1H),8.04–7.88 (m,1H),7.72–7.43(m,3H),7.29–7.12(m,2H),7.00–6.91(m,1H),6.87–6.76(m,1H),6.76–6.64(m,1H) ,5.17–4.94(m,1H),4.34–4.13(m,4H),4.03–3.90(m,1H),3.76–3.61(m,2H),3.59–3.43(m,2H),3.18–3.03( m,4H),2.96–2.80(m,1H),2.61–2.52(m,2H),2.06–1.96(m,1H).
实施例68：化合物68的制备
Embodiment 68: the preparation of compound 68
将11I(400mg,0.78mmol)加入氯化氢的1,4-二氧六环溶液(4mol/L,20mL)，室温反应2h，减压浓缩，加入1,4-二氧六环(20mL)和三乙胺(1mL)，减压浓缩。向此浓缩物中依次加入DMA(20mL)、醋酸(47mg,0.78mmol)、48F(246mg,0.86mmol)，60℃反应1h，冷却至室温，加入三乙酰氧基硼氢化钠(331mg，1.56mmol)，40℃反应过夜，冷却至室温，加入饱和碳酸氢钠溶液(20mL)，乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥，过滤，浓缩，并进一步用制备HPLC((制备方法2)得到化合物68(40mg,产率:8％)。11I (400mg, 0.78mmol) was added into 1,4-dioxane solution of hydrogen chloride (4mol/L, 20mL), reacted at room temperature for 2h, concentrated under reduced pressure, added 1,4-dioxane (20mL) and three Ethylamine (1 mL), concentrated under reduced pressure. Add DMA (20mL), acetic acid (47mg, 0.78mmol), 48F (246mg, 0.86mmol) to this concentrate successively, react at 60°C for 1h, cool to room temperature, add sodium triacetoxyborohydride (331mg, 1.56mmol ), react overnight at 40°C, cool to room temperature, add saturated sodium bicarbonate solution (20mL), extract with ethyl acetate (30mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and further use preparative HPLC ((preparation method 2) Compound 68 (40 mg, yield: 8%) was obtained.
LCMS m/z＝685.2[M+H]+ LCMS m/z=685.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.85–12.71(m,1H),11.89–11.74(m,1H),10.77(s,1H),10.56(br.s,1H),8.54–8.38(m,1H),7.76(br.s,1H),7.55–7.39(m,1H),7.35–7.27(m,1H),7.23–7.07(m,1H),7.07–6.98(m,2H),6.95–6.80(m,3H),3.79–3.64(m,3H),3.17–3.02(m,4H),2.78–2.56(m,7H),2.49–2.30(m,2H),2.20–1.95(m,2H),1.94–1.81(m,2H),1.63–1.43(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.85–12.71(m,1H),11.89–11.74(m,1H),10.77(s,1H),10.56(br.s,1H),8.54–8.38 (m,1H),7.76(br.s,1H),7.55–7.39(m,1H),7.35–7.27(m,1H),7.23–7.07(m,1H),7.07–6.98(m,2H) ,6.95–6.80(m,3H),3.79–3.64(m,3H),3.17–3.02(m,4H),2.78–2.56(m,7H),2.49–2.30(m,2H),2.20–1.95( m,2H),1.94–1.81(m,2H),1.63–1.43(m,2H).
实施例69：化合物69的制备
Embodiment 69: Preparation of compound 69
参考化合物68的合成方法，得到化合物69(30mg，收率：15％)。Referring to the synthetic method of compound 68, compound 69 (30 mg, yield: 15%) was obtained.
LCMS m/z＝689.2[M+H]+ LCMS m/z=689.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.82–12.72(m,1H),11.80(s,1H),10.82–10.28(m,2H),8.54–8.37(m,1H),7.72(br.s,1H),7.55–7.37(m,1H),7.37–7.27(m,1H),7.24–7.07(m,1H),6.99–6.77(m,3H),6.57–6.44(m,1H),4.11–3.96(m,2H),3.74(dd,1H),3.64–3.52(m,2H),3.18–3.04(m,4H),3.03–2.90(m,1H),2.71–2.53(m,7H),2.47–2.41(m,1H),2.22–2.10(m,1H),2.04–1.94(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ12.82–12.72(m,1H),11.80(s,1H),10.82–10.28(m,2H),8.54–8.37(m,1H),7.72(br .s,1H),7.55–7.37(m,1H),7.37–7.27(m,1H),7.24–7.07(m,1H),6.99–6.77(m,3H),6.57–6.44(m,1H) ,4.11–3.96(m,2H),3.74(dd,1H),3.64–3.52(m,2H),3.18–3.04(m,4H),3.03–2.90(m,1H),2.71–2.53(m, 7H),2.47–2.41(m,1H),2.22–2.10(m,1H),2.04–1.94(m,1H).
实施例70：化合物70的制备
Embodiment 70: the preparation of compound 70
第一步：70C的制备Step 1: Preparation of 70C
将70A(7.69g，43.43mmol)，70B(5.00g，43.41mmol)和碳酸钾(12.00g,86.83mmol)依次加入DMF(50mL)中，80℃反应12h。冷却至室温，加入水(150mL)，抽滤，将滤饼干燥，得到70C(11.00g,收率：93％)。70A (7.69g, 43.43mmol), 70B (5.00g, 43.41mmol) and potassium carbonate (12.00g, 86.83mmol) were sequentially added into DMF (50mL) and reacted at 80°C for 12h. Cool to room temperature, add water (150 mL), filter with suction, and dry the filter cake to obtain 70C (11.00 g, yield: 93%).
LCMS m/z＝273.0[M+H]+ LCMS m/z=273.0[M+H] +
第二步：70D的制备Step 2: Preparation of 70D
将70C(10.00g，36.73mmol)溶于甲醇(50mL)中，加入钯碳(3.91g,wt％＝10％)，氢气氛围室温反应2h。硅藻土过滤，滤液减压浓缩，得到70D(8.00g,收率:90％)。70C (10.00 g, 36.73 mmol) was dissolved in methanol (50 mL), palladium carbon (3.91 g, wt% = 10%) was added, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 h. Celite was filtered, and the filtrate was concentrated under reduced pressure to obtain 70D (8.00 g, yield: 90%).
LCMS m/z＝243.2[M+1]+ LCMS m/z=243.2[M+1] +
第三步：70F的制备Step 3: Preparation of 70F
将70D(10.00g，41.28mmol)，70E(12.40g，123.85mmol)和DIPEA(16.01g,123.88mmol)依次加入到乙醇(50mL)中，100℃反应48h。冷却至室温，减压浓缩，残留物通过柱层析分离纯化(流动相：甲醇/二氯甲烷(V/V)＝0-8％)得到70F(6.30g,收率：45％)。70D (10.00g, 41.28mmol), 70E (12.40g, 123.85mmol) and DIPEA (16.01g, 123.88mmol) were sequentially added to ethanol (50mL) and reacted at 100°C for 48h. Cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol/dichloromethane (V/V)=0-8%) to obtain 70F (6.30 g, yield: 45%).
LCMS m/z＝343.3[M+H]+ LCMS m/z=343.3[M+H] +
第四步：70H的制备Step 4: Preparation of 70H
将70F(230mg，0.67mmol)，70G(276mg，1.00mmol)和咪唑(91mg,1.34mmol)依次加入DMF(10mL)中，60℃反应2h。冷却至室温，加入水(100mL)，用乙酸乙酯(50mL)萃取，有机相减压浓缩，残留物通过柱层析分离纯化(流动相：乙酸乙酯/石油醚(V/V)＝0-10％)得到70H(200mg,收率：51％)。70F (230mg, 0.67mmol), 70G (276mg, 1.00mmol) and imidazole (91mg, 1.34mmol) were sequentially added to DMF (10mL) and reacted at 60°C for 2h. Cooled to room temperature, added water (100mL), extracted with ethyl acetate (50mL), concentrated the organic phase under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: ethyl acetate/petroleum ether (V/V)=0 -10%) to give 70H (200 mg, yield: 51%).
LCMS m/z＝581.1[M+H]+ LCMS m/z=581.1[M+H] +
第五步：化合物70I的制备The fifth step: the preparation of compound 70I
将70H(200mg，0.34mmol)和DIPEA(132mg,1.02mmol)溶于二氯甲烷(20mL)中，缓慢加入三光气(111mg,0.37mmol)，室温反应2h。加入氨水(20mL)，继续反应12h。加入水(30mL)，用二氯甲烷(50mL)萃取，有机相减压浓缩，残留物通过柱层析分离纯化(流动相：甲醇/二氯甲烷(V/V)＝0-10％)得到70I(100mg,收率：47％)。70H (200mg, 0.34mmol) and DIPEA (132mg, 1.02mmol) were dissolved in dichloromethane (20mL), triphosgene (111mg, 0.37mmol) was added slowly, and reacted at room temperature for 2h. Aqueous ammonia (20 mL) was added and the reaction was continued for 12 h. Add water (30mL), extract with dichloromethane (50mL), concentrate the organic phase under reduced pressure, and separate and purify the residue by column chromatography (mobile phase: methanol/dichloromethane (V/V)=0-10%) to obtain 70I (100 mg, yield: 47%).
1H NMR(400MHz,DMSO-d6)δ7.68–7.56(m,4H),7.51–7.37(m,6H),7.00–6.86(m,2H),5.85(s,2H),3.96(q,2H),3.75(t,2H),3.56(d,2H),3.21–3.13(m,2H),3.08–2.95(m,2H),2.45(t,2H),1.80–1.60(m,3H),1.40–1.25(m,2H),1.12(t,3H),1.01(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ7.68–7.56(m,4H),7.51–7.37(m,6H),7.00–6.86(m,2H),5.85(s,2H),3.96(q ,2H),3.75(t,2H),3.56(d,2H),3.21–3.13(m,2H),3.08–2.95(m,2H),2.45(t,2H),1.80–1.60(m,3H ),1.40–1.25(m,2H),1.12(t,3H),1.01(s,9H).
第六步：70J的制备Step 6: Preparation of 70J
将70I(2.50g，4.01mmol)加入乙腈(30mL)中，加入苄基三甲基氢氧化铵的甲醇溶液(4.75mL,40％)，60℃反应2h。冷却至室温，加入硅胶，减压浓缩，残留物通过柱层析分离纯化(流动相：乙酸乙酯/石油醚(V/V)＝0-8％)得到70J(900mg,收率：66％)。70I (2.50g, 4.01mmol) was added into acetonitrile (30mL), and benzyltrimethylammonium hydroxide in methanol (4.75mL, 40%) was added, and reacted at 60°C for 2h. Cool to room temperature, add silica gel, concentrate under reduced pressure, and the residue is separated and purified by column chromatography (mobile phase: ethyl acetate/petroleum ether (V/V)=0-8%) to obtain 70J (900mg, yield: 66% ).
LCMS m/z＝340.2[M+H]+ LCMS m/z=340.2[M+H] +
第七步：70K的制备Step 7: Preparation of 70K
将70J(300mg，0.88mmol)加入DMSO(5mL)中，加入2-碘酰基苯甲酸(370mg，1.32mmol)，50℃反应2h。冷却至室温，加入饱和碳酸氢钠水溶液(20mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到70K(280mg,收率：94％)。70J (300mg, 0.88mmol) was added to DMSO (5mL), 2-iodylbenzoic acid (370mg, 1.32mmol) was added, and the reaction was carried out at 50°C for 2h. Cool to room temperature, add saturated aqueous sodium bicarbonate (20mL), extract with ethyl acetate (30mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 70K (280mg, yield: 94% ).
LCMS m/z＝338.6[M+H]+ LCMS m/z=338.6[M+H] +
第八步：化合物70的制备Step 8: Preparation of compound 70
参考化合物68的合成方法，23F先脱Boc，进一步与70K进行还原胺化反应得到化合物70(80mg)。Referring to the synthesis method of compound 68, 23F was de-Boc first, and then reductively aminated with 70K to obtain compound 70 (80 mg).
LCMS m/z＝688.2[M+H]+ LCMS m/z=688.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),12.07(br.s,1H),10.82–10.53(m,1H),10.44(s,1H),7.95(br.s,1H),7.58(d,1H),7.53–7.41(m,1H),7.24–7.01(m,4H),6.93–6.85(m,1H),3.76(t,2H),3.21–2.99(m,8H),2.68(t,2H),2.62–2.52(m,4H),2.29–2.18(m,2H),1.87–1.61(m,3H),1.31–1.24(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.64(s,1H),12.07(br.s,1H),10.82–10.53(m,1H),10.44(s,1H),7.95(br.s ,1H),7.58(d,1H),7.53–7.41(m,1H),7.24–7.01(m,4H),6.93–6.85(m,1H),3.76(t,2H),3.21–2.99(m ,8H),2.68(t,2H),2.62–2.52(m,4H),2.29–2.18(m,2H),1.87–1.61(m,3H),1.31–1.24(m,2H).
实施例71：化合物71的制备
Embodiment 71: Preparation of compound 71
参考化合物68的合成方法，得到化合物71(5mg)。Referring to the synthesis method of compound 68, compound 71 (5 mg) was obtained.
LCMS m/z＝707.1[M+H]+ LCMS m/z=707.1[M+H] +
1H NMR(400MHz,CF3COOD)δ8.79–8.60(m,1H),8.27–8.17(m,1H),8.03(d,1H),7.84(d,1H),7.53(d,1H),7.32–7.12(m,2H),5.18–5.02(m,2H),4.92–4.75(m,2H),4.48–4.27(m,5H),4.27–4.12(m,4H),4.12–3.98(m,3H),3.07–2.86(m,2H),2.55–2.39(m,1H),2.35–2.21(m,1H). 1 H NMR (400MHz, CF 3 COOD) δ8.79–8.60(m,1H),8.27–8.17(m,1H),8.03(d,1H),7.84(d,1H),7.53(d,1H) ,7.32–7.12(m,2H),5.18–5.02(m,2H),4.92–4.75(m,2H),4.48–4.27(m,5H),4.27–4.12(m,4H),4.12–3.98( m,3H),3.07–2.86(m,2H),2.55–2.39(m,1H),2.35–2.21(m,1H).
实施例72：化合物72的制备
Embodiment 72: the preparation of compound 72
参考化合物11的合成方法，以62D为起始原料，得到化合物72(10mg)。Referring to the synthetic method of compound 11, using 62D as the starting material, compound 72 (10 mg) was obtained.
LCMS m/z＝780.9[M+H]+ LCMS m/z=780.9[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.84–12.69(m,1H),11.81(s,1H),11.07(s,1H),10.55(br.s,1H),8.53–8.35(m,1H),7.92–7.56(m,2H),7.45–7.23(m,2H),7.15–6.95(m,1H),6.79(s,1H),6.70–6.59(m,1H),5.06(dd,1H),4.24–4.07(m,2H),3.80–3.65(m,2H),3.12–2.57(m,13H),2.41–2.28(m,1H),2.12–1.89(m,2H),1.02–0.90(m,2H),0.79–0.61(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ12.84–12.69(m,1H),11.81(s,1H),11.07(s,1H),10.55(br.s,1H),8.53–8.35(m ,1H),7.92–7.56(m,2H),7.45–7.23(m,2H),7.15–6.95(m,1H),6.79(s,1H),6.70–6.59(m,1H),5.06(dd ,1H),4.24–4.07(m,2H),3.80–3.65(m,2H),3.12–2.57(m,13H),2.41–2.28(m,1H),2.12–1.89(m,2H),1.02 –0.90(m,2H),0.79–0.61(m,2H).
生物测试例biological test case
测试例1：Jurkat细胞中SLP76磷酸化水平检测Test Example 1: Detection of SLP76 Phosphorylation Level in Jurkat Cells
来源于ATCC的Jurkat细胞置于RPMI-1640完全培养基(添加10％FBS与1％双抗)，在37℃、5％CO2条件下培养。收集处于对数生长期的细胞，用培养基调整细胞密度至5×105个/孔，以1mL/孔的体积加入6孔细胞培养板中。配制待测化合物至终浓度的3倍，给药孔加入500μL不同浓度的化合物，对照孔加入含0.3％DMSO的培养基，于37℃、5％CO2条件下孵育4小时。加入500μL CD3抗体(BD，Cat#555329；终浓度为1μg/mL)，在37℃、5％CO2条件下孵育10分钟。孵育结束后，收集细胞于1.5mL离心管中，用预冷PBS洗涤2次。将蛋白酶抑制剂混合物、磷酸酶抑制剂与裂解液按1:1:100配制后，每个样品加入10μL裂解液重悬细胞，于冰上放置15分钟，期间反复震荡，至细胞彻底裂解后，于12000转/分钟、4℃条件下离心15分钟，收集上清，用BCA法测定蛋白含量。将待测蛋白样品稀释至2mg/mL与0.8mg/mL，用全自动蛋白质表达定量分析仪(ProteinSimple)检测磷酸化的SLP76(p-SLP76)与SLP76总蛋白水平(抗体均来源于CST)。使用全自动蛋白质表达定量分析仪的软件(Compass for SW)进行原始数据处理，计算峰面积A，按A[p-SLP76]/A[SLP76]计算相对于SLP76总蛋白的p-SLP76表达水平R，并按[1-(R给药孔-R阴性 对照)/(R阳性对照-R阴性对照)]×100％计算p-SLP76的抑制率，其中R阴性对照为只加入含0.3％DMSO培养基的对照孔，R阳性对照为加入CD3抗体的对照孔。使用Graphpad 8.3.0软件中的四参数非线性拟合模型计算IC50值。Jurkat cells derived from ATCC were placed in RPMI-1640 complete medium (adding 10% FBS and 1% double antibody), and cultured at 37°C and 5% CO 2 . Collect the cells in the logarithmic growth phase, adjust the cell density to 5×10 5 cells/well with medium, and add them to a 6-well cell culture plate at a volume of 1 mL/well. Prepare the compound to be tested to 3 times the final concentration, add 500 μL of different concentrations of the compound to the administration well, add the medium containing 0.3% DMSO to the control well, and incubate for 4 hours at 37°C and 5% CO 2 . Add 500 μL of CD3 antibody (BD, Cat#555329; final concentration 1 μg/mL) and incubate at 37° C., 5% CO 2 for 10 minutes. After the incubation, the cells were collected in a 1.5 mL centrifuge tube and washed twice with pre-cooled PBS. After preparing the protease inhibitor mixture, phosphatase inhibitor and lysate at a ratio of 1:1:100, add 10 μL of lysate to each sample to resuspend the cells, place on ice for 15 minutes, and shake repeatedly until the cells are completely lysed. Centrifuge at 12,000 rpm and 4°C for 15 minutes, collect the supernatant, and use the BCA method to determine the protein content. The protein samples to be tested were diluted to 2 mg/mL and 0.8 mg/mL, and the phosphorylated SLP76 (p-SLP76) and SLP76 total protein levels were detected with an automatic protein expression quantitative analyzer (ProteinSimple) (both antibodies were derived from CST). Use the software (Compass for SW) of the automatic protein expression quantitative analyzer to process the raw data, calculate the peak area A, and calculate the expression level R of p-SLP76 relative to the total protein of SLP76 by A [p-SLP76] /A [SLP76] , and calculate the inhibition rate of p-SLP76 according to [1-(R administration hole -R negative control )/(R positive control -R negative control )]×100%, wherein the R negative control is only added with 0.3% DMSO culture Base control wells, R positive control is the control wells with CD3 antibody added. IC50 values were calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software.
表1测试化合物在1μM下对Jurkat细胞中p-SLP76的抑制率

Table 1 The inhibitory rate of test compounds to p-SLP76 in Jurkat cells at 1 μM

注：表1中A≥75％，75％>B≥45％，45％>CNote: In Table 1, A≥75%, 75%>B≥45%, 45%>C
结论：本申请化合物对Jurkat细胞中SLP76的磷酸化有良好抑制作用，例如化合物11IC50<0.1nM。Conclusion: The compounds of the present application have a good inhibitory effect on the phosphorylation of SLP76 in Jurkat cells, for example, compound 11 IC 50 <0.1nM.
测试例2：Jurkat细胞中HPK1蛋白表达水平检测Test Example 2: Detection of HPK1 protein expression level in Jurkat cells
来源于ATCC的Jurkat细胞置于RPMI-1640完全培养基(添加10％FBS与1％双抗)，在37℃、5％CO2条件下培养。收集处于对数生长期的细胞，用培养基调整细胞密度至5×105个/孔，以1mL/孔的体积加入6孔细胞培养板中。配制待测化合物至终浓度的2倍，给药孔加入1mL不同浓度的化合物，对照孔加入含0.2％DMSO的培养基，于37℃、5％CO2条件下孵育48小时。收集细胞于1.5mL离心管中，加入25μL RIPA裂解液(含1X蛋白酶抑制剂混合物)，于冰上裂解15分钟后，在12000转/分钟、4℃条件下离心10分钟，收集上清，用BCA法测定蛋白含量。将待测蛋白样品稀释至0.2mg/mL，用全自动蛋白质表达定量分析仪(ProteinSimple)检测HPK1，内参蛋白为β-actin(抗体均来源于CST)。使用全自动蛋白质表达定量分析仪的软件(Compass for SW)进行原始数据处理，计算峰面积以及相对于对照组的HPK1降解率。按照A给药孔/A对照孔×100％计算HPK1的抑制率，其中A给药 孔为给药组相对峰面积，A对照孔为溶媒对照组相对峰面积。使用Graphpad 8.3.0软件中的四参数非线性拟合模型计算DC50值。Jurkat cells derived from ATCC were placed in RPMI-1640 complete medium (adding 10% FBS and 1% double antibody), and cultured at 37°C and 5% CO 2 . Collect the cells in the logarithmic growth phase, adjust the cell density to 5×10 5 cells/well with medium, and add them to a 6-well cell culture plate at a volume of 1 mL/well. Prepare the compound to be tested to 2 times the final concentration, add 1 mL of the compound at different concentrations to the administration well, add 0.2% DMSO-containing medium to the control well, and incubate at 37°C, 5% CO 2 for 48 hours. Collect the cells in a 1.5mL centrifuge tube, add 25μL RIPA lysate (containing 1X protease inhibitor mixture), lyse on ice for 15 minutes, centrifuge at 12,000 rpm and 4°C for 10 minutes, collect the supernatant, and use Protein content was determined by BCA method. The protein sample to be tested was diluted to 0.2 mg/mL, and HPK1 was detected with an automatic protein expression quantitative analyzer (ProteinSimple), and the internal reference protein was β-actin (all antibodies were derived from CST). The software (Compass for SW) of the automatic protein expression quantitative analyzer was used for raw data processing, and the peak area and the degradation rate of HPK1 relative to the control group were calculated. The HPK1 inhibition rate was calculated according to A administration well /A control well × 100%, wherein A administration well was the relative peak area of the administration group, and A control well was the relative peak area of the vehicle control group. DC50 values were calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software.
表2测试化合物在1μM下对Jurkat细胞中HPK1的降解率
Table 2 Degradation rate of test compounds to HPK1 in Jurkat cells at 1 μM
表3测试化合物对Jurkat细胞中HPK1的DC50
Table 3 test compound to the DC 50 of HPK1 in Jurkat cells
结论：本申请化合物对HPK1激酶有降解作用。Conclusion: the compound of the present application can degrade HPK1 kinase.
测试例3：小鼠药代动力学测试Test Example 3: Pharmacokinetic test in mice
试验动物：雄性ICR小鼠，25～30g。购于成都达硕实验动物有限公司。Test animals: male ICR mice, 25-30g. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验设计：试验当天，ICR小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental Design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
表4给药信息
Table 4 Dosing Information
静脉给药溶媒：10％DMA+10％Solutol+80％SalineIntravenous administration vehicle: 10% DMA+10% Solutol+80% Saline
灌胃给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-β-CD)Oral administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-β-CD)
(DMA：N,N-二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；PEG400：聚乙二醇400；SBE-β-CD：磺丁基-β-环糊精)(DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl -β-cyclodextrin)
于给药前及给药后异氟烷麻醉经眼眶取血0.03mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。采血时间点为0,5,15,30min,1,2,4,7,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 0.03 mL of blood was collected through the orbit under isoflurane anesthesia, placed in an EDTAK 2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood collection time points are 0, 5, 15, 30min, 1, 2, 4, 7, 24h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.
表5测试化合物在小鼠血浆中的药代动力学参数

Table 5 Pharmacokinetic parameters of test compounds in mouse plasma

*iv的溶媒为5％DMA+5％Solutol+90％Saline*iv’s solvent is 5% DMA+5% Solutol+90% Saline
结论：本发明化合物具有良好的口服吸收。Conclusion: The compound of the present invention has good oral absorption.
对照化合物1的结构如下，其合成参照专利WO2016205942A1。
The structure of reference compound 1 is as follows, and its synthesis refers to patent WO2016205942A1.
测试例4：大鼠药代动力学测试Test Example 4: Rat pharmacokinetic test
试验动物：雄性SD大鼠，200～220g左右，6～8周龄。购于成都达硕实验动物有限公司。Test animals: male SD rats, about 200-220 g, aged 6-8 weeks. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验设计：试验当天，SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
表6给药信息
Table 6 Dosing Information
静脉给药溶媒：5％DMA+5％Solutol+90％SalineIntravenous administration vehicle: 5% DMA+5% Solutol+90% Saline
灌胃给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-β-CD)Oral administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-β-CD)
(DMA：N,N-二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；PEG400：聚乙二醇400；SBE-β-CD：磺丁基-β-环糊精)(DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl -β-cyclodextrin)
于给药前及给药后异氟烷麻醉经眼眶取血0.15mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。采血时间点为0,5,15,30min,1,2,4,6,7,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。 Before and after administration, 0.15 mL of blood was collected through the orbit under isoflurane anesthesia, placed in an EDTAK 2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood collection time points are 0, 5, 15, 30min, 1, 2, 4, 6, 7, 24h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.
测试例5：比格犬药代动力学测试Test Example 5: Beagle Pharmacokinetic Test
试验动物：雄性比格犬，8～10kg左右，购于北京玛斯生物技术有限公司。Experimental animals: male Beagle dogs, about 8-10 kg, purchased from Beijing Masi Biotechnology Co., Ltd.
试验设计：试验当天，比格犬按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental Design: On the day of the experiment, Beagle dogs were randomly divided into groups according to body weight. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
表7给药信息
Table 7 Dosing Information
静脉给药溶媒：5％DMA+5％Solutol+90％SalineIntravenous administration vehicle: 5% DMA+5% Solutol+90% Saline
灌胃给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-β-CD)Oral administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-β-CD)
(DMA：N,N-二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；PEG400：聚乙二醇400；SBE-β-CD：磺丁基-β-环糊精)(DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl -β-cyclodextrin)
于给药前及给药后通过颈静脉或四肢静脉取血1mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。采血时间点为0,5,15,30min,1,2,4,7,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 mL of blood was collected from the jugular vein or limb vein, placed in an EDTAK 2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. Blood collection time points are 0, 5, 15, 30min, 1, 2, 4, 7, 24h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.
结论：本发明化合物具有良好的犬药代动力学性能，例如化合物11的口服生物利用度为56.5％，对照化合物1为13.9％。Conclusion: the compounds of the present invention have good canine pharmacokinetic properties, for example, the oral bioavailability of compound 11 is 56.5%, and that of the control compound 1 is 13.9%.
测试例6：hERG钾离子通道作用测试Test Example 6: hERG Potassium Channel Action Test
实验平台：电生理手动膜片钳系统Experimental Platform: Electrophysiological Manual Patch Clamp System
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(IhERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。Experimental method: In CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, the current of hERG potassium channel was recorded by whole-cell patch clamp technique at room temperature. The glass microelectrode is made of a glass electrode blank (BF150-86-10, Sutter) drawn by a drawing machine. The tip resistance after filling the electrode inner liquid is about 2-5MΩ. Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After whole-cell recordings were obtained, the cells were clamped at -80mV, and the voltage step of the evoked hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s. back to -80mV. Give this voltage stimulation every 10s, and start the administration process after confirming that the hERG potassium current is stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells (n > 2) were tested at each concentration.
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak value of hERG tail current evoked at -50mV) by different compound concentrations was calculated by the following formula:
Inhibition％＝[1–(I/Io)]×100％Inhibition%＝[1–(I/Io)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。Wherein, Inhibition% represents the inhibitory percentage of the compound on the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current after and before the drug addition, respectively.
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。Wherein, X is the Log value of the detected concentration of the test substance, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages, respectively.
结论：本发明化合物对hERG抑制弱。Conclusion: the compound of the present invention has weak inhibition on hERG.
测试例7：CYP450酶抑制测试Test Example 7: CYP450 Enzyme Inhibition Test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。The purpose of this study is to use an in vitro test system to evaluate the effect of the test substance on the activity of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP). Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, measure the change of CYP enzyme activity, calculate the IC50 value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms.
结论：本发明化合物对CYP酶抑制弱。 Conclusion: the compounds of the present invention have weak inhibition on CYP enzymes.

Claims (15)

  1. 一种化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物，
    B-L-K(I)；    A compound or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group represented by general formula (I) compound of,
    BLK(I);
    L选自键或-C1-50烃基-，所述烃基中有0至20个亚甲基单元任选进一步被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbon group-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
    每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-任选进一步被0至2个选自H、卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, - NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C( =O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH=CH-, -Si( R L ) 2 -, -Si(OH)( RL )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)( RL )-, - S-, -S(=O)-, -S(=O) 2 - or a bond, the -CH 2 - is optionally further replaced by 0 to 2 selected from H, halogen, OH, CN, NH 2 , Substituents of C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl ;
    q各自独立的选自0、1、2、3、4、5或6；q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
    RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述杂芳基含有1至4个选自O、S、N的杂原子； RL are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
    每个-Cy-各自独立地选自键、4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocyclic ring Alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the aryl, Heteroaryl, cycloalkyl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings are optionally further represented by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2. Substituents of =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy, the heteroaryl Base, heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally further 0, 1 or 2 One=O replaces;
    B选自 B from
    Z1、Z2或Z3各自独立的选自S、Se、N、NRz或CRz；Z 1 , Z 2 or Z 3 are each independently selected from S, Se, N, NR z or CR z ;
    Rz选自H、卤素、氰基、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-8碳环基或3至8元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, the said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    作为选择，任意两个Rz直接连接，形成C4-8碳环或者4至8元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Alternatively, any two R z are directly connected to form a C 4-8 carbocycle or a 4 to 8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-6烷基、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子； R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(= O)-R a2 , C 1-6 alkyl, C 3-10 carbocycle or 3 to 10 membered heterocycle, said alkyl, carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1 -6 alkoxy substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    Ra1、Ra2各自独立的选自H、C1-6烷基、-C1-4烷基-C3-10碳环、-C1-4烷基-3至10元杂环、C3-10碳环或3至10元杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基或C1-6烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C 1-4 alkyl-C 3-10 carbocycle, -C 1-4 alkyl-3 to 10 membered heterocycle, C 3-10 carbocyclic rings or 3-10 membered heterocyclic rings, the alkyl, carbocyclic or heterocyclic rings are optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, NH 2 , C 1-6 Alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or C 1-6 alkoxy substituents, said The heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    R2选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-6烷基的取代基所取代；R 2 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-6 alkyl substituents;
    X1选自O、S、NRx，X2选自N、CRx；X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
    Rx各自独立的选自H、卤素、氰基、OH、C1-6烷基、C1-6烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代；R x are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-6 alkyl, C 1-6 alkoxy or C selected from H, halogen, OH, cyano , NH 2 , C 1-6 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
    环B1选自苯环或者5至6元杂芳环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
    R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烷基)、C1-6烷基、C1-6烷氧基、C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基、炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-6烷基、C1-6烷基、C1-6烷氧基、C3-6环烷基或4至8元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl, alkynyl C 1-6 alkyl , C 1-6 alkyl, C 1-6 alkoxy, C 3- Substituted by a 6- cycloalkyl group or a 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    K选自 K selected from
    Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或3-12元杂环基，所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, so The heterocyclic group mentioned above is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1- 4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rq选自H或C1-6烷基；R is selected from H or C 1-6 alkyl;
    A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环或杂芳基含有1至4个选自O、S、N的杂原子；A is selected from C 3-10 carbocyclic group, C 6-10 aryl group, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, and the heterocyclic ring or heteroaryl group contains 1 to 4 members selected from O , S, N heteroatoms;
    F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S、N的杂原子；F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclic group or 5-20 membered heteroaryl, and the heterocyclic group or heteroaryl contains 1 to 4 a heteroatom selected from O, S, N;
    Rk2各自独立地选自键、-CO-、-SO2-、-SO-或-C(Rk3)2-；Each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
    Rk1或Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；R k1 or R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further replaced by 0 to 4 selected from H, F, Cl, Br , I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heterocycle The group contains 1 to 4 heteroatoms selected from O, S, N;
    或者两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-8元碳环或3-8元杂环，所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S、N的杂原子；Or two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocycle or a 3-8 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by O to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
    Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；R k4 are each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, cycloalkane The group or the heterocyclic group is optionally further replaced by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1- 4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from a bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
    M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子； M2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclic group, the alkyl, cycloalkyl Or the heterocyclic group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
    Rk10选自C1-6烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and said alkyl is optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3 Substituents of -6 cycloalkyl are substituted;
    Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基或C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 are each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, C 1-4 Substituents of alkyl or C 1-4 alkoxy;
    Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, F, Substituted by Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
    Rk14选自5-6元杂芳基，所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、 ＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O、S的杂原子；R k14 is selected from 5-6 yuan heteroaryl, and the heteroaryl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkoxy or C 3-6 cycloalkyl The substituent is substituted, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O, S;
    G选自6-10元芳基或5-10元杂芳基，所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O、S的杂原子；G is selected from 6-10 membered aryl groups or 5-10 membered heteroaryl groups, and the aryl group or heteroaryl group is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, = O, CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkoxy or C 3-6 cycloalkyl Replaced by a substituent, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, S;
    n1、n2、n3各自独立的选自0、1、2或3；n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
    p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  2. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2- Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2- Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4- Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2- Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7- Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
    Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、卤素、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further C 1-4 substituted by 0 to 2 selected from H, halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxyl Alkyl, cyano substituted C 1-4 alkyl substituents;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键、4-7元杂单环、4-10元杂并环、5-12元杂 螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterocyclic ring, Spiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 Member heteroaryl or 6-10 member aryl, said aryl, heteroaryl, cycloalkyl, heteromonocycle, heteroheterocycle, heterospiro ring or heterobridged ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C Substituted by 1-4 alkoxy substituents, the heteroaryl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings contain 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;
    q各自独立的选自0、1、2、3或4；q are each independently selected from 0, 1, 2, 3 or 4;
    RL各自独立的选自H或C1-6烷基。 RL are each independently selected from H or C 1-6 alkyl.
  3. 根据权利要求2所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 2 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、C1-4烷基、C1-4烷氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further Substituted by 0 to 2 substituents selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 1-4 alkoxy ;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键、4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述杂单环、杂并环、杂桥环、杂螺环、环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选进一步被0、1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, 4-7 membered nitrogen-containing heteromonocyclic ring, 4-10 membered nitrogen-containing heterocyclic ring, 5-12 membered nitrogen-containing heterospirocyclic ring, 7-10 membered Nitrogen-containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl are optionally further replaced by 0 to 4 members selected from H, F, Cl , Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl or C 1-4 alkoxy The substituent of the base is substituted, and the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from When S, optionally further substituted by 0, 1 or 2 ═O;
    RL各自独立的选自H或C1-4烷基； RL are each independently selected from H or C 1-4 alkyl;
    Rz选自H、卤素、氰基、OH、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-7碳环基或3至7元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R z is selected from H, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Alkoxy, C 3-7 carbocyclyl or 3 to 7 membered heterocyclyl, said alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally further 0 to 4 selected from H, halogen , OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
    作为选择，任意两个Rz直接连接，形成C4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Alternatively, any two R z are directly connected to form a C 4-7 carbocycle or a 4 to 7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, Substituted by cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    R1选自H、卤素、氰基、NRa1Ra2、ORa1、-SO2-NRa1Ra2、-NRa1SO2-Ra2、-SO2-Ra2、-NRa1C(＝O)-Ra2、C1-4烷基、C3-6单环碳环、4至8元单环杂环，所述的烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；R 1 is selected from H, halogen, cyano, NR a1 R a2 , OR a1 , -SO 2 -NR a1 R a2 , -NR a1 SO 2 -R a2 , -SO 2 -R a2 , -NR a1 C(= O)-R a2 , C 1-4 alkyl, C 3-6 monocyclic carbocyclic ring, 4 to 8 membered monocyclic heterocyclic ring, said alkyl, carbocyclic or heterocyclic ring is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkane Substituent group or C 1-4 alkoxy group, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
    Ra1选自H、C1-4烷基；R a1 is selected from H, C 1-4 alkyl;
    Ra2选自H、C1-4烷基、-C1-2烷基-C3-6单环芳环、-C1-2烷基-C3-6单环非芳香环、-C1-2烷基-5至6元芳杂环、-C1-2烷基-4至8元单环非芳香杂环、C5-6单环芳环、C3-6单环非芳香环、5至6元芳杂环、4至8元单环非芳香杂环，所述的烷基、芳环、非芳香环、芳杂环、非芳香杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代 的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的芳杂环、杂环含有1至3个选自O、S、N的杂原子；R a2 is selected from H, C 1-4 alkyl, -C 1-2 alkyl-C 3-6 monocyclic aromatic ring, -C 1-2 alkyl-C 3-6 monocyclic non-aromatic ring, -C 1-2 alkyl-5 to 6-membered aromatic heterocycle, -C 1-2 alkyl-4 to 8-membered monocyclic non-aromatic heterocycle, C 5-6 monocyclic aromatic ring, C 3-6 monocyclic non-aromatic ring, 5 to 6 membered aromatic heterocyclic ring, 4 to 8 membered monocyclic non-aromatic heterocyclic ring. selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl or C 1-4 alkoxy substituents, the aromatic heterocycle, heterocycle contains 1 to 3 selected from O, S, N heteroatoms;
    R2选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、C1-4烷基的取代基所取代；R 2 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, C Substituted by 1-4 alkyl substituents;
    X1选自O、S、NRx，X2选自N、CRx；X 1 is selected from O, S, NR x , X 2 is selected from N, CR x ;
    Rx各自独立的选自H、卤素、氰基、OH、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R x are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or ring Alkyl is optionally further substituted with 0 to 4 C 1-4 alkyl, C 1-4 alkoxy or C selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 3-6 cycloalkyl substituents are substituted;
    环B1选自苯环或者5至6元杂芳环，所述的杂芳环含有1至3个选自O、S、N的杂原子；Ring B1 is selected from a benzene ring or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S, and N;
    R3各自独立的选自H、卤素、OH、氰基、NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基，C3-6环烷基、C2-6炔基，所述的烷基、烷氧基、环烷基、炔基任选进一步被0至4个选自H、卤素、OH、氰基、NH2、卤素取代的C1-4烷基、C1-4烷基、C1-4烷氧基、C3-6环烷基或4至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S、N的杂原子；Each R 3 is independently selected from H, halogen, OH, cyano, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -NH(C 3-6 ring Alkyl), C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, said alkyl, alkoxy, cycloalkyl, alkynyl C 1-4 alkyl , C 1-4 alkyl, C 1-4 alkoxy, C 3- Substituted by a 6- cycloalkyl group or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    K选自
    K selected from
    表示环选自芳香环或非芳香环； Indicates that the ring is selected from an aromatic ring or a non-aromatic ring;
    Q各自独立地选自-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或4-7元杂环基，所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S、N的杂原子；Each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocyclic group, the The heterocyclic group is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkane Oxygen substituents are substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rq选自H或C1-4烷基；R is selected from H or C 1-4 alkyl;
    Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基,所述烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkane Oxygen group, the alkyl or alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH ;
    或者两个Rk1或两个Rk3和与二者直接相连的碳原子或环骨架共同形成3-6元碳环或3-7元杂环，所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S、N的杂原子；Or two R k1 or two R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by O to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
    Rk4各自独立的选自H、OH、NH2、CF3、CN、C1-4烷基；R k4 are each independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
    Rk5各自独立地选自C(CH3)2、CO、CH2、SO2、 R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
    Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；R K6 are each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
    Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
    Rk8各自独立地选自C、N或CH；Each R K8 is independently selected from C, N or CH;
    Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2；R k9 are each independently selected from a bond, C( CH3 ) 2 , CO, CH2 , CH2CH2 or SO2 ;
    A、H1或H2各自独立地选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳基，所述杂环或杂芳 基含有1至4个选自O、S、N的杂原子；A, H1 or H2 are each independently selected from C3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaryl group, the heterocyclic ring or heteroaryl The group contains 1 to 4 heteroatoms selected from O, S, N;
    E各自独立地选自C3-8碳环、苯环、4-7元杂环、8-12元杂环基、7-12元杂芳基或5-6元杂芳基，所述杂环或杂芳基含有1至4个选自O、S、N的杂原子；E are each independently selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring, 8-12 membered heterocyclic group, 7-12 membered heteroaryl group or 5-6 membered heteroaryl group, the heteroaryl The ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
    F各自独立地选自3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、4-7元杂单环、4-10元杂并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基或5-10元杂芳基，所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S、N的杂原子。F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, the heteromonocyclic, heterocyclic, heterocyclic The spiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, N.
  4. 根据权利要求3所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-或者键，所述的-CH2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O) NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, the -CH 2 - is optionally further Substituted by 0 to 2 substituents selected from H, F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, methyl, ethyl, methoxy or ethoxy;
    RL选自H、甲基或乙基； RL is selected from H, methyl or ethyl;
    q各自独立的选自0、1或2；q are each independently selected from 0, 1 or 2;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己烯基、哌啶、吗啉、哌嗪、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环戊基并哌啶、环己基并氮杂环丁基、环己基并氮杂环戊基、环己基并氮杂环己基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环戊基并哌啶、氮杂环己基并氮杂环丁基、氮杂环己基并氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基螺氮杂环丁基、环己基螺氮杂环戊基、环己基螺氮杂环己基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环丁基、氮杂环己基螺氮杂环戊基、氮杂环己基螺氮杂环己基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时，任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, nitrogen Heterocyclopentyl, aziridinyl, piperidine, morpholine, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropyl Cyclobutyl cyclohexyl, cyclobutyl cyclobutyl, cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl cyclohexyl, cyclo Propylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspiro Cyclohexyl, Cyclopentylspirocyclopentyl, Cyclopentylspirocyclohexyl, Cyclohexylspirocyclohexyl, Cyclopropylazetidinyl, Cyclopropylazepinyl, Cyclopropylazepine Cyclohexyl, cyclopropylpiperidine, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazepine, cyclobutylpiperidine, cyclopentyl Azetidinyl, Cyclopentylazetidinyl, Cyclopentylazetidinyl, Cyclopentylpiperidine, Cyclohexylazetidinyl, Cyclohexylazetidinyl, Cyclohexyl azetidinyl, cyclohexyl piperidine, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, nitrogen Heterocyclopentyl azetidinyl, azacyclopentyl azetidinyl, azacyclopentyl azetidinyl, azacyclopentyl azacyclohexyl, azacyclopentyl azetidinyl Pyridine, azacyclohexylazetidinyl, azacyclohexylazetidinyl, azacyclohexylazetidinyl, azacyclohexylpiperidine, cyclobutylspiroazetidinyl base, cyclobutylspiroazacyclopentyl, cyclobutylspiroazepinexyl, cyclopentylspiroazetidinyl, cyclopentylspiroazepine, cyclopentylspiroazepine, Cyclohexylspiroazetidinyl, Cyclohexylspiroazetidinyl, Cyclohexylspiroazetidinyl, Azetidinylspiroazetidinyl, Azetidinylspiroazetidinyl, Azetidinylspiroazetidinyl, Azacyclopentylspiroazetidinyl, Azacyclopentylspiroazacyclopentyl, Azacyclopentylspiroazepinyl, Azacyclohexyl Spiroazetidinyl, Azacyclohexylspiroazacyclopentyl, Azacyclohexylspiroazepinyl, Cyclobutylspiropiperidine, Cyclopentylspiropiperidine, Cyclohexylspiropiperidine, Azepine Cyclobutyl spiropiperidine, Azacyclopentyl spiropiperidine, Azacyclohexyl spiropiperidine, When substituted, C 1- optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen 4 alkyl, hydroxyl substituted C 1-4 alkyl or C 1-4 alkoxy substituents;
    选自 selected from
    Rz选自H、F、Cl、Br、I、NH2、氰基、OH、NHCH3、NHCH2CH3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环己基、环戊基、氮杂环丁基、氮杂环戊基、哌啶基、哌嗪基；R z is selected from H, F, Cl, Br, I, NH 2 , cyano, OH, NHCH 3 , NHCH 2 CH 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl Base, cyclohexyl, cyclopentyl, azetidinyl, azacyclopentyl, piperidinyl, piperazinyl;
    作为选择，任意两个Rz直接连接，形成5元碳环基、6元碳环基或7元碳环基；Alternatively, any two Rz are directly connected to form a 5-membered carbocyclyl, a 6-membered carbocyclyl or a 7-membered carbocyclyl;
    R1选自H、F、Cl、Br、I、氰基、OH、甲氧基、乙氧基、NHRa2、-NHSO2-Ra2、-NHC(＝O)-Ra2、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉或哌嗪；R 1 is selected from H, F, Cl, Br, I, cyano, OH, methoxy, ethoxy, NHR a2 , -NHSO 2 -R a2 , -NHC(=O)-R a2 , cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azecyclohexyl, oxetanyl, oxolyl, oxanyl, morpholine or piperidine Zinc;
    Ra2选自H、取代或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、哌嗪、吡啶、苯基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉、-CH2-哌嗪、-CH2-吡啶、-CH2-苯基，当被取代时，任选进一步被0至4个选自H、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代；R a2 is selected from one of H, substituted or unsubstituted following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolyl, Oxanyl, Morpholine, Piperazine, Pyridine, Phenyl, -CH 2 -Cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, -CH 2 -oxolyl, -CH 2 -oxanyl, -CH 2 -morpholine, -CH 2 -piperazine, -CH 2 -pyridine, - CH 2 -phenyl, when substituted, is optionally further substituted with 0 to 4 C 1-4 alkyl selected from H , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkyl substituted by hydroxy, C 1-4 alkyl substituted by cyano or C 1-4 alkoxy substituent;
    R2选自H；R is selected from H;
    X1选自NH； X is selected from NH;
    X2选自N或CH； X2 is selected from N or CH;
    环B1选自苯环、吡啶、嘧啶；Ring B 1 is selected from benzene ring, pyridine, pyrimidine;
    R3各自独立的选自H、F、Cl、Br、I、OH、氰基、NH2、甲基、乙基、甲氧基、环丙基、乙炔基、丙炔基； R 3 are each independently selected from H, F, Cl, Br, I, OH, cyano, NH 2 , methyl, ethyl, methoxy, cyclopropyl, ethynyl, propynyl;
    K选自
    K selected from
    E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基； E are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
    A各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基；A is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
    F各自独立地选自环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、萘并呋喃基、噻吩并吲哚基、氮杂环丁基、氮杂环戊基、哌啶基、吗啉基、吡啶基、吡啶酮基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并噁唑基、吡啶并咪唑基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基或吡嗪并吡嗪基；F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6,7-dihydro-5H-cyclopenta [c] pyridyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, naphthofuryl, thienoindolyl, azetidinyl, azacyclopentyl, piperidinyl, morphine Linyl, pyridyl, pyridinyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazole base, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzene Pyridazinyl, benzoxazolyl, pyridimidazolyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazo Pyridyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazine base, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl ;
    Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
    p1或p2各自独立的选自0、1或2。p1 or p2 are each independently selected from 0, 1 or 2.
  5. 根据权利要求4所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 4 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自键、-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH -, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O) CH2NH- , -CH2C (=O)NH-, -C(=O)NH- or -NHC(=O)-;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：

    Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted:

    当被取代时，任选进一步被0至4个选自H、F、CF3、甲基、＝O、羟甲基、COOH、CN或NH2的取代基所取代；When substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF 3 , methyl, =O, hydroxymethyl, COOH, CN or NH 2 ;
    B选自表B-1所示的结构片段之一；B is selected from one of the structural fragments shown in Table B-1;
    K选自表K-1所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-1.
  6. 根据权利要求5所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 5 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-。L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2- Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3- , -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3- , -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4- , -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1- Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2- Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3- Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4- Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-.
  7. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键或表L-1所示的基团，其中基团左侧与B连接。L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B.
  8. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键或表L-2所示的基团，其中基团左侧与B连接；L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;
    K选自表K-2所示的基团。K is selected from the groups shown in Table K-2.
  9. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前 药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表S-1结构之一。The compound according to claim 1 or its stereoisomer, tautomer, deuterium, solvate, pro Drug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table S-1.
  10. 一种药物组合物，包括权利要求1-9任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。A pharmaceutical composition, comprising the compound described in any one of claims 1-9 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt Or co-crystal, and pharmaceutically acceptable carrier.
  11. 权利要求1-9任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与HPK1激酶活性或表达量相关疾病的药物中的应用。The compound described in any one of claims 1-9 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation Application of the medicine in treating diseases related to HPK1 kinase activity or expression level.
  12. 一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含选1-1500mg的权利要求1-9任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和药用赋型剂。A pharmaceutical composition or pharmaceutical preparation, said pharmaceutical composition or pharmaceutical preparation comprising selecting 1-1500mg of the compound described in any one of claims 1-9 or its stereoisomers, tautomers, deuterium Substitutes, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals and pharmaceutical excipients.
  13. 权利要求1-9任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解HPK1激酶相关疾病的药物中的应用。The compound described in any one of claims 1-9 or its stereoisomer, tautomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation Application in medicines for treating diseases related to inhibiting or degrading HPK1 kinase.
  14. 根据权利要求11或13所述的应用，其中，所述的疾病选自癌症。The use according to claim 11 or 13, wherein said disease is selected from cancer.
  15. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-9任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求10所述的药物组合物或权利要求12所述的药物组合物或药物制剂，治疗有效量优选1-1500mg，所述的疾病优选癌症。 A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-9 or its stereoisomer, tautomer, deuterium Substitutes, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals or the pharmaceutical composition described in claim 10 or the pharmaceutical composition or pharmaceutical preparation described in claim 12, the therapeutically effective amount is preferably 1- 1500mg, the disease is preferably cancer.
PCT/CN2023/073180 2022-01-27 2023-01-19 Compound for inhibiting or degrading hpk1 kinase and medical use thereof WO2023143384A1 (en)

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Citations (5)

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CN107922431A (en) * 2015-06-25 2018-04-17 大学健康网络 HPK1 inhibitor and its application method
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
WO2021178920A1 (en) * 2020-03-05 2021-09-10 C4 Therapeutics, Inc. Compounds for targeted degradation of brd9
WO2021207828A1 (en) * 2020-04-13 2021-10-21 University Health Network Methods for treating cytokine release syndrome
WO2021226707A1 (en) * 2020-05-11 2021-11-18 University Health Network Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1h-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7h)-one

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CN107922431A (en) * 2015-06-25 2018-04-17 大学健康网络 HPK1 inhibitor and its application method
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
WO2021178920A1 (en) * 2020-03-05 2021-09-10 C4 Therapeutics, Inc. Compounds for targeted degradation of brd9
WO2021207828A1 (en) * 2020-04-13 2021-10-21 University Health Network Methods for treating cytokine release syndrome
WO2021226707A1 (en) * 2020-05-11 2021-11-18 University Health Network Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1h-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7h)-one

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