WO2023143384A1 - Composé pour inhiber ou dégrader la kinase hpk1 et son utilisation médicale - Google Patents

Composé pour inhiber ou dégrader la kinase hpk1 et son utilisation médicale 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.

Abstract

La présente invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un tautomère, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un eutectique de celui-ci, un intermédiaire de ceux-ci et une utilisation de ceux-ci pour une maladie liée à la kinase HPK1 telle qu'un cancer. B-L-K (I)
PCT/CN2023/073180 2022-01-27 2023-01-19 Composé pour inhiber ou dégrader la kinase hpk1 et son utilisation médicale WO2023143384A1 (fr)

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CN202210548396 2022-05-20
CN202210548396.8 2022-05-20
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922431A (zh) * 2015-06-25 2018-04-17 大学健康网络 Hpk1抑制剂及其使用方法
CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途
WO2021178920A1 (fr) * 2020-03-05 2021-09-10 C4 Therapeutics, Inc. Composés pour la dégradation ciblée de la brd9
WO2021207828A1 (fr) * 2020-04-13 2021-10-21 University Health Network Procédés de traitement du syndrome de libération de cytokines
WO2021226707A1 (fr) * 2020-05-11 2021-11-18 University Health Network Formes salines et cristallines de 4-amino-5-(6-(4-méthylpipérazin-1-yl)-1h-benzo[d]imidazol-2-yl)thiéno[2,3-b]pyridin-6(7h)-one

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922431A (zh) * 2015-06-25 2018-04-17 大学健康网络 Hpk1抑制剂及其使用方法
CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途
WO2021178920A1 (fr) * 2020-03-05 2021-09-10 C4 Therapeutics, Inc. Composés pour la dégradation ciblée de la brd9
WO2021207828A1 (fr) * 2020-04-13 2021-10-21 University Health Network Procédés de traitement du syndrome de libération de cytokines
WO2021226707A1 (fr) * 2020-05-11 2021-11-18 University Health Network Formes salines et cristallines de 4-amino-5-(6-(4-méthylpipérazin-1-yl)-1h-benzo[d]imidazol-2-yl)thiéno[2,3-b]pyridin-6(7h)-one

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