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WO2021043077A1 - Composé de pyrazine substituée et procédé de préparation correspondant et son utilisation - Google Patents

Composé de pyrazine substituée et procédé de préparation correspondant et son utilisation Download PDF

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Publication number
WO2021043077A1
WO2021043077A1 PCT/CN2020/112003 CN2020112003W WO2021043077A1 WO 2021043077 A1 WO2021043077 A1 WO 2021043077A1 CN 2020112003 W CN2020112003 W CN 2020112003W WO 2021043077 A1 WO2021043077 A1 WO 2021043077A1
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alkyl
group
cycloalkyl
compound
membered
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Chinese (zh)
Inventor
陈寿军
易磊
宋智泉
王太津
宋立强
王波
刘谦
陈慧萍
杨禹
田强
宋宏梅
薛彤彤
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN202080049558.2A priority Critical patent/CN114127053B/zh
Publication of WO2021043077A1 publication Critical patent/WO2021043077A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a substituted pyrazine compound used as an inhibitor of SHP2 (src homology 2 domain containing phosphotyrosine phosphatase 2), a preparation method thereof, a pharmaceutical composition and its use in the treatment of SHP2 enzyme-related diseases ( Also referred to as "SHP2 phosphatase related diseases” or “SHP2 related diseases”).
  • SHP2 src homology 2 domain containing phosphotyrosine phosphatase 2
  • SHP2 phosphatase related diseases also referred to as "SHP2 phosphatase related diseases” or "SHP2 related diseases”
  • SHP2 is a protein tyrosine phosphatase encoded by the gene PTPN11. It is an intracellular non-receptor member of the PTP family and catalyzes the dephosphorylation of protein tyrosine.
  • SHP2 has two N-terminal SH2 (Srchomology 2) domains (N-SH2 and C-SH2), a protein tyrosine phosphatase (PTP) catalytic domain, and a proline-rich group and tyrosine C-terminal tail of phosphorylation site. These two SH2 domains control the subcellular localization and functional regulation of SHP2.
  • SHP2 In the inactivated state, SHP2 is in a self-inhibited state, and the combination of N-SH2 and PTP inhibits phosphatase activity.
  • cytokines or inflammatory factors such as platelet-derived growth factor (PDGF) and FGF
  • PDGF platelet-derived growth factor
  • FGF platelet-derived growth factor
  • the phosphorylated tyrosine residues Tyr542 and Tyr580 bind to N-SH2
  • the structure of PTP Exposure of the catalytically active site of the domain, and then release the self-inhibition state activate the PTP activity of SHP2, thereby triggering the signal transduction cascade initiated by tyrosine phosphorylation.
  • SHP2 is widely expressed in the human body and participates in multiple signaling pathways such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR and NF-kB, and regulates cell proliferation, differentiation, migration, apoptosis and other physiological functions .
  • the activating mutant of SHP2 is related to the occurrence of many diseases, such as Noonan syndrome, breast cancer, and melanoma.
  • Overexpression of SHP2 can increase the risk of chronic myelogenous leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, suggesting that SHP2 has a wide range of roles in different types of cancers and different stages of cancer development.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism Substance or prodrug:
  • X is a direct bond or selected from S, O, NH and CH 2 ;
  • Y is a direct key
  • W 1 , W 2 and W 3 are each independently selected from CH and N;
  • R 1 is selected from H, -OH, -NH 2 , C 1-6 alkyl and C 3-6 cycloalkyl;
  • any two R 2 together with the atoms to which they are connected form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the hydrocarbon ring, heterocyclic ring, heteroaromatic ring
  • any one of R 2 and X together with the atoms to which they are connected forms a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein
  • the hydrocarbon ring, heterocyclic ring, heteroaromatic ring and benzene ring are each optionally selected from -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl). 2.
  • Substituent substitution of halogen, -CN, O, -OH, -OC 1-6 alkyl, halogenated C 1-6 alkyl and C 1-6 alkyl;
  • any two of R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b form a C 3-10 hydrocarbon ring or 4- 12-membered heterocyclic ring;
  • R 8a and R 8b together with the connected atoms (or direct bonds) form a C 3-8 hydrocarbon ring or a 3-12 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more From -N(R z ) 2 , -NH 2 , halogen, -CN, O, -OH, -OC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 Substituents of membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
  • g 0, 1 or 2;
  • n 0, 1, 2, 3, 4, or 5.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent Compounds, isotopically-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, Use of the metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases.
  • the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need thereof, Esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the present invention.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound,
  • the metabolite or prodrug or the pharmaceutical composition of the present invention is used to prevent or treat SHP2 phosphatase related diseases.
  • the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition.
  • the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope-labeled compound , Metabolites or prodrugs, or the pharmaceutical composition of the present invention combined with another treatment method for the prevention or treatment of SHP2 phosphatase-related diseases, the additional treatment method includes but not limited to: radiotherapy, chemotherapy, immunotherapy Therapies or combinations thereof.
  • Figure 1 shows the volume change of the subcutaneously transplanted tumor in the mouse model of Test Example 4.
  • Figure 2 shows the changes in the body weight of the mice in Test Example 4.
  • Fig. 3 shows the volume change of the subcutaneously transplanted tumor in the mouse model of Test Example 5.
  • Figure 4 shows the changes in the body weight of the mice in Test Example 5.
  • concentrations are by weight and ratios (including percentages) are by moles.
  • one (species) or more (species) can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
  • C 1-6 should be understood to cover any sub-range and each point value therein, such as C 2-5 , C 3-4 , C 1-2 , C 1-3 , C 1-4 , C 1-5 and so on, and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 and so on.
  • C 3-10 should also be understood in a similar manner, for example, it can cover any sub-range and point value contained therein, such as C 3-9 , C 6-9 , C 6-8 , C 6- 7. C 7-10 , C 7-9 , C 7-8 , C 8-9, etc.
  • the expression "3-10 yuan” should be understood to cover any sub-range and each point value, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan. Yuan, 3-9 Yuan, 4-5 Yuan, 4-6 Yuan, 4-7 Yuan, 4-8 Yuan, 5-7 Yuan, 5-8 Yuan, 6-7 Yuan, etc. and 3, 4, 5, 6 , 7, 8, 9, 10 yuan, etc.
  • the expression "5-10 yuan” should also be understood in a similar way, for example, it can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.
  • alkyl when used alone or in combination with other groups herein, refers to a saturated linear or branched hydrocarbon group.
  • C 1-6 alkyl refers to a saturated linear or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms).
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Pentyl or n-hexyl, etc.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group.
  • C 1-6 alkylene refers to a linear or branched divalent hydrocarbon group having 1 to 6 carbon atoms saturated. Including but not limited to methylene, ethylene, propylene or butylene.
  • cycloalkyl when used alone or in combination with other groups herein, refers to a saturated or partially saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl) , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.).
  • C 3 "-12 cycloalkyl refers to a cycloalkyl having 3-12 ring carbon
  • hydrocarbon ring when used herein alone or in combination with other groups, refers to a saturated or saturated or having, for example, 3-10 (suitably 5-8, more suitably 5-6) ring carbon atoms Unsaturated (that is, having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring, including but not limited to cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring , Cycloheptyl ring, cyclooctyl ring, cyclononyl ring, cyclohexenyl ring, etc.
  • halogen when used alone or in combination with other groups herein, means F, Cl, Br, or I.
  • alkenyl refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds.
  • C 2-6 alkenyl refers to a straight or branched hydrocarbon group having 2-6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon-carbon Double bond C 2-6 alkenyl.
  • Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl, etc.
  • alkynyl refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds.
  • C 2-6 alkynyl refers to a straight or branched hydrocarbon group having 2-6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing one carbon-carbon C 2-6 alkenyl with triple bond.
  • Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • heterocyclic group or "heterocyclic ring”, when used alone or in combination with other groups herein, means having, for example, 3-15 (suitably 3-8, more suitably 3-6)
  • a monocyclic or bicyclic non-aromatic ring system of ring atoms for example, 3-15 members, 3-8 members, 3-6 members), wherein at least one ring atom (for example, 1 or 2) is selected from N, O, P And S heteroatoms, and the remaining ring atoms are C.
  • the ring system may be a fused ring system, a bridged ring system or a spiro ring system.
  • the ring system can be saturated (also can be understood as the corresponding "heterocycloalkyl") or unsaturated (that is, having one or more double bonds and/or triple bonds in the ring).
  • heterocyclic groups include, but are not limited to: oxirane, sulfiethane, azaethyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrofuranyl, Hydrothienyl, dioxolyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, 1,4- Thioxanyl, 1,4-dioxanyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, etc.
  • aryl or "aromatic ring”, when used alone or in combination with other groups herein, refers to an all-carbon monocyclic or fused-ring polycyclic (such as bicyclic) aromatic group with a conjugated ⁇ -electron system Or aromatic ring.
  • C 6-10 aryl refers to an aromatic group containing 6-10 carbon atoms. Examples include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl or “heteroaromatic ring”, when used alone or in combination with other groups herein, refers to an aromatic group or aromatic ring with a conjugated ⁇ -electron system, one or more of which (such as 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C.
  • Heteroaryl or heteroaromatic rings can be characterized by the number of ring atoms. For example, a 5-10 membered heteroaryl group may contain 5-10 (e.g., 5, 6, 7, 8, 9 or 10) ring atoms, especially 5, 6, 9, 10 ring atoms.
  • heteroaryl or heteroaromatic ring may optionally be further benzo-fused.
  • heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, three Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzofuranyl, Benzothienyl, indolyl, isoindolyl, etc., and their benzo derivatives.
  • hydroxy means -OH.
  • cyano means -CN.
  • nitro means -NO 2 .
  • amino means -NH 2 .
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group , Provided that the normal valence of the specified atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • substituent can be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the atom or group may be independently selected, optional substituents Substitute. If substituents are described as being “independently selected from” or “each independently being”, then each substituent is independently selected from each other. Therefore, each substituent may be the same or different from another (other) substituent.
  • R groups such as but not limited to R 2 and/or R z
  • R groups such as but not limited to R 2 and/or R z
  • R groups may be the same or different symbols
  • R groups They can be selected independently, that is, they can be the same or different. The same is true for the selection of values such as g and n.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (such as 13 C and 14 C); Isotopes (e.g. 37 Cl); isotopes of iodine (e.g. 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and Isotopes of sulfur (for example 34 S).
  • isotopes of hydrogen such as deuterium
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in a mixture of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • Solid lines (——) and solid wedge shapes can be used in this article.
  • Virtual wedge Depicts the carbon-carbon bonds of the compounds of the invention.
  • the use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that it includes all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, real and imaginary wedges are used to define relative stereochemistry, rather than absolute stereochemistry.
  • the compounds of the present invention may be stereoisomers (including cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist in the form of.
  • the compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).
  • the present invention also covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly administered to patients in need thereof. Or indirectly provide the compound of formula (I) or its metabolites. Therefore, when the "compound of the present invention" is referred to herein, it is also intended to encompass the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • esters means an ester derived from the compounds described herein, which includes physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form) .
  • the compound of the present invention may itself be an ester.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles that can form N-oxides.
  • nitrogen-containing heterocycles that can form N-oxides.
  • tertiary amines can form N-oxides.
  • metabolites of the compounds of the present invention are also included within the scope of the present invention, that is, substances formed in the body when the compounds of the present invention are administered.
  • the metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method in which the compounds of the present invention are contacted with a mammal for a time sufficient to produce their metabolites.
  • the present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less or no pharmacological activity when administered to or on the body. It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage. Usually such prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo. For other information on the use of prodrugs, please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as “pro-moiety (for example, “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups existing in the compounds of the present invention.
  • the present invention also encompasses the compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, and these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • the invention also encompasses methods of preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the conversion.
  • active ingredient refers to a chemical entity that can effectively treat one or more symptoms of the target disorder or condition.
  • the term "effective amount” refers to the amount of the active ingredient that will achieve the desired effect to a certain extent after administration, such as one that relieves the condition being treated One or more symptoms or to prevent the appearance of a disease or its symptoms.
  • treating means reversing, alleviating, inhibiting the progression of one or more symptoms of the disorder or condition to which such term is applied, or preventing such Or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism Substance or prodrug:
  • X is a direct bond or selected from S, O, NH and CH 2 ;
  • Y is a direct key
  • W 1 , W 2 and W 3 are each independently selected from CH and N;
  • R 1 is selected from H, -OH, -NH 2 , C 1-6 alkyl and C 3-6 cycloalkyl;
  • R 2 is independent of each occurrence
  • any two R 2 together with the atoms to which they are connected form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the hydrocarbon ring, heterocyclic ring, heteroaromatic ring
  • any one of R 2 and X together with the atoms to which they are connected forms a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein
  • the hydrocarbon ring, heterocyclic ring, heteroaromatic ring and benzene ring are each optionally selected from -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl). 2.
  • Substituent substitution of halogen, -CN, O, -OH, -OC 1-6 alkyl, halogenated C 1-6 alkyl and C 1-6 alkyl;
  • any two of R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b form a C 3-10 hydrocarbon ring or 4- 12-membered heterocyclic ring;
  • R 8a and R 8b together with the connected atoms (or direct bonds) form a C 3-8 hydrocarbon ring or a 3-12 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more From -N(R z ) 2 , -NH 2 , halogen, -CN, O, -OH, -OC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 Substituents of membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
  • g 0, 1 or 2;
  • n 0, 1, 2, 3, 4, or 5.
  • R 1 is selected from H, -OH, -NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl; in some preferred embodiments, R 1 is selected from H, -NH 2. -CH 3 and cyclopropyl; in some more preferred embodiments, R 1 is selected from -CH 3 and cyclopropyl; in further preferred embodiments, R 1 is selected from -CH 3 .
  • X is selected from a direct bond and S; in some preferred embodiments, X is a direct bond.
  • W 3 is CH, and W 1 and W 2 are each independently selected from CH and N; in some preferred embodiments, Selected from In some more preferred embodiments, Selected from
  • any two of R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b together with the atoms (or direct bonds) to which they are connected form a C 4-8 hydrocarbon Ring or 4-8 membered heterocyclic ring; in some preferred embodiments , any two of R 4a , R 5a , R 6a , and R 7a together with the atoms to which they are connected form a C 4-8 hydrocarbon ring or 4-8 membered ring Heterocycle; In a further preferred embodiment, R 4a and R 7a together with the atoms to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, or R 5a and R 6a together with the atoms to which they are attached form a C 4-6 hydrocarbon Ring; In a further preferred embodiment, R 5a and R 6a together with the atoms to which they are attached form a cyclopenta ring, and R
  • R 4a , R 7a and R 3 together with the atoms to which they are attached form azaadamantane; in some preferred embodiments, R 4a , R 7a and R 3 together with the atoms to which they are attached form nitrogen Heteroadamantane, and R 4b , R 5a , R 5b , R 6a , R 6b , and R 7b are all H.
  • R 3 is selected from H, F, Cl, Br, -OR z , -OH, -CN, C 1-6 alkyl, -C 1-4 alkylene- R z , -C 1-4 alkylene -OR z , C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 3-8 membered heterocyclic group (e.g.
  • R 8a and R 8b are each independently selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, benzene ring, and 5-6 membered heteroaryl.
  • Group, wherein the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group and benzene ring are each optionally selected by one or more selected from -NH 2 , F, Cl, -CN, -CH 3 ,- CH 2 CH 3 , O, -OH, -OC 1-3 alkyl, -CF 3 , -CHF 2 and C 3-6 cycloalkyl substituents are substituted; in some preferred embodiments, R 8a , R 8b are each independently selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CF 3 , -CHF 2 , -CH 2 F, isopropyl, cyclopropyl,
  • R 8a is H
  • R 8b is selected from -CH 3 , -CH 2 CH 3 , isopropyl, cyclopropyl, -CH 2 OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , 2-methan Furanyl, thiazolyl, pyridyl and pyrimidinyl
  • R 3 is selected from H, F, Cl, -CF 3 , -CHF 2 , -CH 2 F, -OH, -OCH 3
  • -CH 2 CH CH 2
  • -CH CH 2
  • -CH 2 C CH
  • -C CH
  • -CH 3 -CH 2 CH 3
  • R 8a is H
  • R 8b is selected from -CH 3 , -CH 2 CH 3 , isopropyl, cyclopropyl, -CH 2 OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , 2-methan Furan-5-yl, thiazol-2-yl, pyridin-3-yl, pyrimidin-2-yl and pyrimidin-5-yl
  • R 3 is selected from H, F, Cl, -CF 3 , -CHF 2 ,- CH 2 F, -OH, -OCH 3
  • -CH 2 CH CH 2
  • -CH CH 2
  • -CH 2 C CH
  • -C CH, -CH 3 , -CH 2 CH 3 , -CH 2 NHCH 3 , -CH 2 -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl,
  • g is 0 or 2.
  • n is 0, 1, 2, or 3; in some preferred embodiments, n is 2 or 3; in some more preferred embodiments, n is 2.
  • the compound of formula (I) of the present invention has the structure of formula (II):
  • each group is as defined above.
  • the compound of formula (I) of the present invention has the structure of formula (III):
  • each group is as defined above.
  • the present invention provides compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites Or prodrugs, wherein the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I)-(III) (ie formula (I), (II) or (III), the same below) or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers.
  • the present invention provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopes thereof Use of the labeled compound, metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases.
  • the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering a compound of formula (I)-(III) or a pharmaceutically acceptable compound thereof to an individual in need Salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs or the pharmaceutical composition of the present invention.
  • the present invention provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopes thereof
  • the labeled compound, metabolite or prodrug or the pharmaceutical composition of the present invention is used to prevent or treat SHP2 phosphatase related diseases.
  • the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition.
  • the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies.
  • the present invention further provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, Isotope-labeled compounds, metabolites or prodrugs or the pharmaceutical composition of the present invention are combined with other treatment methods for the prevention or treatment of SHP2 phosphatase-related diseases, and the additional treatment methods include but are not limited to: radiotherapy, Chemotherapy, immunotherapy or a combination thereof.
  • Another aspect of the present invention also relates to a method for preparing the compound of the present invention, the method comprising:
  • LG 1 and LG 2 each independently represent a halogen leaving group, or a C 1-6 alkylsulfonate leaving group optionally substituted by halogen (for example, a trifluoromethanesulfonate leaving group) Group);
  • LG 2 can also be a hydroxyl group;
  • R c represents H or a leaving group
  • R f is a hydroxymethyl group or a functional group that can be converted into a hydroxymethyl group through one or more reactions;
  • PG 1 represents a protecting group for H or an amino group (for example, methyl, tert-butoxycarbonyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl and methoxymethyl);
  • LG 1 represents halogen, such as iodine or bromine
  • LG 2 represents halogen (such as bromine or chlorine) or hydroxyl
  • R c is selected from H, halogen, boronic acid group, boronic acid ester group, substituted silicon group, substituted metal group, or C 1-6 alkyl sulfonic acid optionally substituted by halogen Ester group. In a more preferred embodiment, R c is a boronic acid group or a boronic acid ester group.
  • R f represents H, F, Cl, Br, I, protected or unprotected hydroxymethyl or ester groups (for example -COOC 2 H 5 );
  • the reaction is carried out in the presence of a metal catalyst.
  • the metal catalyst is a metal palladium catalyst or a copper catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride, 1,2-bis(diphenylphosphineethane)palladium dichloride and bis(triphenylphosphine)palladium dichloride or cuprous iodide, etc.
  • the reaction is carried out in the presence of a base and/or a metal catalyst.
  • the base is an inorganic base, such as potassium phosphate.
  • the metal catalyst is a metal palladium catalyst, such as palladium tetrakistriphenylphosphine, palladium acetate, tris(dibenzylideneacetone)dipalladium, 1,1′-bis(diphenylphosphine)dipalladium Palladium ferrocene chloride, 1,2-bis-diphenylphosphine ethane palladium chloride, and bis(triphenylphosphine) palladium dichloride, etc.
  • the reaction is carried out in the presence of a condensation reagent and a base.
  • the base is an organic base, such as DBU.
  • the condensation reagent is BOP, HATU or PyBOP, etc., preferably BOP.
  • the method of functional group conversion includes but is not limited to the following reactions: 1) reduction reaction (reagents used such as LiBH 4 , DIBAL-H); 2) metal-catalyzed coupling reaction; 3) hydrolysis reaction;
  • the deprotection reaction can be carried out under acid or catalytic hydrogenolysis conditions.
  • the acid is an organic acid, preferably trifluoroformic acid.
  • the metal catalyst used in method 2) is palladium on carbon or palladium hydroxide on carbon.
  • the starting materials of the preparation method of the present invention can be from commercial sources or can be prepared according to known methods.
  • compositions preparations and kits
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I)-(III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent Compounds (such as hydrates), isotopically-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers, and may optionally further include one or more for the treatment of SHP2 phosphatase-related The second therapeutic agent for the disease.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which method comprises combining a compound of formula (I)-(III) or a pharmaceutically acceptable salt, ester, or stereoisomer thereof , Tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs, or their mixtures in combination with one or more pharmaceutically acceptable carriers.
  • the method may further include mixing one or more second therapeutic agents for the treatment of SHP2 phosphatase related diseases.
  • the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc.
  • sterile liquids such as water and oils
  • oils including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc.
  • water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections.
  • Pharmaceutically acceptable carriers include pharmaceutical excipients.
  • Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol , Water, ethanol, etc.
  • the composition may also contain a small amount of wetting agents, emulsifiers, lubricants, stabilizers or pH buffering agents, etc. as needed.
  • Oral preparations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).
  • the pharmaceutical composition can be administered in any form as long as it achieves prevention, alleviation, prevention, or cure of symptoms in human or animal patients.
  • various suitable dosage forms can be prepared according to the route of administration.
  • the pharmaceutical composition When administered orally, the pharmaceutical composition can be made into any orally acceptable preparation form, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions and oral emulsions Wait. When applied transdermally or topically, the pharmaceutical composition can be made into an appropriate ointment, lotion or liniment form, wherein the active ingredient can be suspended or dissolved in one or more carriers.
  • the pharmaceutical composition can also be administered in the form of injection, including injection, sterile powder for injection and concentrated solution for injection.
  • the administration of the compound or pharmaceutical composition of the present invention may be combined with another treatment method.
  • the additional treatment method can be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
  • the compound or pharmaceutical composition of the present invention may be administered before, during, or after the implementation of the additional treatment method.
  • the implementation of other treatment methods and the administration of the compound or pharmaceutical composition of the present invention can be carried out simultaneously, or in close connection before and after, or can be carried out at intervals of time.
  • the method and order of administration can be selected according to the specific treatment situation. Adjustment.
  • Another aspect of the present invention also relates to a pharmaceutical preparation comprising a compound of formula (I)-(III), its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph
  • active ingredients solvates, isotopically-labeled compounds, metabolites or prodrugs, or mixtures thereof, or the pharmaceutical composition of the present invention.
  • the form of the formulation is a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
  • a further object of the present invention is to provide a product, for example, in the form of a kit.
  • the articles used herein are intended to include, but are not limited to, kits and packaging.
  • the article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, including: a compound of formula (I)-(III) Or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolite or prodrug thereof, or a mixture thereof; and (c ) An optional package insert stating that the pharmaceutical composition can be used to treat tumor conditions (as defined above). In other embodiments, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat tumor conditions.
  • the package insert is a trademark, label, label, etc., which enumerate information related to the pharmaceutical composition in the first container.
  • the information listed is usually determined by the regulatory agency (such as the U.S. Food and Drug Administration) that governs the area where the product is to be sold.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert can be made of any material, and the information contained in or on the package can be read from the material.
  • the package instruction is a printable material (for example, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.), on which the required information can be formed (for example, printed or applied).
  • Another object of the present invention is to provide a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering to an individual in need an effective amount of a compound of formula (I)-(III) or its pharmaceutically acceptable Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the present invention.
  • the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition.
  • the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies.
  • the tumor-like disorders include but are not limited to breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , Bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia ( Including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML)), multiple myeloma and lymphoma.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • the disease is a solid tumor, such as breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , Bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer.
  • the compound of the present invention can be used in combination with radiochemotherapy or immunotherapy to prevent or treat cancer.
  • the dosage regimen can be adjusted to provide the best desired response.
  • the medicine when administered in the form of injection, it can be administered as a single bolus injection, bolus injection, and/or continuous infusion, and so on.
  • several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation.
  • the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • the dose of treatment varies, depending on the considerations, such as: the age, gender and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; the symptomatic Duration; and other variables that can be adjusted by individual physicians.
  • the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the administration amount and administration schedule of the pharmaceutical composition can be easily determined by a person of ordinary skill in the clinical field.
  • the composition or compound of the present invention may be administered in divided doses from 4 times a day to once every 3 days, and the dosage may be, for example, 0.01 to 1000 mg/time.
  • the required dose can be administered in one or more times to obtain the desired result.
  • the pharmaceutical composition according to the present invention can also be provided in a unit dosage form.
  • the present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:
  • MS Mass spectrometry
  • HPLC high performance liquid chromatography
  • YMC Shimadzu LC-8A preparative liquid chromatograph
  • ODS 250 ⁇ 20mm chromatographic column
  • Thin-layer chromatography purification uses GF 254 (0.4 ⁇ 0.5nm) silica gel plate produced in Yantai.
  • the reaction is monitored by thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS).
  • TLC thin-layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • the developing solvent systems used include but are not limited to: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, or triethylamine is added for adjustment.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase.
  • the eluent system includes but is not limited to the dichloromethane and methanol system and the n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 30°C).
  • reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology.
  • Dissolve 3-4 (20.1mg, 0.037 ⁇ mol) in dichloromethane (10mL), slowly add DIBAL-H (1M in hexane, 0.5mL) under ice-bath conditions, and slowly warm up to room temperature after the addition is complete 1 hour. After the completion of the reaction, a saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and after thorough stirring, a solid precipitated, filtered, and the filtrate was separated. The aqueous phase was extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: The title compound (3.24 mg, yield 17%) was prepared by 0.05% formic acid aqueous solution).
  • Step 1 Synthesis of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (4-1)
  • Step 2 Synthesis of tert-butyl 4-cyano-4-(methoxymethyl)piperidine-1-carboxylate (4-2)
  • TM3 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • TM4 was synthesized by a method similar to that described in the second to fifth steps of Example 4.
  • Step 5 Preparation of tert-butyl 4-carbamoyl-4-((2-chlorothiazol-4-yl)methyl)piperidine-1-carboxylate (6-6)
  • Steps 7 to 9 (3-(4-(aminomethyl)-4-((2-chlorothiazol-4-yl)methyl)piperidin-1-yl)-6-(2,3 -Dichlorophenyl)-5-methylpyrazin-2-yl)methanol (TM5)
  • TM5 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • the first step the preparation of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (7-1)
  • Step 2 Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (7-2)
  • the third step preparation of ((4-cyanopiperidin-4-yl)methyl) tert-butyl carbamate (7-3)
  • the sixth step 4-(aminomethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)piperidine- Preparation of 4-nitrile (TM6)
  • the crude TM9 was synthesized by a method similar to that described in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain compound TM9.
  • TM10 was synthesized by a method similar to that described in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain compound TM10.
  • Step 1 Preparation of tert-butyl 4-cyano-4-(1-hydroxycyclobutyl)piperidine-1-carboxylate (12-2)
  • Step 2 Preparation of tert-butyl 4-cyano-4-(cyclobut-1-en-1-yl)piperidine-1-carboxylate (12-3)
  • the crude TM11 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 1 Preparation of tert-butyl 4-cyano-4-cyclobutylpiperidine-1-carboxylate (13-1)
  • the crude TM12 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 1 Preparation of tert-butyl 4-benzyl-4-cyanopiperidine-1-carboxylate (14-2)
  • Step 2 Preparation of tert-butyl 4-(aminomethyl)-4-benzylpiperidine-1-carboxylate (14-3)
  • the crude TM13 was synthesized by a method similar to that described in the third to fourth steps in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 1 Synthesis of tert-butyl 4-(2-bromophenyl)-4-cyanopiperidine-1-carboxylate (15-2)
  • Step 2 Synthesis of tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (15-3)
  • Step 1 Synthesis of tert-butyl 4-cyano-4-(cyclohexylmethyl)piperidine-1-carboxylate (16-2)
  • reaction was quenched by adding 20 mL saturated NH 4 Cl aqueous solution, extracted with ethyl acetate (60 mL ⁇ 3), the combined organic phase was washed with saturated brine (60 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, and filtered The solvent was evaporated under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel column chromatography to obtain compound 16-2 (1.5 g, yield 86%).
  • Step 2 Synthesis of tert-butyl 4-(aminomethyl)-4-(cyclohexylmethyl)piperidine-1-carboxylate (16-3)
  • 16-3 (230mg, 0.74mmol) was dissolved in HCl (4M in 1,4-dioxane, 4mL) and reacted at 25°C for one hour. After the reaction, it was directly concentrated to obtain 16-4 hydrochloride (130 mg, yield 71%).
  • the first step the preparation of 1-benzyl 4-methyl 4-cyanopiperidine-1,4-dicarboxylate (17-1)
  • Step 2 Preparation of 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester (17-2)
  • Step 5 to Step 6 (3-(4-(aminomethyl)-4-((difluoromethoxy)methyl)piperidin-1-yl)-6-(2,3-dichloro Preparation of phenyl)-5-methylpyrazin-2-yl)methanol (TM40)
  • the crude TM40 was synthesized by a method similar to that described in the third to fourth steps in Example 3.
  • the crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) purification to obtain the trifluoroacetic acid salt of the title compound.
  • the crude TM85 was synthesized by a method similar to that described in the second to fourth steps in Example 13.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 2 Preparation of ((1-benzyl-4-cyclopropylpiperidin-4-yl)methyl) tert-butyl carbamate (19-3)
  • Dissolve 19-2 (0.40g, 1.66mmol) in methanol (10mL), add cobalt chloride hexahydrate (0.79g, 3.33mmol), cool to 0°C, add sodium borohydride (0.31g, 8.32mmol) to In the reaction system, the temperature was raised to 25°C for 4 hours. The reaction system was first quenched with 1N dilute hydrochloric acid, and then the pH was adjusted to about 10 with potassium carbonate aqueous solution. Subsequently, di-tert-butyl dicarbonate (0.36 g, 1.66 mmol) was added to the reaction system, and the reaction was carried out at 25° C. for 2 h.
  • Step 4 to Step 6 (3-(4-(aminomethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM20)
  • the crude TM20 was synthesized by a method similar to that described in the fourth to sixth steps in Example 7.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 1 to Step 2 Preparation of tert-butyl 4-cyano-4-(cyclopent-1-en-1-yl)piperidine-1-carboxylate (20-2)
  • the crude TM21 was synthesized by a similar method as described in the first to fourth steps in Example 13.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the first step the preparation of 4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (21-2)
  • the third step preparation of 4-(1-(1,1-dimethylethylsulfonamido)ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (21-4)
  • Dissolve 21-3 (5.10g, 21.13mmol) in tetraisopropyl titanate (51mL), add tert-butylsulfinamide (5.12g, 42.27mmol), replace with nitrogen, heat up to 90°C and react for 16 hours, cool After reaching room temperature, saturated sodium chloride solution was added, extracted with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure. The residue was dissolved in methanol (70 mL), sodium borohydride (2.3 g, 60.96 mmol) was slowly added in an ice bath, and the temperature was raised to 25° C. to react for 2 hours.
  • Step 5 to Step 6 (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM131)
  • the crude TM131 was synthesized by a method similar to that described in the third to fourth steps in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the first step 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-(4,5-dichloropyridine-3- Preparation of ethyl)-5-methylpyrazine-2-carboxylate (26-2)
  • Example 3 A method similar to that described in Example 3 was used to synthesize the crude product of TM23 except that 3-bromomethylpyridine was used in the first step of this example instead of the benzyl chloromethyl ether in the first step of Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Ethyl N-tert-butoxycarbonyl-4-piperidinecarboxylate (1.70g, 6.61mmol) was dissolved in THF (15mL), protected by nitrogen, cooled to -78°C, and LDA (2M in THF, 4.29mL) was added dropwise , React at this temperature for 30 minutes, then add 32-2 (1.26 g, 8.59 mmol), continue the reaction at this temperature for 2 hours, and then slowly rise to room temperature to react for 5 hours.
  • reaction was quenched by adding saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 32-3 (0.75g, yield 28%) ).
  • the crude TM92 was synthesized by a method similar to that described in the third to fifth steps in Example 2.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the crude TM93 was synthesized by a method similar to that described in the third to fourth steps of Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the crude TM22 was synthesized by a method similar to that described in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the first step 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-fluoropyridine-4 -Yl)-5-methylpyrazine-2-carboxylic acid ethyl ester (39-2)
  • reaction solution was concentrated to dryness, and the crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound (10.8 mg, yield 28%) ).
  • Step 4 Preparation of tert-butyl 4-(1-aminoethyl)-4-hydroxypiperidine-1-carboxylate (40-5)
  • Step 5 to Step 7 4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazine-2 -Yl)piperidin-4-ol (TM99) preparation
  • the crude TM99 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the first step the preparation of 4-(1-azidoethyl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (41-1)
  • Steps 2 to 5 (3-(4-(1-aminoethyl)-4-methoxypiperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM100)
  • the crude TM100 was synthesized by a method similar to that described in the fourth to seventh steps in Example 40.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Step 2 Preparation of tert-butyl 4-cyano-4-(oxazol-4-ylmethyl)piperidine-1-carboxylate (42-3)
  • the crude TM149 was synthesized by a method similar to that described in the second to fourth steps in Example 3.
  • the crude product was reversed Purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title compound.
  • the first step 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-((2,3-dichloropyridine-4 -Yl)thio)-5-methylpyrazine-2-carboxylic acid ethyl ester (43-2)
  • the crude TM114 was synthesized by a method similar to that described in the third step of Example 25.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • the first step the preparation of 4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (44-1)
  • Dissolve 7-2 (0.5g, 1.33mmol) in anhydrous tetrahydrofuran (5mL), cool to 0°C, add NaH (0.11g, 2.66mmol, 60%), stir for 10min, add methyl iodide (0.38g, 2.66mmol), after the addition, stir at 0°C for 10 minutes, and then slowly warm up to room temperature to react for 1 hour. After the reaction is complete, add water (15mL) and ethyl acetate (15mL) to the reaction solution, stir well and separate the liquids. The organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated to obtain crude product 44-1 (0.5g). Used directly in the next reaction.
  • Steps 2 to 4 3-(4-cyano-4-((methylamino)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of ethyl methylpyrazine-2-carboxylate (44-4)
  • Steps 2 to 3 (6-((2-amino-3-chloropyridin-4-yl)thio)-3-(4-(1-aminoethyl)-4-methylpiperidine- Preparation of 1-yl)pyrazin-2-yl)methanol (TM174)
  • Example 46 (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridin-4-yl )Sulfanyl)-5-methylpyrazin-2-yl)methanol (TM164) preparation
  • Step 1 Preparation of tert-butyl 4-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (46-1)
  • the reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oily substance.
  • the oil was dissolved in THF (25 mL), sodium carbonate (4.39 g, 41.44 mmol) was added, the temperature was lowered to 0° C., NBS (4.06 g, 22.79 mmol) was added in portions, and then the temperature was raised to 25° C. to react for 4 hours.
  • Step 6 to Step 7 (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridine) -4-yl)sulfanyl)-5-methylpyrazin-2-yl)methanol (TM164)
  • Step 1 Preparation of 1-(tert-butyl)4-ethyl 4-(fluoromethyl)piperidine-1,4-dicarboxylate (50-2)
  • Ethyl N-Boc-4-piperidinecarboxylate (5.0g, 19.43mmol) was dissolved in THF (40mL), cooled to -78°C, LDA (2M in tetrahydrofuran, 16.5mL) was added dropwise, and reacted at -78°C for 1 hour . Subsequently, fluorobromomethane (2.8g, 24.93mmol) was added dropwise, the temperature was maintained for 1 hour, and the temperature was raised to 25°C for 1 hour.
  • Step 2 Preparation of tert-butyl 4-(fluoromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (50-3)
  • the third step preparation of tert-butyl 4-(fluoromethyl)-4-formylpiperidine-1-carboxylate (50-4)
  • Step 5 Preparation of tert-butyl 4-(1-((tert-butylsulfinyl)amino)ethyl)-4-(fluoromethyl)piperidine-1-carboxylate (50-6)
  • Steps 7 to 8 (3-(4-(1-aminoethyl)-4-(fluoromethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM109)
  • the crude product of TM109 was synthesized by a method similar to that described in the third to fourth steps in Example 3.
  • the crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous sodium bicarbonate) purification to obtain the title compound.
  • Example 51 (6-((2-Amino-3-chloropyridin-4-yl)thio)-3-(4-(1-aminoethyl)-4-(fluoromethyl)piperidine-1 -Yl)-5-methylpyrazin-2-yl)methanol (TM167)
  • 51-1 was synthesized by a method similar to that described in the first step in Example 25.
  • Step 1 Preparation of 1-(tert-butyl)4-ethyl 4-formylpiperidine-1,4-dicarboxylate (52-2)
  • Step 2 Preparation of 1-(tert-butyl)4-ethyl 4-(difluoromethyl)piperidine-1,4-dicarboxylate (52-3)
  • Step 8 to Step 10 (3-(4-(1-aminoethyl)-4-(difluoromethyl)piperidin-1-yl)-6-(2,3-dichloropyridine-4 -Yl)-5-methylpyrazin-2-yl)methanol (TM176)
  • the crude product of TM176 was synthesized by a method similar to that described in the first to third steps in Example 25.
  • the crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) purification to obtain the trifluoroacetic acid salt of the title compound.
  • Example 54 1-(4-((5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)-3-methylpyrazine -2-yl)sulfanyl)-3-chloropyridin-2-yl)azetidine-3-ol (TM178)
  • compound 54-2 was synthesized by a method similar to that described in the first step in Example 43.
  • the third step (1-(1-(5-((3-chloro-2-(3-hydroxyazetidin-1-yl)pyridin-4-yl)thio)-3-(hydroxymethyl (Yl)-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl)ethyl) tert-butyl carbamate (54-3)
  • Dissolve 54-2 (30.00mg, 55.30umol) in isopropanol (2mL), add azetidine-3-ol (8.08mg, 110.59umol) and DIPEA (28.59mg, 221.19umol), and react in microwave The reactor was heated to 120°C and reacted for 2 hours. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated and purified by thin layer chromatography to obtain compound 54-3 (12 mg, yield 37%).
  • Example 55 (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridin-4-yl ) Preparation of thio)pyrazin-2-yl)methanol (TM179).
  • the crude TM179 was synthesized by a method similar to that described in the first to third steps of Example 45
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetic acid salt of the title compound.
  • Example 56 (3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridine-4 -Yl)thio)pyrazin-2-yl)methanol (TM180) preparation
  • Step 5 Preparation of tert-butyl 4-(1-amino-2-methoxyethyl)-4-methylpiperidine-1-carboxylate (56-6)
  • Step 1 Preparation of 2-ethylhexyl 3-((7-chloro-1H-indazol-6-yl)thio)propionate (57-2)
  • the third step (1-(1-(5-((7-chloro-1H-indazol-6-yl)sulfanyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl )-4-methylpiperidin-4-yl)ethyl) tert-butyl carbamate (57-4)
  • the crude product of TM181 was synthesized by a method similar to that described in the fourth step in Example 54.
  • the crude product was subjected to reversed-phase HPLC (mobile Phase A: Acetonitrile, mobile phase B: 0.05% trifluoroacetic acid in water) was purified to obtain the trifluoroacetic acid salt of the title compound.
  • Example 59 (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1-methyl-1H-indazole-6- Yl)thio)-5-methylpyrazin-2-yl)methanol and (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7 -Preparation of chloro-2-methyl-2H-indazol-6-yl)thio)-5-methylpyrazin-2-yl)methanol (TM182A and TM182B).
  • Step 1 Preparation of 6-bromo-7-chloro-1-methyl-1H-indazole and 6-bromo-7-chloro-2-methyl-2H-indazole (59-1A and 59-1B)
  • Steps 2 to 5 (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1-methyl-1H-indyl) (Azol-6-yl)thio)-5-methylpyrazin-2-yl)methanol and (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6 -Preparation of ((7-chloro-2-methyl-2H-indazol-6-yl)thio)-5-methylpyrazin-2-yl)methanol (TM182A and TM182B).
  • Step 1 to Step 2 Preparation of 8-chloroimidazo[1,2-a]pyridine-7-thiolate (60-3)
  • the compound 60-3 was synthesized by a method similar to that described in the first to second steps in Example 57.
  • Example 61 (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloro-[1,2,4]triazolo[4 ,3-a]Pyridin-7-yl)thio)pyrazin-2-yl)methanol (TM184)
  • Step 1 to Step 2 Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-thiolate (61-3)
  • the compound 61-3 was synthesized by a method similar to that described in the first to second steps in Example 57.
  • the third step to the fourth step (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloro-[1,2,4] three Preparation of azolo[4,3-a]pyridin-7-yl)thio)pyrazin-2-yl)methanol (TM184)
  • Example 62 (R)-(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)- 5-methylpyrazin-2-yl)methanol (TR87) and (S)-(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2 , 3-Dichloropyridin-4-yl)-5-methylpyrazin-2-yl)methanol (TS87)
  • the peak 1 retention time was 8.560 min, and the peak 2 retention time was 10.306 min.
  • TM185 was synthesized by a method similar to that described in the first to second steps of Example 43.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous sodium bicarbonate solution) to obtain the title compound.
  • Step 1 to Step 3 Preparation of 1-(4-cyclopropylpiperidin-4-yl)ethan-1-amine hydrochloride (64-4)
  • Step 4 to Step 6 3-(4-(1-aminoethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM104)
  • the crude TM104 was synthesized by a method similar to that described in the first to third steps of Example 25.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.
  • Example 65 (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(4-chloro-5-methoxypyridin-3-yl)-5 -Methylpyrazin-2-yl) methanol (TM128) preparation
  • Example 66 6-((2-Amino-3-chloropyridin-4-yl)thio)-(3-(4-(1-aminoethyl)-4-cyclopropylpiperidin-1-yl )-5-methylpyrazin-2-yl)methanol (TM172) preparation
  • Example 68 (3-(4-(1-amino-2-fluoroethyl)-4-(fluoromethyl)piperidin-1-yl)-6-((2-amino-3-chloropyridine- Preparation of 4-yl)thio)-5-methylpyrazin-2-yl)methanol (TM186)
  • Step 1 Preparation of tert-butyl 4-(fluoromethyl)-4-(1-hydroxyethyl)piperidine-1-carboxylate (68-1)
  • Step 2 Preparation of tert-butyl 4-acetyl-4-(fluoromethyl)piperidine-1-carboxylate (68-2)
  • Steps 3 to 9 (3-(4-(1-amino-2-fluoroethyl)-4-(fluoromethyl)piperidin-1-yl)-6-((2-amino-3 -Chloropyridin-4-yl)thio)-5-methylpyrazin-2-yl)methanol (TM186)
  • the crude TM186 was synthesized by a method similar to that described in the first to seventh steps in Example 46.
  • the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the formate salt of the title compound.
  • control compounds SHP099 and TNO-155 used in the biological examples are as follows:
  • Test example 1 SHP2 (protein phosphatase) in vitro enzyme activity inhibition test test test system:
  • Termination reagent bpv(phen) (Abcam Catalog: ab141436)
  • Buffer system 60mM Hepes pH7.2; 75mM NaCl; 75mM KCl; 0.05% P20; 1mM EDTA; 5mM DTT
  • Reaction time between enzyme and substrate 30 minutes at room temperature
  • Microplate reader parameters BMG PHERAstar Fluorescence, excitation wavelength 340nm, emission wavelength 450nm
  • the vehicle group (containing 0.5nM SHP2, 200 ⁇ M DiFMUP, 0.5 ⁇ M IRS-1, 160 ⁇ M bpv, 0.05% DMSO) was used as the negative control and the reaction buffer group (200 ⁇ M DiFMUP, 0.5 ⁇ M IRS-1, 160 ⁇ M bpv, 0.05% DMSO)
  • the reaction buffer group 200 ⁇ M DiFMUP, 0.5 ⁇ M IRS-1, 160 ⁇ M bpv, 0.05% DMSO
  • the curve was fitted according to the four-parameter model, and the half inhibitory concentration (IC 50 ) of the compound was calculated.
  • Example 47 19.5
  • Example 49 25.2
  • Example 50 22.8
  • Example 51 19.9
  • Example 54 19.9
  • Example 55 1.1
  • Example 56 8.4
  • Example 59 6.8 and 14.2
  • Example 60 8.9
  • Example 62 22.7 and 18.1
  • Example 67 8.2
  • the compound of the present invention showed strong inhibitory activity.
  • Test Example 2 Inhibition test of compound on the proliferation activity of KYSE-520 cells (human esophageal squamous cell carcinoma)
  • Kit name/manufacturer Luminescent Cell Viability Assay, Promega
  • the cells were cultured in a medium containing 10% fetal bovine serum and placed at 37°C and 5% CO 2 for culture. Pour an appropriate amount of cells into a 96-well plate and culture overnight in an incubator to allow the cells to adhere to the wall. The next day, the medium was removed, complete medium containing the pre-diluted compound was added, and incubated at 37°C for 5 days. On the fifth day, the detection reagent CellTiter-GLo was added to each well, and the relative luminescence unit (RLU) of each well was detected by chemiluminescence.
  • RLU relative luminescence unit
  • CellTiter-Glo with cell-free medium was used to obtain the background value.
  • the compound's inhibitory activity on the proliferation of KYSE-520 was determined according to the above method, and the results are shown in Table 2.
  • Example 19 2.52 ⁇ 0.22 Example 21 0.66 ⁇ 0.13 Example 24 2.79 ⁇ 0.1 Example 25 1.22 ⁇ 0.38 Example 26 2.30 ⁇ 0.83 Example 27 2.44 ⁇ 0.40 Example 28 2.55 ⁇ 0.79 Example 35 2.59 ⁇ 0.17 Example 36 2.11 ⁇ 0.53 Example 45 0.22 ⁇ 0.06 Example 51 1.07 ⁇ 0.32 Example 56 0.29 ⁇ 0.00 Example 57 0.98 ⁇ 0.11 Example 58 1.94 ⁇ 0.34 Example 62 1.31 ⁇ 0.3 and 0.92 ⁇ 0.14 Example 63 1.19 ⁇ 0.26 Example 67 1.12 ⁇ 0.42
  • the compound of the present invention has strong cell proliferation inhibitory activity against KYSE-520.
  • Test Example 3 Biochemical hERG inhibition test
  • Kit Predictor TM hERG Fluorescence Polarization Assay, ThermoFisher, PV5366
  • Percent inhibition rate (%) (1-(mP of test compound-30 ⁇ M mP of E4031)/(mP of experiment buffer-30 ⁇ M E4031))*100
  • Example 62 >10 and >10
  • Example 66 >10
  • Example 67 >10
  • test results show that the compound of the present invention has a low affinity with hERG, and the IC 50 of competition with the affinity tracer Tracer is greater than or close to 10 ⁇ M.
  • Test Example 4 Tumor inhibition test on KYSE-520 transplanted tumor model
  • Test purpose To construct an animal model of CDX xenograft tumor by subcutaneously inoculating KYSE-520 cells in nu-nu mice, orally once a day after tumor formation, to evaluate the efficacy of different test compounds in vivo.
  • KYSE-520 cells were cultured in a monolayer in vitro, and the culture conditions were RPMI 1640 medium with 10% fetal bovine serum and cultured in an incubator at 37°C and 5% CO 2 air. Use trypsin for digestion and passaging twice a week. When the cells are in the exponential growth phase, the cells are collected and counted.
  • the KYSE-520 cell line cultured to the logarithmic growth phase was prepared into a single cell suspension (cells were resuspended in PBS, mixed with phenol red-free matrigel 1:1, and the final cell density was 5 ⁇ 10 7 /ml).
  • Nude mice were inoculated with 0.1ml and subcutaneously inoculated into the right axillary of nude mice to construct a nude mouse xenograft model of esophageal cancer. When the tumor grew to 130mm 3 , the nude mice were randomly divided into 6 groups for administration.
  • the dosing schedule is shown in the table As shown in 1 (orally administered once a day for 20 days), the vehicle is 5% DMSO + 5% Solutol + 90% H 2 O.
  • Routine inspections include observing the effects of drug treatment on the daily behavior of animals, such as behavioral activities, food (water) intake, physical signs or other abnormalities, and make corresponding records.
  • mice were weighed twice a week and the tumor volume was measured, and the data was recorded.
  • Tumor volume (V) calculation formula: V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width respectively.
  • the volume of the transplanted tumor and the weight of the mouse are shown in Figure 1 and Figure 2, respectively.
  • TGI (%) (tumor volume) [1-(T Vt -T V0 )/(C Vt -C V0 ) when the tumor does not regress ] ⁇ 100%
  • T V0 is the average tumor volume of the test compound group at the time of grouping
  • T Vt is the average tumor volume of the test compound group at day t after administration
  • C V0 is the average tumor volume of the vehicle group at the time of grouping
  • C Vt It the average tumor volume of the vehicle group at day t after administration; when the tumor has subsided
  • TGI (%) (tumor volume) 100%-(T Vt- T V0 )/T V0 ⁇ 100%.
  • the tumor is smaller than the initial volume, that is, when Vt ⁇ V0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • Test Example 5 Tumor inhibition test on NCI-H358 transplanted tumor model
  • Test purpose To construct a subcutaneous xenograft mouse model by subcutaneously inoculating human non-small cell lung cancer cell NCI-H358 into the right scapula of Balb/c-nu mice. After tumor formation, it was administered orally once a day to evaluate different effects. Test compound in vivo efficacy.
  • the NCI-H358 cells were cultured in a monolayer in vitro under the conditions of RPMI1640 medium plus 10% fetal bovine serum and cultured in an incubator at 37°C and 5% CO 2. Use pancreatin-EDTA for digestion and passage 2-3 times a week. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
  • test mice were identified by the earrings with special mouse numbers.
  • mice's right scapula was subcutaneously inoculated with 1 ⁇ 10 6 NCI-H358 cells (suspended in 0.1ml PBS + Matrigel).
  • the average tumor volume is expected to be ⁇ 200mm 3 on the seventh day.
  • 30 mice with regular tumor shapes and uniform volume were screened out, and they were randomly divided into 5 groups and administered according to the test protocol (The dosing schedule is shown in Table 2 (orally administered once a day for 20 days)), the vehicle is 5% DMSO + 5% Solutol + 90% H 2 O.
  • Tumor volume (V) calculation formula: V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width respectively.
  • the volume of the transplanted tumor and the weight of the mouse are shown in Figure 3 and Figure 4, respectively.
  • TGI (%) (tumor volume) [1-(T Vt -T V0 )/(C Vt -C V0 ) when the tumor does not regress ] ⁇ 100%
  • T V0 is the average tumor volume of the test compound group at the time of grouping
  • T Vt is the average tumor volume of the test compound group at day t after administration
  • C V0 is the average tumor volume of the vehicle group at the time of grouping
  • C Vt It the average tumor volume of the vehicle group at day t after administration; when the tumor has subsided
  • TGI (%) (tumor volume) 100%-(T Vt- T V0 )/T V0 ⁇ 100%.
  • the tumor is smaller than the initial volume, that is, when Vt ⁇ V0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • the present invention provides a series of highly active SHP2 phosphatase inhibitors with novel structures, which have demonstrated good efficacy in mouse KYSE-520 CDX model and NCI-H358 CDX model, and have great potential for development. Become a drug for tumor diseases.

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Abstract

(I) La présente invention concerne un composé de pyrazine substituée utilisé en tant qu'inhibiteur de la phosphatase SHP2. Spécifiquement, la présente invention concerne le composé de formule (I) ou un sel pharmaceutiquement acceptable, un ester, un stéréoisomère, un tautomère, un polymorphe, un solvate, un composé marqué isotopiquement, un métabolite ou un promédicament de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant le composé, et son utilisation dans la prévention et le traitement de maladies associées à la phosphatase SHP2.
PCT/CN2020/112003 2019-09-06 2020-08-28 Composé de pyrazine substituée et procédé de préparation correspondant et son utilisation Ceased WO2021043077A1 (fr)

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WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
EP4039685A1 (fr) * 2021-02-08 2022-08-10 Irbm S.P.A. Inhibiteurs azabicycliques de shp2
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022259157A1 (fr) 2021-06-09 2022-12-15 Novartis Ag Combinaison pharmaceutique triple comprenant du dabrafenib, du trametinib et un inhibiteur de shp2
WO2022269525A1 (fr) 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023282702A1 (fr) * 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation
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WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
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WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
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WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
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WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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US20230219946A1 (en) * 2020-01-19 2023-07-13 Beijing Innocare Pharma Tech Co., Ltd. Pyrimidin-4(3h)-one heterocyclic compound, preparation method thereof, and pharmaceutical use thereof
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
EP4039685A1 (fr) * 2021-02-08 2022-08-10 Irbm S.P.A. Inhibiteurs azabicycliques de shp2
WO2022167682A1 (fr) * 2021-02-08 2022-08-11 Irbm S.P.A. Inhibiteurs de shp2 azabicycliques
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022259157A1 (fr) 2021-06-09 2022-12-15 Novartis Ag Combinaison pharmaceutique triple comprenant du dabrafenib, du trametinib et un inhibiteur de shp2
WO2022269525A1 (fr) 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023282702A1 (fr) * 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation
KR20230011245A (ko) * 2021-07-09 2023-01-20 주식회사 카나프테라퓨틱스 Shp2 억제제 및 이의 용도
US12029739B2 (en) 2021-07-09 2024-07-09 Kanaph Therapeutics Inc. SHP2 inhibitor and use thereof
KR102682323B1 (ko) 2021-07-09 2024-07-09 주식회사 카나프테라퓨틱스 Shp2 억제제 및 이의 용도
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024147703A1 (fr) * 2023-01-05 2024-07-11 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et ses utilisations
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025110772A1 (fr) * 2023-11-22 2025-05-30 엘젠테라퓨틱스 주식회사 Dérivés d'imidazolo-pyridine et leurs utilisations
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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