WO2023221721A1 - Shp2 inhibitor and use thereof - Google Patents

Shp2 inhibitor and use thereof Download PDF

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WO2023221721A1
WO2023221721A1 PCT/CN2023/089203 CN2023089203W WO2023221721A1 WO 2023221721 A1 WO2023221721 A1 WO 2023221721A1 CN 2023089203 W CN2023089203 W CN 2023089203W WO 2023221721 A1 WO2023221721 A1 WO 2023221721A1
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compound
alkyl
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shp2 inhibitor
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PCT/CN2023/089203
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李志文
刘明清
刘相军
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安徽中科拓苒药物科学研究有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to a class of SHP2 inhibitors and their uses.
  • SHP2 is a non-receptor protein tyrosine phosphatase encoded by the gene PTPN11. It can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases and phospholipids, etc.), thereby regulating downstream signals. It is the current protein tyrosine phosphatase. It is the only confirmed proto-oncoprotein in the amino acid phosphatase (PTP) family. SHP2 usually forms a complex with growth factor receptor binding protein 2 (GRB2), GRB2-associated binding protein (GAB1), and signaling molecule protein (SOS), thereby activating the growth signaling pathway RAS-MAPK to promote oncogenic signaling.
  • GRB2 growth factor receptor binding protein 2
  • GRB1 GRB2-associated binding protein
  • SOS signaling molecule protein
  • Dysregulation of SHP2 can lead to the occurrence of a variety of diseases: mutations that activate PTPN11 usually disrupt the N-SH2/PTP domain interaction in the closed conformation, tending SHP2 to the open conformation, and increase the activation of downstream RAS/MAPK; and this signaling Activation will lead to the occurrence of various hematological malignancies. This proves that PTPN11 is a true oncogene.
  • SHP2 is widely expressed in various cells of the body and participates in important cell life activities including cell proliferation, activation, migration, differentiation, etc.
  • SHP2-mediated activation of RAS-MAPK signaling and its negative regulatory effect on JAK-STAT signaling make SHP2 an important participant in oncogenic or tumor suppressor signaling pathways.
  • Gain-of-function SHP2 mutations result in increased phosphatase activity leading to Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndromes, acute lymphoblastic leukemia) and Various solid tumors (eg, lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Therefore, SHP2 is a potential therapeutic target for various cancers, and the development of SHP2 inhibitors has attracted more and more attention. Therefore, discovering and searching for SHP2 inhibitors with good druggability has become a popular target in industry and academia. Currently, no SHP2 inhibitor has been approved for marketing, so there is still a clinical need to explore highly active SHP2 inhibitors.
  • leukemia e.g., juvenile myelomonocytic leukemia,
  • One object of the present invention is to provide a new class of SHP2 enzyme inhibitors that can be used to treat cancer and other diseases.
  • the present invention relates to a compound as an inhibitor of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, isomer, solvate, chelate, Polymorphs, acids, esters, metabolites or prodrugs of the compound represented by Formula I:
  • A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
  • n are each independently 0, 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6
  • R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably, R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen and C1-6 alkoxy. Additionally preferably, R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
  • R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or linked together to form ethylene;
  • R 3 is selected from H, hydroxyl, and fluorine;
  • R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyri
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or pro- Body medicine, the compound is shown in Formula Ia:
  • A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is H
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
  • R 5 is C1-C4 alkyl (preferably methyl);
  • R 6 is selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably selected from
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by halogen or C1-6 alkoxy, more preferably by fluorine or methyl. Oxygen substitution.
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ib:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4 ethyl), and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
  • Each R 6 is independently selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy, more preferably substituted by methoxy.
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ic:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
  • A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H;
  • R 3 is H
  • R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
  • R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
  • R 5 is C1-C4 hydroxyalkyl, more preferably hydroxymethyl.
  • the application also provides compounds of Formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites thereof or a pharmaceutical composition of a prodrug, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.
  • the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Methods and uses of prodrugs for inhibiting SHP2 activity.
  • the application also relates to a compound of formula I, Ia, Ib or Ic or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs, methods and uses for treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Use of prodrugs in the preparation of medicaments for treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • specific definitions are provided, the nomenclature and laboratory procedures and techniques chemically relevant to the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can So it is a monovalent group or a bivalent group (i.e. alkylene group).
  • the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • alkoxyalkyl means an alkyl group as defined herein substituted by an alkoxy group as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • alkyl(cycloalkyl) or "cycloalkylalkyl” means an alkyl group as defined herein substituted by a cycloalkyl group as defined herein.
  • Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • aryl refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
  • Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted.
  • aryl includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg, pyridine).
  • the term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl means an aryl ring in which each ring-constituting atom is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyr
  • alkyl(aryl) or “aralkyl” means an alkyl group as defined herein substituted by an aryl group as defined herein.
  • No Limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.
  • alkyl(heteroaryl) or “heteroarylalkyl” means an alkyl group as defined herein substituted by a heteroaryl group as defined herein.
  • heteroalkyl as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • Heterocycloalkyl rings may be monocyclic or polycyclic rings composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • alkyl(heterocycloalkyl) or “heterocycloalkylalkyl” means an alkyl group as defined herein substituted by a heterocycloalkyl group as defined herein.
  • alkoxy(heterocycloalkyl) or “heterocycloalkylalkoxy” means an alkoxy group as defined herein substituted by a heterocycloalkyl group as defined herein.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
  • oxadiazolyl refers to the isomeric forms of oxadiazolyl including 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. Azolyl.
  • oxazolyl refers to oxazolyl groups including 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl and other isomeric forms.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amino refers to the -NH group .
  • aminoacyl refers to the -CO- NH2 group.
  • alkylaminoacyl refers to the group -CO-NH-R, where R is alkyl as defined herein.
  • amide or “amido” refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted by one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that - NRR' is not -NH 2 .
  • Alkylamino includes groups of compounds in which the -NH2 nitrogen is bonded to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkylamino includes groups in which the nitrogen of -NH2 is bonded to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • arylamino and diarylamino refer to amino substituents further substituted by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, Lower alkyl, or aryl, wherein N is connected to at least one or two aryl groups respectively.
  • cycloalkylamino refers to an amino substituent further substituted by one or two cycloalkyl groups as defined herein.
  • heteroalkylamino refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
  • aralkyl amino herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • heteroarylamino refers to an amino substituent further substituted by one or two heteroaryl groups as defined herein.
  • heterocycloalkylamino means an amino group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • alkylaminoalkyl means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted by one or more hydroxyl groups.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • acyl refers to the monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid.
  • the general formula is R-M(O)-, where M is usually C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted by an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, caproyl, etc.
  • arylcarbonyl means a carbonyl group as defined herein substituted by an aryl group as defined herein.
  • alkoxycarbonyl refers to a carbonyl group further substituted by an alkoxy group.
  • heterocycloalkylcarbonyl refers to a carbonyl group further substituted by a heterocycloalkyl group.
  • alkylaminocarbonyl cycloalkylaminocarbonyl
  • arylaminocarbonyl aralkylaminocarbonyl
  • heteroarylaminocarbonyl respectively refer to a carbonyl group as defined herein.
  • alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted by an alkylcarbonyl group.
  • alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted by an alkylcarbonyl group.
  • heterocycloalkylcarbonylalkyl refers to an alkyl group further substituted by a heterocycloalkylcarbonyl group.
  • mercapto refers to the -SH group.
  • alkylthio means a mercapto group, as defined herein, substituted by an alkyl group, as defined herein.
  • alkylaminosulfone means a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.
  • quaternary ammonium refers to -N + RR'R", where R, R' and R" are each independently selected from alkyl groups having 1 to 8 carbon atoms.
  • optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.
  • Solvate or “solvate” refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of the substance, where the water maintains its molecular state as H2O .
  • a “metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes by which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucuryltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • the term "modulate” means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • prodrug refers to a derivative that may not be pharmacologically active but, in some cases, may be administered orally or parenterally and is thereafter metabolized in the body to form a pharmacologically active drug.
  • Active compounds of the invention include: esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals Aldehydes and ketals, etc.
  • an “effective amount” refers to an amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal, or human being studied, for example, by a researcher or physician.
  • therapeutically effective amount refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, as compared to a corresponding subject who does not receive such amount. Also included within the term are amounts effective to enhance normal physiological functions.
  • treating refers to alleviating at least one symptom of a disease, disorder or condition.
  • the term includes administration and/or application to a subject of one or more compounds described herein to provide management or treatment of a condition.
  • Treatment for the purposes of this disclosure may, but need not, provide a cure; rather, “treatment” may be a form of management of the condition.
  • treating includes partial or complete destruction of the harmful proliferating cells with minimal destructive effect on normal cells. The required mechanism for dealing with harmful rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
  • prevention includes co-preventing or slowing the onset of the development of clinically significant disease or preventing or slowing the onset of a preclinically significant stage of disease in an at-risk individual. This includes preventive treatment of individuals at risk of developing the disease.
  • subject or “patient” includes an organism capable of suffering from a condition or condition associated with reduced or insufficient programmed cell death (apoptosis) or otherwise deriving from administration of a compound of the invention.
  • beneficial organisms such as humans and non-human animals.
  • Preferred humans include those suffering from, or prone to suffering from, as described herein or related conditions in human patients.
  • non-human animals includes vertebrates such as mammals such as non-human primates, sheep, cattle, dogs, cats and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc. .
  • the GI 50 used herein refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring the effect.
  • EC50 refers to the dose, concentration, or amount of a test compound that elicits a dose-dependent response of 50% of the maximal expression of a specific response induced, stimulated, or potentiated by a particular test compound.
  • the present invention relates to a SHP2 inhibitor, which includes a compound as described in formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs:
  • A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
  • n are each independently 0, 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6
  • R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen (eg, fluorine) and C1-6 alkoxy (eg, methoxy).
  • halogen eg, fluorine
  • C1-6 alkoxy eg, methoxy
  • R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or linked together to form ethylene;
  • R 3 is selected from H, hydroxyl, and fluorine;
  • R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyri
  • R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, Esters, metabolites or prodrugs:
  • A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
  • A is selected from phenyl, and imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is H
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
  • R 5 is C1-C4 alkyl (preferably methyl);
  • R 6 is selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, in particular imidazo[4,5-b]pyridyl, more particularly selected from Additionally preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein pentyl is substituted by amino and phenyl optionally by halogen (eg fluorine) or C1-6 alkoxy (eg methoxy) replace.
  • halogen eg fluorine
  • C1-6 alkoxy eg methoxy
  • the present invention relates to compounds represented by Formula I or Formula Ia listed in Table 1 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, Acids, esters, metabolites or prodrugs:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), and oxadiazolyl (e.g. [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4-ethyl), and phenyl, pyridyl, pyrimidinyl optionally substituted by 1 to 3 R6 , or isoxazolyl;
  • Each R 6 is independently selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Further preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy (eg methoxy).
  • the present invention relates to the compounds represented by Formula I or Formula Ib listed in Table 2 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, etc. , ester, metabolite or prodrug:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
  • A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and Isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H;
  • R 3 is H
  • R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
  • R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Also preferably, R 5 is C1-C4 hydroxyalkyl, especially hydroxymethyl.
  • the present invention relates to the compounds represented by Formula I or Formula Ic listed in Table 3 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • a compound described herein is administered to an organism in need thereof and is metabolized in the body to produce metabolites that are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be prepared and/or used as pharmaceutically acceptable salts.
  • Types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxy
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any thereof. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of aqueous solutions, lyophilization.
  • Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis.
  • Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the compound of formula I, Ia, Ib or Ic of the present invention or its pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug, can Inhibit SHP2 activity, thereby achieving the purpose of treating, preventing or alleviating diseases mediated by SHP2.
  • SHP2 activity thereby achieving the purpose of treating, preventing or alleviating diseases mediated by SHP2.
  • this application protects compounds of formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites or precursors thereof Use of a medicament in the preparation of a medicament for inhibiting SHP2 activity, or treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer , colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer , colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration.
  • the amount of a given drug will depend on factors such as the specific dosage regimen, the type and severity of the disease or condition, and the uniqueness of the subject or host in need of treatment (e.g., body weight). ), however, the dosage to be administered may be routinely determined by methods known in the art, depending upon the particular surrounding circumstances, including, for example, the particular drug being employed, the route of administration, the condition being treated, and the subject or host being treated.
  • the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic scheme. Compounds can be synthesized using methods similar to those described below, using appropriate alternative starting materials.
  • reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • PE petroleum ether
  • NMO N-methylmorpholine N-oxide
  • Ar Argon gas
  • IM5-2 (0.7g, 2.11mmol) was added to a 100mL single-neck flask, TFA (5.0mL) was added, iron powder (0.6g) was added, and the reaction was stirred for 3 hours.
  • LCMS detection showed that the raw materials were completely consumed. After adsorbing and removing the iron powder with a magnetic rod, the temperature was raised to reflux and the reaction was carried out for 10 hours. LCMS monitoring showed that the reaction was complete. Concentrate under reduced pressure to remove the solvent, dilute the residue with EA, neutralize the reaction solution with saturated sodium bicarbonate solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter the concentrated target compound, and proceed to the next reaction without purification.
  • Dissolve compound IM16-2 (900mg, 3.3mmol) and sodium hydroxide (0.53g, 13.2mmol) in tetrahydrofuran (5mL) at room temperature, raise the temperature to 80-90°C and stir for 12-16 hours.
  • LCMS monitoring shows the reaction. completely. Lower the temperature, add water to it, extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter and concentrate to obtain 0.7g of the target substance.
  • the synthesis method of reference compound 2-1 was obtained through the synthesis of intermediates IM16 and IM13, with a mass spectrum [M+H] of 587.2.
  • reaction solution Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
  • reaction solution Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
  • the synthesis method of reference compound 1-1 is obtained through the synthesis of intermediates IM15 and IM18, [M+H]635.
  • the catalytic activity of SHP2 was determined using the end-point fluorescent enzymatic method with DiFMUP as the alternative substrate to determine the IC 50 value of the compound. Dephosphorization reactions were performed on black, 384-well light polystyrene plates. The total reaction volume was set to 24 ⁇ L/well. In order to keep the concentration of DMSO at a low level, compounds were diluted 4-fold with DMSO starting from 10 mM, for a total of 8 concentrations.
  • reaction buffer 60mM HEPES pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.02% BSA, 5mM DTT
  • 0.5 nM SHP2 purchased from Signalchem, USA, p38-20G-10 was pre-incubated with 1 ⁇ M p-IRS1 peptide (Gill Biochemical, 86703) for 5 to 10 minutes to activate the enzyme, and then different concentrations of compound solutions or DMSO were added as a control.
  • the present invention provides a SHP2 inhibitor compound that can be used to inhibit SHP2 activity and/or treat, prevent or alleviate diseases mediated by SHP2 in a subject. Therefore, it can be made into corresponding drugs and suitable for industrial applications.

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Abstract

An SHP2 inhibitor, comprising a compound of formula (I), or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof. The present invention further relates to a pharmaceutical composition comprising the SHP2 inhibitor, and a use of the SHP2 inhibitor in inhibiting SHP2 activity, or treating, preventing or alleviating SHP2-mediated diseases.

Description

SHP2抑制剂及其用途SHP2 inhibitors and their uses 技术领域Technical field
本发明属于药物化学领域，具体地，涉及一类SHP2抑制剂及其用途。The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of SHP2 inhibitors and their uses.
背景技术Background technique
SHP2是由基因PTPN11编码的一种非受体型蛋白酪氨酸磷酸酶，可以催化磷酸化的底物(如受体、激酶和磷脂等)去磷酸化，从而调控下游信号，是目前蛋白质酪氨酸磷酸酶(PTP)家族中唯一被证实的原癌蛋白。SHP2通常与生长因子受体结合蛋白2(GRB2)、GRB2相关结合蛋白(GAB1)以及信号分子蛋白(SOS)形成复合物，从而激活生长信号通路RAS-MAPK，以促进致癌信号传导。SHP2调节异常会导致多种疾病的发生：激活PTPN11的突变通常会破坏封闭构象的N-SH2/PTP域间相互作用，使SHP2倾向于开放构象，并增加下游RAS/MAPK的激活；而该信号的激活将导致多种血液系统恶性肿瘤的发生。这证明了PTPN11是真正的致癌基因。作为多种细胞因子、生长因子以及其它胞外刺激因素的胞内响应信号分子，SHP2在机体的各种细胞中广泛表达，参与包括细胞增殖、活化、迁移、分化等重要的细胞生命活动。SHP2介导的RAS-MAPK信号激活及其对JAK-STAT信号的负调控作用使得SHP2成为致癌或抑癌信号通路的重要参与者。SHP2 is a non-receptor protein tyrosine phosphatase encoded by the gene PTPN11. It can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases and phospholipids, etc.), thereby regulating downstream signals. It is the current protein tyrosine phosphatase. It is the only confirmed proto-oncoprotein in the amino acid phosphatase (PTP) family. SHP2 usually forms a complex with growth factor receptor binding protein 2 (GRB2), GRB2-associated binding protein (GAB1), and signaling molecule protein (SOS), thereby activating the growth signaling pathway RAS-MAPK to promote oncogenic signaling. Dysregulation of SHP2 can lead to the occurrence of a variety of diseases: mutations that activate PTPN11 usually disrupt the N-SH2/PTP domain interaction in the closed conformation, tending SHP2 to the open conformation, and increase the activation of downstream RAS/MAPK; and this signaling Activation will lead to the occurrence of various hematological malignancies. This proves that PTPN11 is a true oncogene. As an intracellular response signaling molecule to a variety of cytokines, growth factors, and other extracellular stimuli, SHP2 is widely expressed in various cells of the body and participates in important cell life activities including cell proliferation, activation, migration, differentiation, etc. SHP2-mediated activation of RAS-MAPK signaling and its negative regulatory effect on JAK-STAT signaling make SHP2 an important participant in oncogenic or tumor suppressor signaling pathways.
功能获得性SHP2突变导致了增加的磷酸酶活性导致的Noonan综合征，以及多种形式的白血病(例如，青少年髓单核细胞白血病、急性骨髓性白血病、骨髓增生异常综合征、急性淋巴白血病)和多种实体瘤(例如，肺腺癌、结肠癌、成神经细胞瘤、成胶质细胞瘤、黑素瘤、肝细胞癌和前列腺癌)。因此，SHP2是多种癌症的潜在的治疗靶点，SHP2抑制剂的开发吸引越来越多的关注。因此，发现和寻找具有较好成药性的SHP2抑制剂成为工业界和学术界的热门靶点。目前尚无SHP2抑制剂获批上市，因此探索高活性的SHP2抑制剂依然有临床需求。Gain-of-function SHP2 mutations result in increased phosphatase activity leading to Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndromes, acute lymphoblastic leukemia) and Various solid tumors (eg, lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Therefore, SHP2 is a potential therapeutic target for various cancers, and the development of SHP2 inhibitors has attracted more and more attention. Therefore, discovering and searching for SHP2 inhibitors with good druggability has become a popular target in industry and academia. Currently, no SHP2 inhibitor has been approved for marketing, so there is still a clinical need to explore highly active SHP2 inhibitors.
发明内容Contents of the invention
本发明的一个目的在于提供一类新型的SHP2酶抑制剂，可用于治疗癌症等疾病。One object of the present invention is to provide a new class of SHP2 enzyme inhibitors that can be used to treat cancer and other diseases.
一方面，本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式I所示：
In one aspect, the present invention relates to a compound as an inhibitor of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, isomer, solvate, chelate, Polymorphs, acids, esters, metabolites or prodrugs of the compound represented by Formula I:
其中，in,
A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
B为含氮不饱和单环或双环，优选地选自吡嗪(例如)、吡唑并嘧啶酮(例如)、和吡唑并吡嗪(例如)；B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
m和n各自独立地为0、1或2；m and n are each independently 0, 1 or 2;
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代；R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group;
R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6 One-membered heterocycloalkyl, 5- or 6-membered heterocycloalkyl C1-6 alkyl, and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地，R1和R1'一起形成 当存在R6时，R6选自卤素和C1-6烷氧基。另外优选地，R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。Preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably, R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen and C1-6 alkoxy. Additionally preferably, R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
在其他优选的实施方式中，R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R2和R2'各自为H，或连接在一起形成亚乙基；R3选自H、羟基、和氟；R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；R6各自独立地选自氟、氯、氨基和C1-3烷氧基。In other preferred embodiments, R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; R 2 and R 2 ' are each H, or linked together to form ethylene; R 3 is selected from H, hydroxyl, and fluorine; R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyridyl, pyrimidinyl, or isoxazolyl; R 5 is each independently selected from C1-C2 alkyl, C1-C2 hydroxyalkyl and C1-C2 alkoxycarbonyl; R 6 is each independently selected from fluorine , chlorine, amino and C1-3 alkoxy.
在优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ia所示：
In a preferred aspect, the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or pro- Body medicine, the compound is shown in Formula Ia:
其中，A、n、R1和R1'、R2和R2'、R3、R4、以及R5如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
R3为H； R 3 is H;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基(优选四氢呋喃基)；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
R5为C1-C4烷基(优选甲基)；R 5 is C1-C4 alkyl (preferably methyl);
R6选自卤素和C1-6烷氧基。R 6 is selected from halogen and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选地选自 Further preferably, A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably selected from
另外进一步优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素或C1-6烷氧基取代，更优选地被氟或甲氧基取代。Further preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by halogen or C1-6 alkoxy, more preferably by fluorine or methyl. Oxygen substitution.
在另外优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ib所示：
In another preferred aspect, the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ib:
其中，A、n、R1和R1'、R2和R2'、R3、以及R4如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基(优选四氢呋喃基或四氢吡喃基)、5或6元杂环烷基 C1-6烷基(优选吗啉-4基乙基)、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4 ethyl), and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
R6各自独立地选自卤素和C1-6烷氧基。Each R 6 is independently selected from halogen and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选 Further preferably, A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
另外进一步优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基取代，更优选地被甲氧基取代。Further preferably R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy, more preferably substituted by methoxy.
在其他优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ic所示：
In other preferred aspects, the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ic:
其中，A、n、R1和R1'、R2和R2'、R3、以及R5如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
优选地，A选自咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
R2和R2'各自为H；R 2 and R 2 ' are each H;
R3为H；R 3 is H;
R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选 Further preferably, A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
另外进一步优选地，R5是C1-C4羟基烷基，更优选羟甲基。Further preferably, R 5 is C1-C4 hydroxyalkyl, more preferably hydroxymethyl.
另一方面，本申请还提供包括式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物、和药学上可接受的稀释剂或载体、以及任选的其他活性药物成分的药物组合物。On the other hand, the application also provides compounds of Formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites thereof or a pharmaceutical composition of a prodrug, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.
在其他方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物用于抑制SHP2活性的方法和用途。In other aspects, the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Methods and uses of prodrugs for inhibiting SHP2 activity.
在另一方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物用于治疗、预防或缓和由SHP2介导的疾病的方法和用途。在优选的方面，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。在更优选的方面，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。In another aspect, the application also relates to a compound of formula I, Ia, Ib or Ic or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs, methods and uses for treating, preventing or alleviating diseases mediated by SHP2. In a preferred aspect, the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease. In a more preferred aspect, the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
在其他方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物在制备用于治疗、预防或缓和由SHP2介导的疾病的药物中的用途。在优选的方面，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。在更优选的方面，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。In other aspects, the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Use of prodrugs in the preparation of medicaments for treating, preventing or alleviating diseases mediated by SHP2. In a preferred aspect, the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease. In a more preferred aspect, the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
具体实施方式Detailed ways
术语the term
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。Unless otherwise stated, the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques chemically relevant to the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art. In general, the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可 以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异戊基、新戊基、叔戊基、和戊-3-基等。The term "alkyl" refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can So it is a monovalent group or a bivalent group (i.e. alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that the "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group. For example, the "propyl" mentioned herein includes n-propyl and isopropyl, and the "butyl" includes n-butyl. base, isobutyl and tert-butyl, "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。The term "alkoxy" refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
术语“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。The term "alkoxyalkyl" means an alkyl group as defined herein substituted by an alkoxy group as defined herein.
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
术语“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。The term "alkyl(cycloalkyl)" or "cycloalkylalkyl" means an alkyl group as defined herein substituted by a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。The term "aryl" refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer. Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms. Aryl groups may be optionally substituted. The term "aryl" includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaryl") groups (eg, pyridine). The term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。As used herein, the term "aryl" means an aryl ring in which each ring-constituting atom is a carbon atom. Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。The term "aryloxy" refers to -O-aryl, where aryl is as defined herein.
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。The term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyridyl, etc.
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非 限制性的烷基(芳基)包括苄基、苯乙基等。The term "alkyl(aryl)" or "aralkyl" means an alkyl group as defined herein substituted by an aryl group as defined herein. No Limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group as defined herein substituted by a heteroaryl group as defined herein.
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。The term "heteroalkyl" as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以是由三、四、五、六、七、八、九或多于九个原子构成的单环或多环。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。The term "heterocycloalkyl" or "heterocyclyl" as used herein refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Heterocycloalkyl rings may be monocyclic or polycyclic rings composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, bazoline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1 ,3-dithiolane, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazolidine, thiazolidine and 1,3-Oxathiolane. Depending on the structure, a heterocycloalkyl group can be a monovalent group or a bivalent group (i.e., heterocycloalkylene group).
术语“烷基(杂环烷基)”或“杂环烷基烷基”是指本文定义的烷基被本文定义的杂环烷基取代。The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group as defined herein substituted by a heterocycloalkyl group as defined herein.
术语“烷氧基(杂环烷基)”或“杂环烷基烷氧基”是指本文定义的烷氧基被本文定义的杂环烷基取代。The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group as defined herein substituted by a heterocycloalkyl group as defined herein.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。The terms "haloalkyl", "haloalkoxy" and "halogenated heteroalkyl" include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
术语“噁二唑基”是指包括1,2,4-噁二唑基、1,2,5-噁二唑基和1,3,4-噁二唑基等异构体形式的噁二唑基。The term "oxadiazolyl" refers to the isomeric forms of oxadiazolyl including 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. Azolyl.
术语“噁唑基”是指包括1,2-噁唑基(异噁唑基)、1,3-噁唑基等异构体形式的噁唑基。The term "oxazolyl" refers to oxazolyl groups including 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl and other isomeric forms.
术语“羟基”是指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to the -CN group.
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。The term "ester group" refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
术语“氨基”是指-NH2基团。The term "amino" refers to the -NH group .
术语“氨酰基”是指-CO-NH2基团。 The term "aminoacyl" refers to the -CO- NH2 group.
术语“烷基氨酰基”是指-CO-NH-R基团，其中R为本文定义的烷基。The term "alkylaminoacyl" refers to the group -CO-NH-R, where R is alkyl as defined herein.
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。The term "amide" or "amido" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH2。“烷基氨基”包括其中-NH2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。The term "alkylamino" refers to an amino substituent further substituted by one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that - NRR' is not -NH 2 . "Alkylamino" includes groups of compounds in which the -NH2 nitrogen is bonded to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups in which the nitrogen of -NH2 is bonded to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
术语“芳基氨基”和“二芳基氨基”是指进一步被一个或两个芳基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢、低级烷基、或芳基，其中N分别连接至少一个或两个芳基基团。The terms "arylamino" and "diarylamino" refer to amino substituents further substituted by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, Lower alkyl, or aryl, wherein N is connected to at least one or two aryl groups respectively.
术语“环烷基氨基”是指进一步被一个或两个本文所定义的环烷基取代的氨基取代基。The term "cycloalkylamino" refers to an amino substituent further substituted by one or two cycloalkyl groups as defined herein.
术语“杂烷基氨基”是指进一步被一个或两个本文所定义的杂烷基取代的氨基取代基。The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
本文的术语“芳烷基氨基”是指其中R是低级芳烷基且R’是氢、低级烷基、芳基或低级芳烷基的基团-NRR’。The term "aralkyl amino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
术语“杂芳基氨基”是指进一步被一个或两个本文所定义的杂芳基取代的氨基取代基。The term "heteroarylamino" refers to an amino substituent further substituted by one or two heteroaryl groups as defined herein.
术语“杂环烷基氨基”是指本文定义的氨基被本文定义的杂环烷基取代。The term "heterocycloalkylamino" means an amino group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
术语“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.
术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.
术语“氨基烷氧基”是指进一步被一个或多个氨基取代的烷氧基取代基。The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.
术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted by one or more hydroxyl groups.
术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。The term "acyl" refers to the monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid. The general formula is R-M(O)-, where M is usually C.
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。The term "carbonyl" is an organic functional group consisting of two atoms, carbon and oxygen, joined by a double bond (C=O).
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted by an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, caproyl, etc.
术语“芳基羰基”是指本文定义的羰基被本文定义的芳基取代。The term "arylcarbonyl" means a carbonyl group as defined herein substituted by an aryl group as defined herein.
术语“烷氧基羰基”是指进一步被一个烷氧基取代的羰基。The term "alkoxycarbonyl" refers to a carbonyl group further substituted by an alkoxy group.
术语“杂环烷基羰基”是指进一步被一个杂环烷基取代的羰基。The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted by a heterocycloalkyl group.
术语“烷基氨基羰基”、“环烷基氨基羰基”、“芳基氨基羰基”、“芳烷基氨基羰基”、“杂芳基氨基羰基”分别是指本文定义的羰基分别被本文定义的烷基氨基、环 烷基氨基、芳基氨基、芳烷基氨基、或杂芳基氨基取代。The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl" and "heteroarylaminocarbonyl" respectively refer to a carbonyl group as defined herein. Alkylamino, ring Alkylamino, arylamino, aralkylamino, or heteroarylamino substitution.
术语“烷基羰基烷基”或“烷酰基烷基”是指进一步被一个烷基羰基取代的烷基。The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted by an alkylcarbonyl group.
术语“烷基羰基烷氧基”或“烷酰基烷氧基”是指进一步被一个烷基羰基取代的烷氧基。The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted by an alkylcarbonyl group.
术语“杂环烷基羰基烷基”是指进一步被一个杂环烷基羰基取代的烷基。The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted by a heterocycloalkylcarbonyl group.
术语“巯基”是指-SH基团。术语“烷硫基”是指本文所定义的巯基被本文所定义的烷基取代。The term "mercapto" refers to the -SH group. The term "alkylthio" means a mercapto group, as defined herein, substituted by an alkyl group, as defined herein.
术语“砜基”或“磺酰基”是指磺酸失去羟基后的官能团，具体是指-S(＝O)2-基团。The term "sulfone group" or "sulfonyl group" refers to the functional group of sulfonic acid after losing its hydroxyl group, specifically the -S(=O) 2 - group.
术语“亚砜基”或“亚磺酰基”是指-S(＝O)-。The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.
术语“氨基砜基”或“氨基磺酰基”是指-S(＝O)2-NH2基团。The term "aminosulfone" or "aminosulfonyl" refers to the -S(=O) 2- NH2 group.
术语“烷基亚砜基”或“烷基亚磺酰基”是指烷基-S(＝O)-。The term "alkylsulfoxide" or "alkylsulfinyl" refers to alkyl -S(=O)-.
术语“烷基砜基”或“烷基磺酰基”是指-S(＝O)2-R，其中R为烷基。The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O) 2 -R, where R is alkyl.
术语“烷基氨基砜基”是指本文定义的砜基被本文定义的烷基氨基取代。The term "alkylaminosulfone" means a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.
术语“烷基砜基氨基”或“烷基磺酰氨基”，以及“环烷基砜基氨基”或“环烷基磺酰氨基”是指本文定义的氨基被本文定义的烷基砜基或环烷基砜基取代，即-NH-S(＝O)2-R，其中R分别为烷基和环烷基。The terms "alkylsulfonylamino" or "alkylsulfonylamino" and "cycloalkylsulfonylamino" or "cycloalkylsulfonylamino" mean that an amino group as defined herein is replaced by an alkylsulfone group as defined herein or Cycloalkyl sulfone substitution is -NH-S(=O) 2 -R, where R are alkyl and cycloalkyl respectively.
术语“环烷基砜基”和“环烷基磺酰基”是指-S(＝O)2-R，其中R为环烷基。The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O) 2 -R, where R is cycloalkyl.
术语“季铵基”是指-N+RR’R”，其中R、R’和R”各自独立地选自具有1-8个碳原子的烷基。The term "quaternary ammonium" refers to -N + RR'R", where R, R' and R" are each independently selected from alkyl groups having 1 to 8 carbon atoms.
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。The term "optional" means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
本文术语“药学上可接受的盐”指的是保留主题化合物的所需生物学活性且显示最小的不希望的毒理学效应的盐。这些药学上可接受的盐可以在化合物的最终分离和纯化过程中原位制备，或通过单独使纯化化合物的游离酸或游离碱形式分别与合适的碱或酸反应来制备。The term "pharmaceutically acceptable salt" herein refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.
“溶剂化物”或“溶剂合物”指的是含有化学计量或非化学计量溶剂的溶剂加成形式。一些化合物趋于以晶状固态捕集固定摩尔比例的溶剂分子，从而形成溶剂合物。若溶剂是水，则形成的溶剂合物是水合物；若溶剂是醇，则形成的溶剂合物是醇化物。水合物通过使一个或多个水分子与所述物质的一个分子结合而形成，其中所述水保持其分子状态为H2O。"Solvate" or "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of the substance, where the water maintains its molecular state as H2O .
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。 术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the sum of the processes by which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphate glucuryltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.
本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。As used herein, the term "modulate" means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
术语“前药”或“前体药物”是指如下衍生物，其可能不具有药理学活性，但在某些情况下，可口服或肠胃外给予并在这之后在体内代谢以形成具有药理学活性的本发明化合物。前药的非限制性实例包括：酯、碳酸酯、半酯、磷酸酯、硝基酯、硫酸酯、亚砜、酰胺、氨基甲酸酯、含氮化合物、磷酰胺、糖苷、醚、乙缩醛和酮缩醇等。The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, in some cases, may be administered orally or parenterally and is thereafter metabolized in the body to form a pharmacologically active drug. Active compounds of the invention. Non-limiting examples of prodrugs include: esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals Aldehydes and ketals, etc.
“有效量”指，将引发例如研究者或医师在研的组织、系统、动物或人的生物学或医学反应的药物或药学制剂的量。此外，术语“治疗有效量”指与没有接受该量的相应对象相比，引起疾病、紊乱、或副作用改良的治疗、治愈、预防、或缓解、或者疾病或紊乱发展速率降低的任何量。该术语范围内还包括有效提高正常生理功能的量。An "effective amount" refers to an amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal, or human being studied, for example, by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, as compared to a corresponding subject who does not receive such amount. Also included within the term are amounts effective to enhance normal physiological functions.
本文所用的术语“治疗”指缓解疾病、紊乱或病症的至少一种症状。该术语包括向对象给药和/或应用一种或多种本文所述化合物以提供病症的管理或治疗。用于本公开目的的“治疗”可以但不必须提供治愈；而是指，“治疗”可以是病症的管理形式。当本文所述化合物用于处理有害的增殖细胞(包括癌)时，“治疗”包括部分或完全破坏所述有害的增殖细胞，但对正常细胞的破坏影响最小。有害的快速增殖细胞(包括癌细胞)的所需处理机制在细胞水平上是凋亡。The term "treating" or "treating" as used herein refers to alleviating at least one symptom of a disease, disorder or condition. The term includes administration and/or application to a subject of one or more compounds described herein to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but need not, provide a cure; rather, "treatment" may be a form of management of the condition. When the compounds described herein are used to treat harmful proliferating cells, including cancer, "treating" includes partial or complete destruction of the harmful proliferating cells with minimal destructive effect on normal cells. The required mechanism for dealing with harmful rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
本文所用的术语“预防”包括共同预防或减缓临床上显著疾病发展的开始或者预防或减缓风险个体中的临床前显著疾病阶段的开始。这包括预防性治疗有疾病发展风险的个人。The term "prevention" as used herein includes co-preventing or slowing the onset of the development of clinically significant disease or preventing or slowing the onset of a preclinically significant stage of disease in an at-risk individual. This includes preventive treatment of individuals at risk of developing the disease.
术语“受试者”或“患者”包括能患有病症或与降低的或不足的程序性细胞死亡(细胞凋亡)相关的病症的有机体或能以其他方式从本发明化合物的给药中获益的有机体，例如人类和非人类动物。优选的人类包括患有或倾向患有如本文所述 的病症或相关状况的人类患者。术语“非人类动物”包括脊椎动物，例如哺乳动物，如非人类灵长类动物、羊、牛、狗、猫和啮齿动物如小鼠，以及非哺乳动物，如鸡、两栖动物、爬行动物等。The term "subject" or "patient" includes an organism capable of suffering from a condition or condition associated with reduced or insufficient programmed cell death (apoptosis) or otherwise deriving from administration of a compound of the invention. beneficial organisms, such as humans and non-human animals. Preferred humans include those suffering from, or prone to suffering from, as described herein or related conditions in human patients. The term "non-human animals" includes vertebrates such as mammals such as non-human primates, sheep, cattle, dogs, cats and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc. .
本文使用的GI50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。The GI 50 used herein refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
本文使用的IC50是指在测量效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。As used herein, IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring the effect.
本文使用的EC50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。As used herein, EC50 refers to the dose, concentration, or amount of a test compound that elicits a dose-dependent response of 50% of the maximal expression of a specific response induced, stimulated, or potentiated by a particular test compound.
本发明的激酶抑制剂Kinase inhibitors of the invention
本发明涉及一种SHP2抑制剂，其包括如式I所述的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
The present invention relates to a SHP2 inhibitor, which includes a compound as described in formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs:
其中，in,
A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
B为含氮不饱和单环或双环，优选地选自吡嗪(例如)、吡唑并嘧啶酮(例如)、和吡唑并吡嗪(例如)；B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
m和n各自独立地为0、1或2；m and n are each independently 0, 1 or 2;
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代； R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group;
R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6 One-membered heterocycloalkyl, 5- or 6-membered heterocycloalkyl C1-6 alkyl, and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地R1和R1'一起形成 当存在R6时，R6选自卤素(例如氟)和C1-6烷氧基(例如甲氧基)。Preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen (eg, fluorine) and C1-6 alkoxy (eg, methoxy).
在其他优选的实施方式中，R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R2和R2'各自为H，或连接在一起形成亚乙基；R3选自H、羟基、和氟；R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；R6各自独立地选自氟、氯、氨基和C1-3烷氧基。In other preferred embodiments, R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; R 2 and R 2 ' are each H, or linked together to form ethylene; R 3 is selected from H, hydroxyl, and fluorine; R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyridyl, pyrimidinyl, or isoxazolyl; R 5 is each independently selected from C1-C2 alkyl, C1-C2 hydroxyalkyl and C1-C2 alkoxycarbonyl; R 6 is each independently selected from fluorine , chlorine, amino and C1-3 alkoxy.
另外优选地，R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。Additionally preferably, R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
在优选的方面，本发明涉及一种SHP2抑制剂，其包括式Ia所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
In a preferred aspect, the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, Esters, metabolites or prodrugs:
其中，A、n、R1和R1'、R2和R2'、R3、R4、以及R5如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
优选地，A选自苯基、和咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from phenyl, and imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
R3为H；R 3 is H;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基(优选四氢呋喃基)；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
R5为C1-C4烷基(优选甲基)；R 5 is C1-C4 alkyl (preferably methyl);
R6选自卤素和C1-6烷氧基。R 6 is selected from halogen and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别地选自另外优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素(例如氟)或C1-6烷氧基(例如甲氧基)取代。Further preferably, A is imidazopyridyl, in particular imidazo[4,5-b]pyridyl, more particularly selected from Additionally preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein pentyl is substituted by amino and phenyl optionally by halogen (eg fluorine) or C1-6 alkoxy (eg methoxy) replace.
特别优选地，本发明涉及下表1所列的式I或式Ia所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。 Particularly preferably, the present invention relates to compounds represented by Formula I or Formula Ia listed in Table 1 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
表1
Table 1
在另外优选的方面，本发明涉及一种SHP2抑制剂，其包括如式Ib所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
In another preferred aspect, the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, Acids, esters, metabolites or prodrugs:
其中，A、n、R1和R1'、R2和R2'、R3、以及R4如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、和噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), and oxadiazolyl (e.g. [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基(优选四氢呋喃基或四氢吡喃基)、5或6元杂环烷基C1-6烷基(优选吗啉-4基乙基)、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4-ethyl), and phenyl, pyridyl, pyrimidinyl optionally substituted by 1 to 3 R6 , or isoxazolyl;
R6各自独立地选自卤素和C1-6烷氧基。Each R 6 is independently selected from halogen and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别是另外优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基(例如甲氧基)取代。Further preferably, A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Further preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy (eg methoxy).
特别优选地，本发明涉及下表2所列的式I或式Ib所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。 Particularly preferably, the present invention relates to the compounds represented by Formula I or Formula Ib listed in Table 2 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
表2

Table 2

在其他优选的方面，本发明涉及一种SHP2抑制剂，其包括式Ic所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
In other preferred aspects, the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, etc. , ester, metabolite or prodrug:
其中，A、n、R1和R1'、R2和R2'、R3、以及R5如上所定义。Among them, A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
优选地，A选自咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和 异噁唑基(例如异噁唑-3-基，特别是)；Preferably, A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and Isoxazolyl (e.g. isoxazol-3-yl, especially );
n为1或2；n is 1 or 2;
R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
R2和R2'各自为H；R 2 and R 2 ' are each H;
R3为H；R 3 is H;
R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别是另外优选地，R5是C1-C4羟基烷基，特别是羟甲基。Further preferably, A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Also preferably, R 5 is C1-C4 hydroxyalkyl, especially hydroxymethyl.
特别优选地，本发明涉及下表3所列的式I或式Ic所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。Particularly preferably, the present invention relates to the compounds represented by Formula I or Formula Ic listed in Table 3 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
表3

table 3

对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。For each variable, any combination of the above mentioned groups is also considered in this paper. It will be appreciated that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide compounds that are chemically stable and can be synthesized using techniques known in the art and set forth herein.
本文也描述了此化合物的药学可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。Pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites or prodrugs of this compound are also described herein.
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。In additional or further embodiments, a compound described herein is administered to an organism in need thereof and is metabolized in the body to produce metabolites that are then used to produce the desired effect, including the desired therapeutic effect.
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐，通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱或无机碱配位，可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。The compounds described herein can be prepared and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, 2-naphthalene Sulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, Dialkyl sulfate, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) Base addition salt, the acidic proton in the parent compound is replaced by a metal ion When formed, for example, alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, Triethanolamine, trimethylamine, N-methylglucosamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。The corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any thereof. combination.
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of aqueous solutions, lyophilization.
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。 Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
本发明的药物用途Medicinal uses of the present invention
本发明的式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，能够抑制SHP2活性，从而达到治疗、预防或缓和由SHP2介导的疾病的的目的。在优选的方面，The compound of formula I, Ia, Ib or Ic of the present invention or its pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug, can Inhibit SHP2 activity, thereby achieving the purpose of treating, preventing or alleviating diseases mediated by SHP2. In the preferred aspect,
因此，本申请要保护式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，在制备用于抑制SHP2活性、或治疗、预防或缓和由SHP2介导的疾病的药物中的用途。Accordingly, this application protects compounds of formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites or precursors thereof Use of a medicament in the preparation of a medicament for inhibiting SHP2 activity, or treating, preventing or alleviating diseases mediated by SHP2.
优选地，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。Preferably, the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
更优选地，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。More preferably, the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer , colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
在本发明的实施方式中，可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。In embodiments of the present invention, a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration. When treating patients in accordance with the present invention, the amount of a given drug will depend on factors such as the specific dosage regimen, the type and severity of the disease or condition, and the uniqueness of the subject or host in need of treatment (e.g., body weight). ), however, the dosage to be administered may be routinely determined by methods known in the art, depending upon the particular surrounding circumstances, including, for example, the particular drug being employed, the route of administration, the condition being treated, and the subject or host being treated. In general, with respect to dosages for therapeutic use in adults, the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day. The required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day. Those skilled in the art can understand that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
化合物的制备Preparation of compounds
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成本发明的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。Compounds of the present invention may be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. Additionally, solvents, temperatures, and other reaction conditions given herein may be varied according to skill in the art. As further guidance, the following synthesis methods may also be utilized.
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。The reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
在某些实施方式中，本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。In certain embodiments, provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of using them. In certain embodiments, the compounds described herein can be synthesized using the following synthetic scheme. Compounds can be synthesized using methods similar to those described below, using appropriate alternative starting materials.
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。 从商业购买的原料未进行进一步纯化，除非另有说明。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。Starting materials for the synthesis of compounds described herein may be synthesized or may be obtained from commercial sources. Starting materials were purchased commercially without further purification unless otherwise stated. The compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。If necessary, the reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)，薄层色谱采用青岛化工生产的硅胶板，核磁共振色谱使用布鲁克核磁共振仪，液质联用(LCMS)使用安捷伦1200系列液相质谱仪。Column chromatography uses silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd., thin layer chromatography uses silica gel plates produced by Qingdao Chemical Co., Ltd., nuclear magnetic resonance chromatography uses a Bruker nuclear magnetic resonance instrument, and liquid mass spectrometry (LCMS) uses Agilent 1200 series. Liquid mass spectrometer.
实施例的合成中使用了如下缩略词：The following abbreviations are used in the synthesis of the examples:
DCM：二氯甲烷DCM: dichloromethane
ACN：乙腈ACN: Acetonitrile
DIEPA：N,N-二异丙基乙胺DIEPA: N,N-diisopropylethylamine
DME：乙二醇二甲醚DME: ethylene glycol dimethyl ether
DMF：N,N-二甲基甲酰胺DMF: N,N-dimethylformamide
DMAc：二甲基乙酰胺DMAc: Dimethylacetamide
DMAP：4-二甲氨基吡啶DMAP: 4-dimethylaminopyridine
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
EA：乙酸乙酯EA: Ethyl acetate
LCMS：液相色谱-质谱联用LCMS: liquid chromatography-mass spectrometry
TEA：三乙胺TEA: triethylamine
PE：石油醚PE: petroleum ether
TFA：三氟乙酸TFA: trifluoroacetic acid
Ti(OEt)4：钛酸四乙酯Ti(OEt) 4 : Tetraethyl titanate
TLC：薄层色谱TLC: thin layer chromatography
DAST:：二乙胺基三氟化硫DAST:: Diethylamine sulfur trifluoride
THP：四氢吡喃THP: tetrahydropyran
DHP：3,4-二氢-2H-吡喃DHP: 3,4-dihydro-2H-pyran
NIS：N-碘代丁二酰亚胺NIS: N-iodosuccinimide
NBS:N-溴代丁二酰亚胺NBS:N-bromosuccinimide
NMO：N-甲基吗啉N-氧化物NMO: N-methylmorpholine N-oxide
LDA：二异丙基氨基锂LDA: lithium diisopropylamide
Ar：氩气。 Ar: Argon gas.
中间体化合物IM1的合成：
Synthesis of intermediate compound IM1:
步骤1：化合物IM1-3的合成Step 1: Synthesis of compound IM1-3
室温下，将化合物IM1-1(10g)、IM1-2(19.8g)溶于DMF中，降温至0℃，N2保护，分批向其中加入氢化钠(9g)。加完后，保温搅拌反应30-40分钟，升温至60℃，搅拌反应12-16小时。LCMS监测显示原料消失，降温至0℃，向其中滴加水淬灭反应。加入EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析分离得目标物3.83g。Dissolve compounds IM1-1 (10g) and IM1-2 (19.8g) in DMF at room temperature, cool to 0°C, protect with N2 , and add sodium hydride (9g) in batches. After the addition is completed, keep the temperature and stir the reaction for 30-40 minutes, raise the temperature to 60°C, and stir the reaction for 12-16 hours. LCMS monitoring showed that the raw materials disappeared, the temperature was lowered to 0°C, and water was added dropwise to quench the reaction. Add EA to extract the reaction solution twice, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter, concentrate, and separate by column chromatography to obtain 3.83g of the target compound.
步骤2：化合物IM1-4的合成Step 2: Synthesis of compound IM1-4
室温下，将化合物IM1-3(3.83g)、R-叔丁基亚磺酰胺(4g)溶于钛酸四乙酯中，升温至90℃搅拌反应12-16小时。LCMS监测显示反应完全，降温室温，向其中加入水，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩得目标物3.1g。Dissolve compound IM1-3 (3.83g) and R-tert-butylsulfenamide (4g) in tetraethyl titanate at room temperature, raise the temperature to 90°C and stir for 12-16 hours. LCMS monitoring showed that the reaction was complete, the temperature was lowered, water was added, the reaction solution was extracted with EA twice, the organic phase was washed twice with water, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to obtain 3.1 g of the target compound.
步骤3：化合物IM1-5的合成Step 3: Synthesis of Compound IM1-5
室温下，将化合物IM1-4(3.1g)，溶于THF中，分批加入硼氢化钠(0.33g)，室温搅拌反应12-14小时。LCMS监测显示反应完全，向其中加入饱和氯化铵水溶液淬灭反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物2.5g。Dissolve compound IM1-4 (3.1g) in THF at room temperature, add sodium borohydride (0.33g) in batches, and stir the reaction at room temperature for 12-14 hours. LCMS monitoring showed that the reaction was complete. Add saturated ammonium chloride aqueous solution to quench the reaction solution. Extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter, concentrate, and obtain the target compound by column chromatography. 2.5g.
步骤4：化合物IM1的合成Step 4: Synthesis of Compound IM1
室温下，将化合物IM1-5(2.5g)溶于DCM中，加入三氟乙酸(0.66mL)，室温搅拌反应5-7小时。LCMS监测显示反应完全，减压浓缩除去溶剂和多余的三氟乙酸。向其中加入饱和碳酸氢钠水溶液中和反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物1.5g。[M+H]+325.20。 Dissolve compound IM1-5 (2.5g) in DCM at room temperature, add trifluoroacetic acid (0.66mL), and stir for 5-7 hours at room temperature. LCMS monitoring showed that the reaction was complete, and the solvent and excess trifluoroacetic acid were concentrated under reduced pressure. Add saturated sodium bicarbonate aqueous solution to neutralize the reaction solution, extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter, concentrate, and obtain 1.5 g of the target compound by column chromatography. [M+H] + 325.20.
参考以上方法合成如下中间体：
Refer to the above method to synthesize the following intermediates:
中间体化合物IM5的合成：
Synthesis of intermediate compound IM5:
步骤1：化合物IM5-2的合成Step 1: Synthesis of compound IM5-2
向100mL单口烧瓶中加入IM5-1(2.5g,10.55mmol)、SM(1.5g,11.6mmol)、碳酸铯(6.86g,21.1mmol)，室温(10℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应1小时。LCMS监测显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩得目标物2.51g。Add IM5-1 (2.5g, 10.55mmol), SM (1.5g, 11.6mmol), and cesium carbonate (6.86g, 21.1mmol) to a 100mL single-neck flask, add anhydrous DMF to it at room temperature (10°C), and raise the temperature. to 60°C (internal temperature), stir and react for 1 hour. LCMS monitoring showed that the raw materials were completely consumed. Cool down, dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, and concentrate to obtain 2.51 g of the target compound.
步骤2～3：化合物IM5-4的合成Steps 2～3: Synthesis of compound IM5-4
向100mL单口烧瓶中加入IM5-2(0.7g,2.11mmol)，向其中加入TFA(5.0mL)，加入铁粉(0.6g)，搅拌反应3小时。LCMS检测显示原料消耗完全，用磁吸棒将铁粉吸附除去后，升温至回流，反应10小时，LCMS监测显示反应完全。减压浓缩除去溶剂，EA稀释残留物，饱和碳酸氢钠溶液中和反应液，分液，无水硫酸钠干燥有机相，过滤浓缩的目标物，不纯化直接进行下一步反应。IM5-2 (0.7g, 2.11mmol) was added to a 100mL single-neck flask, TFA (5.0mL) was added, iron powder (0.6g) was added, and the reaction was stirred for 3 hours. LCMS detection showed that the raw materials were completely consumed. After adsorbing and removing the iron powder with a magnetic rod, the temperature was raised to reflux and the reaction was carried out for 10 hours. LCMS monitoring showed that the reaction was complete. Concentrate under reduced pressure to remove the solvent, dilute the residue with EA, neutralize the reaction solution with saturated sodium bicarbonate solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter the concentrated target compound, and proceed to the next reaction without purification.
步骤4：化合物IM5的合成Step 4: Synthesis of compound IM5
向100mL单口烧瓶中加入IM5-4(0.57g,1.5mmol)、联硼酸频哪醇酯(0.76 g,3.0mmol)、醋酸钾(0.36g,3.76mmol)、Pd(dppf)Cl2DCM(0.25g,0.3mmol)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环，升温至100℃，搅拌反应12小时。LCMS监测显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，制得棕黑色油状目标物0.6g，收率87％。[M+H]+427.2202。Add IM5-4 (0.57g, 1.5mmol), pinacol diborate (0.76 g, 3.0mmol), potassium acetate (0.36g, 3.76mmol), Pd(dppf)Cl 2 DCM (0.25g, 0.3mmol), N 2 replacement 4-5 times, pumped in under negative pressure at room temperature (30°C) dioxane, raise the temperature to 100°C, stir and react for 12 hours. LCMS monitoring showed that the raw materials were completely consumed. Cool down, dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, and concentrate to obtain a brown-black oily target. 0.6g of product, yield 87%. [M+H] + 427.2202.
参考以上方法合成如下中间体：
Refer to the above method to synthesize the following intermediates:
中间体化合物IM13、IM14：
Intermediate compounds IM13, IM14:
中间体化合物IM15的合成：
Synthesis of intermediate compound IM15:
步骤1：化合物IM15-2的合成Step 1: Synthesis of compound IM15-2
向100mL圆底烧瓶中加入IM15-1(50mg)、NIS(145mg)、1mL乙腈。混合物在85℃反应2小时。TLC监控反应终点(PE/EA＝5/1)，显示反应完毕。反应液冷却至室温然后抽滤，滤饼旋干得黄色固体90mg，收率：99％。[M+H]+280.8。Add IM15-1 (50 mg), NIS (145 mg), and 1 mL acetonitrile to a 100 mL round-bottomed flask. The mixture was reacted at 85°C for 2 hours. TLC monitors the reaction end point (PE/EA=5/1), indicating that the reaction is completed. The reaction solution was cooled to room temperature and then filtered with suction. The filter cake was spin-dried to obtain 90 mg of yellow solid, yield: 99%. [M+H] + 280.8.
步骤2：化合物IM15的合成Step 2: Synthesis of compound IM15
称取IM15-2(90mg)于100mL圆底烧瓶，加DCM(1mL)溶解，然后加入DHP(81mg)、TsOH(16.6mg)，混合物在25℃反应10分钟。TLC监控反应终点(PE/EA＝20/1)，显示反应完毕，反应液加NaHCO3淬灭。用DCM进行萃取，滤液旋干得粗品。粗品柱层析(PE/EA＝20/1)得白色固体40mg，收率：34％。[M+H]+364.9。Weigh IM15-2 (90 mg) into a 100 mL round-bottomed flask, add DCM (1 mL) to dissolve, then add DHP (81 mg) and TsOH (16.6 mg), and react the mixture at 25°C for 10 minutes. TLC monitors the reaction end point (PE/EA=20/1), indicating that the reaction is complete. NaHCO 3 is added to the reaction solution to quench it. Extract with DCM, and spin the filtrate to obtain crude product. The crude product was subjected to column chromatography (PE/EA=20/1) to obtain 40 mg of white solid, yield: 34%. [M+H] + 364.9.
中间体化合物IM16的合成：
Synthesis of intermediate compound IM16:
步骤1：化合物IM16-2的合成Step 1: Synthesis of compound IM16-2
称取IM16-1(1.0g,5.3mmol)于100mL圆底烧瓶，加DCM(5.0mL)溶解，然后加入DHP(0.49g,5.82mmol)、TsOH(91mg,0.53mmol)，混合物在25℃反应20分钟。TLC监控反应终点(PE/EA＝20/1)，显示反应完毕。反应液加NaHCO3淬灭，然后用DCM进行萃取，滤液旋干得粗品。粗品柱层析(PE/EA＝20/1)得 白色固体900mg，收率：34％。[M+H]+274.12。Weigh IM16-1 (1.0g, 5.3mmol) into a 100mL round-bottomed flask, add DCM (5.0mL) to dissolve, then add DHP (0.49g, 5.82mmol) and TsOH (91mg, 0.53mmol), and react the mixture at 25°C 20 minutes. TLC monitors the reaction end point (PE/EA=20/1), indicating that the reaction is completed. The reaction solution was quenched by adding NaHCO 3 , then extracted with DCM, and the filtrate was spin-dried to obtain crude product. Column chromatography of the crude product (PE/EA=20/1) yielded White solid 900 mg, yield: 34%. [M+H] + 274.12.
步骤2：化合物IM16-3的合成Step 2: Synthesis of compound IM16-3
室温下，将化合物IM16-2(900mg,3.3mmol)、氢氧化钠(0.53g,13.2mmol)溶于四氢呋喃(5mL)中，升温至80-90℃搅拌反应12-16小时，LCMS监测显示反应完全。降温室温，向其中加入水，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩得目标物0.7g。Dissolve compound IM16-2 (900mg, 3.3mmol) and sodium hydroxide (0.53g, 13.2mmol) in tetrahydrofuran (5mL) at room temperature, raise the temperature to 80-90°C and stir for 12-16 hours. LCMS monitoring shows the reaction. completely. Lower the temperature, add water to it, extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter and concentrate to obtain 0.7g of the target substance.
步骤3：化合物IM16-4的合成Step 3: Synthesis of compound IM16-4
室温下，将化合物IM16-3(0.7g,2.74mmol)、K2CO3(0.76g,5.50mmol)溶于THF中，加入碘甲烷(0.5g,3.57mmol)，55-60℃搅拌反应12-14小时，LCMS监测显示反应完全。向其中加入饱和氯化铵水溶液淬灭反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物0.85g。Dissolve compound IM16-3 (0.7g, 2.74mmol) and K 2 CO 3 (0.76g, 5.50mmol) in THF at room temperature, add methyl iodide (0.5g, 3.57mmol), and stir the reaction at 55-60°C for 12 -14 hours, LCMS monitoring showed that the reaction was complete. Add saturated ammonium chloride aqueous solution to quench the reaction solution, extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter, concentrate, and obtain 0.85g of the target compound by column chromatography.
步骤4：化合物IM16的合成Step 4: Synthesis of compound IM16
向100mL圆底烧瓶中加入IM16-4(0.85g,3.16mmol)、NIS(0.78g,3.48mmol)、ACN(6.0mL)。混合物在85℃反应2小时。TLC监控反应终点(PE/EA＝5/1)，显示反应完毕。反应液冷却至室温然后抽滤，滤饼旋干得黄色固体90mg。[M+H]+395.60。IM16-4 (0.85g, 3.16mmol), NIS (0.78g, 3.48mmol), and ACN (6.0mL) were added to a 100mL round-bottomed flask. The mixture was reacted at 85°C for 2 hours. TLC monitors the reaction end point (PE/EA=5/1), indicating that the reaction is completed. The reaction solution was cooled to room temperature and then filtered with suction, and the filter cake was spin-dried to obtain 90 mg of yellow solid. [M+H] + 395.60.
实施例1化合物1的合成
Example 1 Synthesis of Compound 1
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
称取化合物IM16(200mg)于50mL圆底烧瓶中，加入IM18(234.4mg)、CsF(210.2mg)，室温下加入无水DMAc(2mL)溶解，置于80℃油浴中搅拌反应1小时，TLC监测反应终点(展开剂：MeOH/DCM＝1/20)。反应液中加入乙酸乙酯，用水洗两次，饱和食盐水洗一次，有机相用无水硫酸钠干燥，减压旋干后拌样柱层析，得中间体1-1共计430mg，收率99％。质谱：[M+H]+645.29。 Weigh compound IM16 (200mg) into a 50mL round-bottomed flask, add IM18 (234.4mg) and CsF (210.2mg), add anhydrous DMAc (2mL) at room temperature to dissolve, place in an 80°C oil bath and stir for 1 hour. The reaction end point was monitored by TLC (developing agent: MeOH/DCM=1/20). Ethyl acetate was added to the reaction solution, washed twice with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, spin-dried under reduced pressure and then subjected to column chromatography to obtain a total of 430 mg of intermediate 1-1, with a yield of 99 %. Mass spectrum: [M+H] + 645.29.
步骤2：化合物1-2的合成Step 2: Synthesis of Compound 1-2
称取化合物1-1(430mg)于100mL圆底烧瓶中，加入二氯苯硼酸(148.1mg)，室温下加入Pd(dppf)Cl2(74.8mg)、磷酸钾(178.8mg)、二氧六环(5mL)和水(0.5mL)，氩气置换三次后，置于100℃油浴中搅拌反应16小时。TLC监测反应终点(展开剂：MeOH/DCM＝1/12.5)。减压旋干反应液后拌样柱层析，得中间体1-2共计300mg，收率65％，[M+H]+683.23。Weigh compound 1-1 (430 mg) into a 100 mL round-bottomed flask, add dichlorophenylboronic acid (148.1 mg), and add Pd(dppf)Cl 2 (74.8 mg), potassium phosphate (178.8 mg), and dioxane at room temperature. Ring (5 mL) and water (0.5 mL), replaced with argon three times, placed in a 100°C oil bath and stirred for 16 hours. The reaction end point was monitored by TLC (developing agent: MeOH/DCM=1/12.5). The reaction solution was spin-dried under reduced pressure and then subjected to sample column chromatography to obtain a total of 300 mg of intermediate 1-2, with a yield of 65%, [M+H] + 683.23.
步骤3：化合物1的合成Step 3: Synthesis of Compound 1
称取化合物1-2(300mg)于100mL圆底烧瓶中，室温下加入甲醇(10mL)，搅拌下缓慢加入盐酸/甲醇溶液(4N,10mL)，室温下搅拌反应16小时。LCMS监测反应终点，反应液减压旋干，加入饱和碳酸钠水溶液中和，再用二氯甲烷萃取三次后，合并有机相用无水硫酸钠干燥。旋干后用制备板分离纯化，得终产品70mg，收率32％。质谱：[M+H]+495.19；1H NMR(DMSO-d6,500MHz)δ13.60(s,1H),7.73(dd,J＝7.4,2.2Hz,1H),7.51–7.37(m,3H),7.32–7.17(m,3H),4.08(s,1H),3.54–3.44(m,2H),3.40(s,3H),3.05(d,J＝14.6Hz,2H),2.75(d,J＝15.9Hz,1H),2.00–1.83(m,2H),1.56(d,J＝13.3Hz,1H),1.32(d,J＝12.9Hz,1H)。Weigh compound 1-2 (300 mg) into a 100 mL round-bottomed flask, add methanol (10 mL) at room temperature, slowly add hydrochloric acid/methanol solution (4N, 10 mL) under stirring, and stir for 16 hours at room temperature. LCMS monitored the end point of the reaction. The reaction solution was spin-dried under reduced pressure, neutralized by adding saturated aqueous sodium carbonate solution, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. After spinning to dryness, it was separated and purified using a preparation plate to obtain 70 mg of the final product, with a yield of 32%. Mass spectrum: [M+H] + 495.19; 1 H NMR (DMSO-d 6 , 500MHz) δ 13.60 (s, 1H), 7.73 (dd, J = 7.4, 2.2Hz, 1H), 7.51–7.37 (m, 3H),7.32–7.17(m,3H),4.08(s,1H),3.54–3.44(m,2H),3.40(s,3H),3.05(d,J＝14.6Hz,2H),2.75(d ,J＝15.9Hz,1H),2.00–1.83(m,2H),1.56(d,J＝13.3Hz,1H),1.32(d,J＝12.9Hz,1H).
实施例2：化合物2的合成
Example 2: Synthesis of Compound 2
步骤1：化合物2-1的合成Step 1: Synthesis of compound 2-1
称取IM16(100mg，0.25mmol)、IM13(69mg，0.30mmol)、DIPEA(66mg，0.50mmol)于100mL圆底烧瓶中，然后加DMF(2mL)溶解，混合物在60℃油浴中反应6小时。TLC监控反应终点(DCM/MeOH＝20/1)，显示反应完毕。反应液加入水中析出黄色固体，抽滤，滤饼旋干得粗品无色油状物2-1粗品110mg，收率74％，[M+H]+587.21。Weigh IM16 (100 mg, 0.25 mmol), IM13 (69 mg, 0.30 mmol), and DIPEA (66 mg, 0.50 mmol) in a 100 mL round-bottomed flask, then add DMF (2 mL) to dissolve, and react the mixture in a 60°C oil bath for 6 hours. . TLC monitored the reaction end point (DCM/MeOH=20/1), indicating that the reaction was completed. The reaction solution was added to water to precipitate a yellow solid, which was suction-filtered, and the filter cake was spin-dried to obtain 110 mg of crude colorless oil 2-1, yield 74%, [M+H] + 587.21.
步骤2：化合物2-2的合成Step 2: Synthesis of compound 2-2
称取2-1(110mg，0.19mmol)、三丁基乙烯基锡(322mg，0.28mmol)、Pd(PPh3)4(43.4mg，0.038mmol)，TEA(38mg，0.37mmol)于100mL圆底烧 瓶中，然后加DMF(5mL)溶解，混合物用氩气置换3次气体后置于110℃油浴中反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品。粗品柱层析分离(DCM/MeOH＝40/1)得黄色油状物80mg，收率：88％。[M+H]+487.61。Weigh 2-1 (110 mg, 0.19 mmol), tributyl vinyl tin (322 mg, 0.28 mmol), Pd(PPh 3 ) 4 (43.4 mg, 0.038 mmol), and TEA (38 mg, 0.37 mmol) in a 100 mL round bottom burn bottle, and then add DMF (5 mL) to dissolve. The mixture was replaced with argon three times and then placed in a 110°C oil bath for reaction for 12 hours. TLC monitored the reaction end point (DCM/MeOH=40/1), and the reaction was completed after about 12 hours. The reaction solution was suction-filtered through diatomaceous earth, and the filtrate was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=40/1) to obtain 80 mg of yellow oil, yield: 88%. [M+H] + 487.61.
步骤3：化合物2-3的合成Step 3: Synthesis of Compound 2-3
称取2-2(80mg，0.16mmol)、K2OsO4·2H2O(5.5mg，0.016mmol)、NaIO4(35mg，0.16mmol)，于100mL圆底烧瓶中，然后加THF(2mL)和H2O(2mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加亚硫酸氢钠水溶液淬灭，然后用EA萃取，有机相旋干得粗品90mg，不纯化直接进行下一步。[M+H]+488.6。Weigh 2-2 (80mg, 0.16mmol), K 2 OsO 4· 2H 2 O (5.5mg, 0.016mmol), and NaIO 4 (35mg, 0.16mmol) into a 100mL round-bottomed flask, then add THF (2mL) and H 2 O (2 mL) were dissolved, and the mixture was reacted at 25°C for 12 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 12 hours. The reaction solution was quenched by adding sodium bisulfite aqueous solution, and then extracted with EA. The organic phase was spin-dried to obtain 90 mg of crude product. The next step was carried out without purification. [M+H] + 488.6.
步骤4：化合物2-4的合成Step 4: Synthesis of Compound 2-4
称取2-3(90mg，0.18mmol)、盐酸羟胺NH2OH·HCl(14.1mg，0.21mmol)于100mL圆底烧瓶中，然后加EtOH(1mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得黄色固体60mg，[M+H]+503.3。Weigh 2-3 (90 mg, 0.18 mmol) and hydroxylamine hydrochloride NH 2 OH·HCl (14.1 mg, 0.21 mmol) into a 100 mL round-bottomed flask, then add EtOH (1 mL) to dissolve, and the mixture was reacted at 25°C for 12 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 12 hours. The reaction solution was quenched with water, then extracted with DCM, and the organic phase was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=20/1) to obtain 60 mg of yellow solid, [M+H] + 503.3.
步骤5：化合物2-5的合成Step 5: Synthesis of Compounds 2-5
称取2-4(60mg，0.12mmol)于25mL圆底烧瓶中，加MeOH(3mL)和H2O(0.6mL)溶解，然后加入苯乙炔(6mg，0.24mmol)、PhI(AcO)2(57.6mg，0.18mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得无色油状物31mg，[M+H]+604.30。Weigh 2-4 (60 mg, 0.12 mmol) in a 25 mL round bottom flask, add MeOH (3 mL) and H 2 O (0.6 mL) to dissolve, then add phenylacetylene (6 mg, 0.24 mmol), PhI(AcO) 2 ( 57.6 mg, 0.18 mmol), and the mixture was reacted at 25°C for 12 hours. TLC monitored the reaction end point (DCM/MeOH=40/1), and the reaction was completed after about 12 hours. The reaction solution was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=20/1) to obtain 31 mg of colorless oil, [M+H] + 604.30.
步骤6：化合物2的合成Step 6: Synthesis of Compound 2
称取化合物2-5(31mg)于100mL圆底烧瓶中，室温下加入甲醇(4mL)，搅拌下缓慢加入盐酸/甲醇溶液(4N，4mL)，室温下搅拌反应16小时。LCMS监测反应终点，反应液减压旋干，加入饱和碳酸钠水溶液中和，再用二氯甲烷萃取三次后，合并有机相用无水硫酸钠干燥。旋干后用制备板分离纯化，得终产品10mg。质谱：[M+H]420.2。 Weigh compound 2-5 (31 mg) into a 100 mL round-bottomed flask, add methanol (4 mL) at room temperature, slowly add hydrochloric acid/methanol solution (4N, 4 mL) under stirring, and stir for 16 hours at room temperature. LCMS monitored the end point of the reaction. The reaction solution was spin-dried under reduced pressure, neutralized by adding saturated aqueous sodium carbonate solution, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. After spin drying, use a preparation plate to separate and purify, and obtain 10 mg of the final product. Mass spectrum: [M+H] 420.2.
实施例3：化合物3的合成
Example 3: Synthesis of Compound 3
步骤1：化合物3-1的合成Step 1: Synthesis of compound 3-1
参考化合物2-1的合成方法经由中间体IM16和IM13合成得到，质谱[M+H]587.2。The synthesis method of reference compound 2-1 was obtained through the synthesis of intermediates IM16 and IM13, with a mass spectrum [M+H] of 587.2.
步骤2：化合物3-2的合成Step 2: Synthesis of compound 3-2
向100mL单口烧瓶中加入3-1(100mg，0.16mmol)、Zn(CN)2(28.28mg，0.24mmol)、Pd2(dba)3(14.8mg，0.016mmol)、Pd(dppf)Cl2DCM(13.2mg，0.016mmol)，室温(30℃)下向其中加入水/DMF(2/14mL)，升温至110℃(内温)，搅拌反应5小时。LCMS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物78mg。[M+H]+486.3。Add 3-1 (100mg, 0.16mmol), Zn(CN) 2 (28.28mg, 0.24mmol), Pd 2 (dba) 3 (14.8mg, 0.016mmol), Pd(dppf)Cl 2 DCM to the 100mL single-neck flask. (13.2 mg, 0.016 mmol), add water/DMF (2/14 mL) to it at room temperature (30°C), raise the temperature to 110°C (internal temperature), and stir for 5 hours. LCMS monitoring showed that the raw materials were completely consumed and the temperature dropped. Dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, concentrate, and obtain 78 mg of the target compound by column chromatography. [M+H] + 486.3.
步骤3：化合物3-3的合成Step 3: Synthesis of compound 3-3
向100mL单口烧瓶中加入3-2(78mg，0.15mmol)、盐酸羟胺(15.3mg，0.22mmol)、碳酸氢钠(24.6mg，0.29mmol)，加入乙醇搅拌反应12小时。LCMS监测显示原料反应完全，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次。合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩得目标物0.1g。[M+H]+519.3。Add 3-2 (78 mg, 0.15 mmol), hydroxylamine hydrochloride (15.3 mg, 0.22 mmol), and sodium bicarbonate (24.6 mg, 0.29 mmol) to a 100 mL single-neck flask, add ethanol, and stir for 12 hours. LCMS monitoring showed that the reaction of the raw materials was complete. EA (5 mL) diluted the reaction solution, and water (10 mL) was added to wash the organic phase twice. The organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to obtain 0.1g of the target compound. [M+H] + 519.3.
步骤4：化合物3-4的合成Step 4: Synthesis of Compound 3-4
向100mL单口烧瓶中加入3-3(0.10g，0.19mmol)、苯甲酰氯(32.74mg，0.23mmol)、TEA(23.57mg，0.23mmol)、甲苯(3mL)，0℃搅拌反应1小时，升温至回流搅拌反应12小时。LC-MS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得目标物50mg，[M+H]+605.3。Add 3-3 (0.10g, 0.19mmol), benzoyl chloride (32.74mg, 0.23mmol), TEA (23.57mg, 0.23mmol), and toluene (3mL) to a 100mL single-neck flask, stir and react at 0°C for 1 hour, and raise the temperature. The reaction was stirred under reflux for 12 hours. LC-MS monitoring showed that the raw materials were completely consumed and the temperature dropped. Dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter and concentrate. Column chromatography (PE/EA 5:1) prepared 50 mg of the target compound, [M+H] + 605.3.
步骤5：化合物3的合成Step 5: Synthesis of Compound 3
向100mL单口烧瓶中加入3-4(50mg)，室温(30℃)下加入盐酸甲醇(3mL)，搅拌反应2-3小时，LCMS监测显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和，加入乙酸乙酯(10mL)并萃取反应液，水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 20:1) 并冻干得类白色目标物8mg。质谱：[M+H]421.2。Add 3-4 (50 mg) to a 100 mL single-neck flask, add methanol hydrochloride (3 mL) at room temperature (30°C), and stir for 2-3 hours. LCMS monitoring shows that the raw materials are completely consumed. Add saturated sodium bicarbonate solution to the reaction solution to neutralize, add ethyl acetate (10 mL) and extract the reaction solution, wash the organic phase twice with water (10 mL), combine the organic phases, and dry over anhydrous sodium sulfate for 30 minutes. Filtration, concentration, column chromatography (DCM/MeOH 20:1) And freeze-dried to obtain 8mg of off-white target substance. Mass spectrum: [M+H] 421.2.
经由不同的起始原料和相应的试剂，采用与前述实施例1相似的方法合成得到下列目标物。



Using different starting materials and corresponding reagents, the following target substances were synthesized using a method similar to that of Example 1.



实施例7：化合物7的合成
Example 7: Synthesis of Compound 7
步骤1：化合物7-1的合成Step 1: Synthesis of compound 7-1
向250mL三口瓶中加入THF(80mL)和SM2(3g)，开启搅拌，Ar置换三次后降温至-40℃，缓慢滴加甲基溴化镁(溶于THF,1.0mol/L,63mL)，滴毕于-40℃下继续搅拌约30分钟后置于室温反应。TLC监控反应终点(PE/EA＝5/1)，反应约2小时后显示反应完毕。将反应液缓慢加入至约100mL饱和氯化铵溶液中，分液，有机相用水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，EA洗涤滤饼，滤液真空浓缩至干得产物2.59g，收率：80％。[M+H]+232。Add THF (80 mL) and SM2 (3 g) to a 250 mL three-neck flask, start stirring, replace Ar three times, then cool to -40°C, and slowly add methylmagnesium bromide (dissolved in THF, 1.0 mol/L, 63 mL) dropwise. After the dropwise addition, continue stirring at -40°C for about 30 minutes and then place at room temperature for reaction. TLC monitors the reaction end point (PE/EA=5/1), and the reaction is completed after about 2 hours. Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
步骤2：化合物7-2的合成Step 2: Synthesis of compound 7-2
向50mL单口瓶中加入7-1(0.5g)、Pd/C(50mg)和10mL甲醇，开启搅拌，氢气置换三次后于室温过夜反应。LC-MS监控反应终点，反应约16小时后显示反应完毕。硅藻土过滤去除Pd/C，滤饼用甲醇洗涤2次，合并洗滤液真空浓缩至干得粗品0.43g。[M+H]+142。Add 7-1 (0.5g), Pd/C (50mg) and 10mL methanol to a 50mL single-neck bottle, start stirring, replace with hydrogen three times, and react at room temperature overnight. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 16 hours of reaction. Pd/C was removed by diatomaceous earth filtration, the filter cake was washed twice with methanol, and the combined filtrate was concentrated in vacuum to dryness to obtain 0.43g of crude product. [M+H] + 142.
步骤3：化合物7-3的合成Step 3: Synthesis of compound 7-3
向10mL反应管中加入7-2(100mg)、IM16(43mg)、碳酸钾(173mg)和DMF(2mL)，开启搅拌，升温至60℃反应。LC-MS监控反应终点，反应约2小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤，合并洗滤液真空浓缩至干得粗品70mg。[M+H]+500。Add 7-2 (100 mg), IM16 (43 mg), potassium carbonate (173 mg) and DMF (2 mL) to the 10 mL reaction tube, start stirring, and heat to 60°C for reaction. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 2 hours of reaction. After cooling to room temperature, add water to quench, extract with DCM 3 times, wash the organic phase 3 times with water, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, wash the filter cake with DCM, combine the filtrate and vacuum concentrate to dryness to obtain 70 mg of crude product . [M+H] + 500.
步骤4：化合物7-4的合成Step 4: Synthesis of compound 7-4
向10mL封管中加入7-3(70mg)、二氯苯硼酸(33mg)、PdCl2(dppf)(23mg)、碳酸钾(58mg)、二氧六环(2mL)和水(0.5mL)，氩气置换后于搅拌状态下升温至90℃反应。TLC监控反应终点(PE/EA＝1/1)，反应约2小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干，柱层析(PE/EA＝1/1)，得产物31mg，收率：43％。[M+H]+518。Add 7-3 (70mg), dichlorophenylboronic acid (33mg), PdCl 2 (dppf) (23mg), potassium carbonate (58mg), dioxane (2mL) and water (0.5mL) to the 10mL sealed tube. After argon replacement, the temperature was raised to 90°C for reaction under stirring. TLC monitors the reaction end point (PE/EA=1/1), and the reaction is completed after about 2 hours. After cooling to room temperature, add water to quench, extract with DCM three times, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, filter, and wash the filter cake with DCM. The combined filtrate was concentrated to dryness under vacuum and subjected to column chromatography (PE/EA=1/1) to obtain 31 mg of product, yield: 43%. [M+H] +518 .
步骤5：目标化合物7的合成 Step 5: Synthesis of target compound 7
向25mL反应瓶中加入7-4(31mg)和TFA(5mL)，开启搅拌于室温反应。LC-MS监控反应终点，反应约2小时后显示反应完毕。真空浓缩除尽TFA，加入碳酸钠水溶液，DCM萃取三次，饱和碳酸氢钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤饼DCM洗涤，柱层析(PE/EA＝1/1)，得产物12mg，收率：46％。[M+H]+434。1H NMR(500MHz,DMSO)δ13.40(s,1H),7.71(dd,J＝7.3,2.3Hz,1H),7.48–7.35(m,2H),4.22(d,J＝13.0Hz,3H),3.39(s,3H),2.22(d,J＝6.8Hz,2H),1.98–1.85(m,4H),1.77(d,J＝13.2Hz,2H),1.12(s,3H)。Add 7-4 (31 mg) and TFA (5 mL) to a 25 mL reaction flask, start stirring and react at room temperature. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 2 hours of reaction. Concentrate under vacuum to remove TFA, add sodium carbonate aqueous solution, extract three times with DCM, wash once with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, filter, wash the filter cake with DCM, and perform column chromatography (PE/EA=1/1) to obtain Product 12 mg, yield: 46%. [M+H] +434 . 1 H NMR (500MHz, DMSO) δ13.40(s,1H),7.71(dd,J＝7.3,2.3Hz,1H),7.48–7.35(m,2H),4.22(d,J＝13.0Hz,3H ),3.39(s,3H),2.22(d,J＝6.8Hz,2H),1.98–1.85(m,4H),1.77(d,J＝13.2Hz,2H),1.12(s,3H).
实施例15：化合物15的合成：
Example 15: Synthesis of Compound 15:
参考实施例2的合成方法，经由中间体IM15、IM13合成得到该化合物，[M+H]390.2。Referring to the synthesis method of Example 2, the compound, [M+H] 390.2, was synthesized via intermediates IM15 and IM13.
经由不同的起始原料和相应的试剂，采用与前述实施例1相似的方法合成得到下列目标物。





Using different starting materials and corresponding reagents, the following target substances were synthesized using a method similar to that of Example 1.





实施例19：化合物19的合成
Example 19: Synthesis of Compound 19
步骤1：化合物19-1的合成Step 1: Synthesis of Compound 19-1
向250mL三口瓶中加入THF(80mL)和SM2(3g)，开启搅拌，Ar气置换三次后降温至-40℃，缓慢滴加甲基溴化镁(溶于THF，1.0mol/L，63mL)，滴毕于-40℃下继续搅拌约30分钟后置于室温反应。TLC监控反应终点(PE/EA＝5/1)，反应约2小时后显示反应完毕。将反应液缓慢加入至约100mL饱和氯化铵溶液中，分液，有机相用水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，EA洗涤滤饼，滤液真空浓缩至干得产物2.59g，收率：80％。[M+H]+232。Add THF (80 mL) and SM2 (3 g) to a 250 mL three-neck flask, start stirring, replace Ar gas three times, then cool to -40°C, slowly add methylmagnesium bromide (dissolved in THF, 1.0 mol/L, 63 mL) dropwise , after dropping, continue stirring at -40°C for about 30 minutes and then place at room temperature for reaction. TLC monitors the reaction end point (PE/EA=5/1), and the reaction is completed after about 2 hours. Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
步骤2：化合物19-2的合成Step 2: Synthesis of Compound 19-2
向100mL单口瓶中加入19-1(1.65g)和50mL乙腈，开启搅拌，冰浴下缓慢滴加浓硫酸(7mL)，滴加完毕后撤除冰浴，置于室温反应。LCMS监控反应进程，反应约3小时后显示反应完毕。将反应液置于冰浴中，缓慢加饱和碳酸钠水溶液调节反应液pH至碱性，采用EA萃取三次，合并有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼用EA洗涤两次，合并洗滤液真空浓缩至干得粗品0.86g，[M+H]+273。Add 19-1 (1.65g) and 50mL acetonitrile to a 100mL single-neck bottle, start stirring, and slowly add concentrated sulfuric acid (7mL) dropwise in an ice bath. After the dropwise addition is completed, remove the ice bath and leave it at room temperature for reaction. LCMS monitored the reaction progress and showed that the reaction was complete after about 3 hours of reaction. Place the reaction solution in an ice bath, slowly add saturated sodium carbonate aqueous solution to adjust the pH of the reaction solution to alkalinity, extract three times with EA, wash the combined organic phases three times with water, once with saturated brine, dry over anhydrous sodium sulfate, and filter. , the filter cake was washed twice with EA, the filtrate was combined and concentrated to dryness under vacuum to obtain 0.86g of crude product, [M+H] + 273.
步骤3：化合物19-3的合成Step 3: Synthesis of Compound 19-3
向50mL单口瓶中加入19-2(220mg)，Pd/C(25mg)和甲醇(5mL)，开启搅拌，氢气置换三次后于室温过夜反应。LC-MS监控反应终点，反应约5小时后显示反应完毕。硅藻土过滤去除Pd/C，滤饼用甲醇洗涤2次，合并洗滤液真空浓缩至干得粗品165mg，[M+H]+183。Add 19-2 (220 mg), Pd/C (25 mg) and methanol (5 mL) to a 50 mL single-neck bottle, start stirring, replace with hydrogen three times, and react at room temperature overnight. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 5 hours of reaction. Filter through diatomaceous earth to remove Pd/C, wash the filter cake twice with methanol, combine the filtrate and concentrate to dryness under vacuum to obtain 165 mg of crude product, [M+H] + 183.
步骤4：化合物19-4的合成Step 4: Synthesis of compound 19-4
向25mL单口瓶中加入19-3(109mg)、IM15(66mg)、碳酸钾(124mg)和DMF(3mL)，开启搅拌，升温至60℃反应。LC-MS监控反应终点，反应约16小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干后柱层析(PE/EA＝1/3)，得产物56mg，收率37％。[M+H]+511。Add 19-3 (109 mg), IM15 (66 mg), potassium carbonate (124 mg) and DMF (3 mL) to a 25 mL single-neck bottle, start stirring, and heat to 60°C for reaction. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 16 hours of reaction. After cooling to room temperature, water was added to quench, extracted with DCM three times, the organic phase was washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The combined filtrate was concentrated to dryness under vacuum and then subjected to column chromatography (PE/EA=1/3) to obtain 56 mg of product with a yield of 37%. [M+H] +511 .
步骤5：化合物19-5的合成Step 5: Synthesis of Compound 19-5
向10mL封管中加入19-4(56mg)、二氯苯硼酸(23mg)、PdCl2(dppf)(16 mg)、碳酸钾(42mg)、二氧六环(2mL)和水(0.5mL)，氩气置换后于搅拌状态下升温至90℃反应，LC-MS监控反应终点，反应约16小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干，柱层析(PE/EA＝1/2)，得产物23mg，收率：39％。[M+H]+529。Add 19-4 (56 mg), dichlorophenylboronic acid (23 mg), and PdCl 2 (dppf) (16 mg), potassium carbonate (42 mg), dioxane (2 mL) and water (0.5 mL), after argon replacement, the temperature was raised to 90°C with stirring and the reaction was carried out. LC-MS monitored the reaction end point, which was displayed after about 16 hours of reaction. The reaction is complete. After cooling to room temperature, add water to quench, extract with DCM three times, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, filter, and wash the filter cake with DCM. The combined filtrate was concentrated to dryness under vacuum and subjected to column chromatography (PE/EA=1/2) to obtain 23 mg of product, yield: 39%. [M+H] +529 .
步骤6：化合物19的合成Step 6: Synthesis of Compound 19
向25mL单口瓶中加入19-5(23mg)和TFA(5mL)，开启搅拌于室温反应。LC-MS监控反应终点，反应约14小时后显示反应完毕。真空浓缩除尽TFA，加入碳酸钠水溶液，DCM萃取三次，饱和碳酸氢钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。柱层析(PE/EA＝1/2)，得产物16mg，收率：83％。[M+H]+445。1H NMR(500MHz,DMSO-d6)δ13.39(s,1H),8.28(s,1H),7.72(ddd,J＝17.3,7.9,1.5Hz,2H),7.61(s,1H),7.49(t,J＝7.9Hz,1H),4.68(s,2H),2.53(d,J＝14.9Hz,2H),2.13(d,J＝7.5Hz,2H),2.00–1.88(m,2H),1.83(s,3H),1.65(d,J＝12.8Hz,2H),1.09(s,3H)。Add 19-5 (23 mg) and TFA (5 mL) to a 25 mL single-neck bottle, start stirring and react at room temperature. LC-MS monitors the reaction endpoint and shows that the reaction is complete after about 14 hours of reaction. Concentrate under vacuum to remove all TFA, add sodium carbonate aqueous solution, extract three times with DCM, wash once with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, filter, and wash the filter cake with DCM. Column chromatography (PE/EA=1/2) yielded 16 mg of product, yield: 83%. [M+H] +445 . 1 H NMR (500MHz, DMSO-d 6 ) δ13.39 (s, 1H), 8.28 (s, 1H), 7.72 (ddd, J = 17.3, 7.9, 1.5Hz, 2H), 7.61 (s, 1H), 7.49(t,J＝7.9Hz,1H),4.68(s,2H),2.53(d,J＝14.9Hz,2H),2.13(d,J＝7.5Hz,2H),2.00–1.88(m,2H ), 1.83 (s, 3H), 1.65 (d, J = 12.8Hz, 2H), 1.09 (s, 3H).
实施例20：化合物20的合成
Example 20: Synthesis of Compound 20
步骤1：化合物SM1的合成Step 1: Synthesis of Compound SM1
向100mL单口烧瓶中加入SM1-1(5.0g)、二氯甲烷(5mL)，室温(30℃)下向其中加入无水三氟乙酸(2mL)，搅拌反应1小时，LCMS监测显示原料消耗完全。减压浓缩除去二氯甲烷和三氟乙酸，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物4.0g，收率81％。Add SM1-1 (5.0g) and dichloromethane (5mL) to a 100mL single-neck flask, add anhydrous trifluoroacetic acid (2mL) at room temperature (30°C), and stir for 1 hour. LCMS monitoring shows that the raw materials are completely consumed. . Concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, concentrate, and column chromatography (PE/EA 5:1) 4.0 g of the light yellow target substance was obtained, with a yield of 81%.
步骤2：化合物20-1的合成Step 2: Synthesis of Compound 20-1
向100mL单口烧瓶中加入SM1(71.7mg)、IM15(0.1g)、碳酸钾(77.1mg)，室温(30℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入 水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物0.1g，收率83％。Add SM1 (71.7mg), IM15 (0.1g), and potassium carbonate (77.1mg) to a 100mL single-neck flask, add anhydrous DMF to it at room temperature (30°C), raise the temperature to 60°C (internal temperature), and stir for 5 seconds. hours, TLC monitoring (PE/EA 5:1) showed that the raw materials were completely consumed. Cool down, dilute the reaction solution with EA (5mL), and add Wash the organic phase twice with water (10 mL), combine the organic phases, dry with anhydrous sodium sulfate for 30 minutes, filter, concentrate, and column chromatography (PE/EA 5:1) to obtain 0.1g of the light yellow target substance, yield 83% .
步骤3：化合物20-2的合成Step 3: Synthesis of compound 20-2
向100mL单口烧瓶中加入二氯苯硼酸(50.51mg)、20-1(0.1g)、磷酸钾(60.98mg)、Pd(dppf)Cl2(5.4mg)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环/水混合溶剂，升温至80-85℃(内温)，搅拌反应5小时。TLC监测(PE/EA 5:1)显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA2:1)制得淡黄色目标物0.09g，收率90％。[M+H]+472。Add dichlorophenylboronic acid (50.51mg), 20-1 (0.1g), potassium phosphate (60.98mg), Pd(dppf)Cl 2 (5.4mg) to a 100mL single- neck flask, replace with N 4-5 times, and bring to room temperature. (30°C), pump in the dioxane/water mixed solvent under negative pressure, raise the temperature to 80-85°C (internal temperature), and stir for 5 hours. TLC monitoring (PE/EA 5:1) shows that the raw materials are completely consumed, cool down, dilute the reaction solution with EA (5mL), add water (10mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, concentrate. Column chromatography (PE/EA2:1) prepared 0.09g of the light yellow target substance with a yield of 90%. [M+H] +472 .
步骤4：化合物20-3的合成Step 4: Synthesis of compound 20-3
向100mL单口烧瓶中加入20-2(90mg)，室温(30℃)下加入盐酸甲醇溶液，并搅拌反应2-3小时，TLC监测(PE/EA 5:1)显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和反应液，加入EA(5mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 20:1)并冻干得类白色目标物30mg，收率40.5％。[M+H]+388.0763。1H NMR(500MHz,DMSO-d6)δ13.58(s,1H),8.49(s,1H),7.73(ddd,J＝21.7,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),4.98(s,2H),2.74(dd,J＝15.6,4.4Hz,2H),2.32(d,J＝15.6Hz,2H),2.15(d,J＝9.8Hz,2H),1.76(d,J＝7.6Hz,3H)。Add 20-2 (90 mg) to a 100 mL single-neck flask, add hydrochloric acid methanol solution at room temperature (30°C), and stir for 2-3 hours. TLC monitoring (PE/EA 5:1) shows that the raw materials are completely consumed. Add saturated sodium bicarbonate solution to the reaction solution to neutralize the reaction solution, add EA (5 mL) to extract the reaction solution twice, wash the organic phase once with water (10 mL), combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, and filter. concentrate. Column chromatography (DCM/MeOH 20:1) and freeze-drying gave 30 mg of the off-white target substance, with a yield of 40.5%. [M+H] + 388.0763. 1 H NMR (500MHz, DMSO-d 6 ) δ13.58 (s, 1H), 8.49 (s, 1H), 7.73 (ddd, J＝21.7, 7.8, 1.6Hz, 2H), 7.50 (t, J＝7.9 Hz,1H),4.98(s,2H),2.74(dd,J＝15.6,4.4Hz,2H),2.32(d,J＝15.6Hz,2H),2.15(d,J＝9.8Hz,2H), 1.76(d,J=7.6Hz,3H).
步骤5：化合物20的合成Step 5: Synthesis of Compound 20
向100mL单口烧瓶中加入20-3(30mg)，室温(30℃)下加入THF(2mL)，加入硼氢化钠(5mg)并搅拌反应2-3小时，TLC监测(PE/EA 5:1)显示原料消耗完全。向反应液中加入饱和氯化铵溶液淬灭反应。加入水、EA(5mL)萃取反应液两次，水(10mL)洗涤有机相2次，合并有机相，无水硫酸镁干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 10:1)并冻干得类白色目标物9mg，收率30％。[M+H]+390.0876。1H NMR(500MHz,DMSO-d6)δ13.44(s,1H),8.31(s,1H),7.72(ddd,J＝22.1,7.9,1.6Hz,2H),7.49(t,J＝7.9Hz,1H),4.71(q,J＝4.0,3.3Hz,2H),4.43(d,J＝6.3Hz,1H),4.04(dq,J＝10.8,5.3Hz,1H),2.00(dd,J＝8.6,4.1Hz,2H),1.92–1.77(m,4H),1.51(t,J＝11.6Hz,2H)。 Add 20-3 (30mg) to a 100mL single-neck flask, add THF (2mL) at room temperature (30°C), add sodium borohydride (5mg) and stir for 2-3 hours, monitor by TLC (PE/EA 5:1) It shows that the raw materials are completely consumed. Add saturated ammonium chloride solution to the reaction solution to quench the reaction. Add water and EA (5 mL) to extract the reaction solution twice, wash the organic phase twice with water (10 mL), combine the organic phases, dry over anhydrous magnesium sulfate for 30 minutes, filter and concentrate. Column chromatography (DCM/MeOH 10:1) and freeze-drying gave 9 mg of the off-white target substance, with a yield of 30%. [M+H] + 390.0876. 1 H NMR (500MHz, DMSO-d 6 ) δ13.44(s,1H),8.31(s,1H),7.72(ddd,J＝22.1,7.9,1.6Hz,2H),7.49(t,J＝7.9 Hz,1H),4.71(q,J＝4.0,3.3Hz,2H),4.43(d,J＝6.3Hz,1H),4.04(dq,J＝10.8,5.3Hz,1H),2.00(dd,J =8.6,4.1Hz,2H),1.92–1.77(m,4H),1.51(t,J=11.6Hz,2H).
实施例21：化合物21的合成
Example 21: Synthesis of Compound 21
步骤1：化合物SM1的合成Step 1: Synthesis of Compound SM1
参考上述实施例20中间体SM1的合成方法。Refer to the synthesis method of intermediate SM1 in Example 20 above.
步骤2：化合物21-1的合成Step 2: Synthesis of compound 21-1
向100mL单口烧瓶中加入SM1(0.36g)、IM15(0.5g)、碳酸钾(0.39g)，室温(30℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物0.45g，收率62％。Add SM1 (0.36g), IM15 (0.5g), and potassium carbonate (0.39g) to a 100mL single-neck flask, add anhydrous DMF to it at room temperature (30°C), raise the temperature to 60°C (internal temperature), and stir for 5 seconds. Hours, TLC monitoring (PE/EA 5:1) shows that the raw materials are completely consumed. Cool down, dilute the reaction solution with EA (5mL), add water (10mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, concentrate, and prepare by column chromatography (PE/EA 5:1) 0.45g of light yellow target substance, yield 62%.
步骤3：化合物21-2的合成Step 3: Synthesis of compound 21-2
向100mL单口烧瓶中加入二氯苯硼酸(45.45mg)、21-1(90mg)、碳酸钾(55.12mg)、Pd(dppf)Cl2DCM(0.51mg)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环/水混合溶剂，升温至80-85℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得淡黄色目标物78mg，收率96％。[M+H]+472.1312。Add dichlorophenylboronic acid (45.45mg), 21-1 (90mg), potassium carbonate (55.12mg), Pd(dppf)Cl 2 DCM (0.51mg) to a 100mL single - neck flask, replace with N 4-5 times, room temperature (30°C), pump in the dioxane/water mixed solvent under negative pressure, raise the temperature to 80-85°C (internal temperature), stir and react for 5 hours, TLC monitoring (PE/EA 5:1) shows that the raw materials are completely consumed. Cool the temperature, dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter and concentrate. Column chromatography (PE/EA 5:1) prepared 78 mg of the light yellow target substance with a yield of 96%. [M+H] + 472.1312.
步骤4.中间体21-3的合成Step 4. Synthesis of Intermediate 21-3
向250mL三口烧瓶中加入KOH(10.8mg)、甲醇(2mL)，0℃搅拌。向其中滴加21-2的甲醇溶液(1mL)，滴加完成后保温反应25分钟，加入醋酸碘苯(20.84mg)，保温反应3-4小时。LCMS监测显示反应完全。向反应液中加入乙酸乙酯(10mL)、水(10mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，不进一步纯化，下一步直接使用。[M+H]+534.1670。 Add KOH (10.8 mg) and methanol (2 mL) to a 250 mL three-necked flask, and stir at 0°C. A methanol solution of 21-2 (1 mL) was added dropwise to it. After the dropwise addition was completed, the reaction was incubated for 25 minutes. Iodobenzene acetate (20.84 mg) was added and the reaction was incubated for 3-4 hours. LCMS monitoring showed that the reaction was complete. Add ethyl acetate (10 mL) and water (10 mL) to the reaction solution to extract the reaction solution twice, wash the organic phase once with water (10 mL), combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, and concentrate without further treatment. Purified and used directly in the next step. [M+H] + 534.1670.
步骤5.化合物21的合成Step 5. Synthesis of Compound 21
向100mL单口烧瓶中加入21-3(90mg)，室温(30℃)下加入二氯甲烷溶解，并加入三氟乙酸(2mL)，搅拌反应2-3小时，TLC监测(PE/EA 1:1)显示原料消耗完全。减压浓缩除去溶剂和三氟乙酸，向反应液中加入乙酸乙酯(10mL)，饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 10:1)并冻干得类白色目标物7mg，收率11％。[M+H]+404.0717。1H NMR(500MHz,DMSO-d6)δ13.60(s,1H),8.50(s,1H),7.73(ddd,J＝21.8,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.61(d,J＝4.9Hz,1H),4.97(t,J＝6.0Hz,1H),4.84(t,J＝5.8Hz,1H),4.14(d,J＝5.5Hz,1H),2.83(d,J＝15.4Hz,1H),2.36(dd,J＝14.7,1.8Hz,1H),2.14–2.07(m,1H),2.00–1.90(m,2H),1.62(ddd,J＝13.5,9.6,4.6Hz,1H)。Add 21-3 (90mg) to a 100mL single-neck flask, add methylene chloride at room temperature (30°C) to dissolve, add trifluoroacetic acid (2mL), stir and react for 2-3 hours, monitor by TLC (PE/EA 1:1 ) shows that the raw materials are completely consumed. Concentrate under reduced pressure to remove the solvent and trifluoroacetic acid. Add ethyl acetate (10 mL) to the reaction solution. Neutralize and extract the reaction solution with saturated sodium bicarbonate solution. Wash the organic phase once with water (10 mL). Combine the organic phases and remove anhydrous. Dry over sodium sulfate for 30 minutes, filter and concentrate. Column chromatography (DCM/MeOH 10:1) and freeze-drying gave 7 mg of the off-white target substance, with a yield of 11%. [M+H] + 404.0717. 1 H NMR (500MHz, DMSO-d 6 ) δ13.60 (s, 1H), 8.50 (s, 1H), 7.73 (ddd, J＝21.8, 7.8, 1.6Hz, 2H), 7.50 (t, J＝7.9 Hz,1H),5.61(d,J＝4.9Hz,1H),4.97(t,J＝6.0Hz,1H),4.84(t,J＝5.8Hz,1H),4.14(d,J＝5.5Hz, 1H),2.83(d,J＝15.4Hz,1H),2.36(dd,J＝14.7,1.8Hz,1H),2.14–2.07(m,1H),2.00–1.90(m,2H),1.62(ddd ,J=13.5,9.6,4.6Hz,1H).
实施例28：化合物28的合成
Example 28: Synthesis of Compound 28
步骤1：化合物28-1的合成Step 1: Synthesis of Compound 28-1
向50mL三口烧瓶中加入21-3(100mg)、DCM(2mL)，0℃搅拌。向其中滴加DAST(60.33mg，0.37mmol)，滴加完成后转移至室温(25℃)反应2小时。取样LCMS监测显示反应完全，室温浓缩至干，向其中加入乙酸乙酯(10mL)、碳酸氢钠水溶液(10mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析制得80mg，收率70％。[M+H]+536.15。Add 21-3 (100 mg) and DCM (2 mL) to a 50 mL three-necked flask, and stir at 0°C. DAST (60.33 mg, 0.37 mmol) was added dropwise thereto. After the dropwise addition was completed, the mixture was transferred to room temperature (25°C) and allowed to react for 2 hours. Sampling LCMS monitoring showed that the reaction was complete. Concentrate to dryness at room temperature. Add ethyl acetate (10 mL) and sodium bicarbonate aqueous solution (10 mL) to extract the reaction solution twice. Wash the organic phase once with water (10 mL). Combine the organic phases. Dry over sodium sulfate for 30 minutes, filter and concentrate. 80 mg was obtained by column chromatography, with a yield of 70%. [M+H] + 536.15.
步骤2：化合物28-2的合成Step 2: Synthesis of Compound 28-2
向100mL单口烧瓶中加入28-1(80mg)，室温(30℃)下加入二氯甲烷溶解，并加入三氟乙酸(2mL)，搅拌反应2-3小时。TLC监测(PE/EA 1:1)显示原料消耗完全。减压浓缩除去溶剂和三氟乙酸，向反应液中加入乙酸乙酯(10mL)， 饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 10:1)并冻干得类白色目标物60mg，收率54％。[M+H]+406.0642。1H NMR(500MHz,DMSO-d6)δ13.62(s,1H),8.47(s,1H),7.73(ddd,J＝31.6,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H)。Add 28-1 (80 mg) to a 100 mL single-neck flask, add dichloromethane at room temperature (30°C) to dissolve, add trifluoroacetic acid (2 mL), and stir for 2-3 hours. TLC monitoring (PE/EA 1:1) showed complete consumption of raw materials. Concentrate under reduced pressure to remove the solvent and trifluoroacetic acid, and add ethyl acetate (10 mL) to the reaction solution. Neutralize and extract the reaction solution with saturated sodium bicarbonate solution, wash the organic phase once with water (10 mL), combine the organic phases, and dry over anhydrous sodium sulfate for 30 minutes. Filter, concentrate, column chromatography (DCM/MeOH 10:1) and freeze-dry to obtain 60 mg of off-white target substance, yield 54%. [M+H] + 406.0642. 1 H NMR (500MHz, DMSO-d 6 ) δ13.62 (s, 1H), 8.47 (s, 1H), 7.73 (ddd, J = 31.6, 7.8, 1.6Hz, 2H), 7.50 (t, J = 7.9 Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz ,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H).
步骤3：化合物28-3的合成Step 3: Synthesis of Compound 28-3
向100mL单口烧瓶中加入28-2(0.16g)、叔丁基亚磺酰胺(57.14mg)、钛酸四乙酯(0.58g，33％)，室温(25℃)下向其中加入无水THF，升温至80℃(内温)，搅拌反应12-16小时。LCMS监测显示原料消耗完全，降温，向其中加入NaBH4，25℃反应5小时，LCMS监测显示反应完全。EA(5mL)稀释反应液，加入水(10mL)，有大量固体析出，过滤，水洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩得目标物粗品0.1g。[M+H]+511.12499。Add 28-2 (0.16g), tert-butylsulfinamide (57.14mg), and tetraethyl titanate (0.58g, 33%) to a 100mL single-neck flask, and add anhydrous THF to it at room temperature (25°C) , raise the temperature to 80°C (internal temperature), stir and react for 12-16 hours. LCMS monitoring showed that the raw materials were completely consumed. The temperature was lowered, NaBH 4 was added, and the reaction was carried out at 25° C. for 5 hours. LCMS monitoring showed that the reaction was complete. Dilute the reaction solution with EA (5 mL), add water (10 mL), a large amount of solid precipitates, filter, wash the organic phase with water twice, combine the organic phases, and dry over anhydrous sodium sulfate for 30 minutes. Filter and concentrate to obtain 0.1g of the target crude product. [M+H] + 511.12499.
步骤4：化合物28的合成Step 4: Synthesis of Compound 28
向100mL单口烧瓶中加入28-3(100mg)，室温(30℃)下加入盐酸甲醇溶液，搅拌反应2-3小时。TLC监测(PE/EA 1:1)显示原料消耗完全，减压浓缩，向反应液中加入乙酸乙酯(10mL)，饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 10:1)并冻干得类白色目标物8mg，收率10％。[M+H]+407.0978。1H NMR(500MHz,DMSO-d6)δ13.48(s,1H),8.30(s,1H),7.71(ddd,J＝31.5,7.9,1.6Hz,2H),7.49(t,J＝7.9Hz,1H),4.87(dd,J＝10.9,6.2Hz,1H),4.82–4.66(m,3H),3.82(dt,J＝11.5,5.8Hz,1H),2.57–2.52(m,1H),2.45–2.32(m,1H),2.04(dd,J＝12.7,6.2Hz,1H),1.89(d,J＝18.8Hz,1H),1.76–1.66(m,1H),1.54(dd,J＝13.1,5.9Hz,1H)。Add 28-3 (100mg) to a 100mL single-necked flask, add hydrochloric acid methanol solution at room temperature (30°C), and stir for 2-3 hours. TLC monitoring (PE/EA 1:1) showed that the raw materials were completely consumed. Concentrate under reduced pressure. Add ethyl acetate (10 mL) to the reaction solution. Neutralize and extract the reaction solution with saturated sodium bicarbonate solution. Wash the organic phase with water (10 mL). Once, combine the organic phases and dry over anhydrous sodium sulfate for 30 minutes. Filter, concentrate, column chromatography (DCM/MeOH 10:1) and freeze-dry to obtain 8 mg of off-white target substance, yield 10%. [M+H] + 407.0978. 1 H NMR (500MHz, DMSO-d 6 ) δ13.48 (s, 1H), 8.30 (s, 1H), 7.71 (ddd, J = 31.5, 7.9, 1.6Hz, 2H), 7.49 (t, J = 7.9 Hz,1H),4.87(dd,J＝10.9,6.2Hz,1H),4.82–4.66(m,3H),3.82(dt,J＝11.5,5.8Hz,1H),2.57–2.52(m,1H) ,2.45–2.32(m,1H),2.04(dd,J＝12.7,6.2Hz,1H),1.89(d,J＝18.8Hz,1H),1.76–1.66(m,1H),1.54(dd,J =13.1,5.9Hz,1H).
实施例29：化合物29的合成
Example 29: Synthesis of Compound 29
步骤1：化合物29-1的合成Step 1: Synthesis of Compound 29-1
参考化合物1-1的合成方法经由中间体IM15和IM18合成得到，[M+H]635。The synthesis method of reference compound 1-1 is obtained through the synthesis of intermediates IM15 and IM18, [M+H]635.
步骤2：化合物29-2的合成Step 2: Synthesis of compound 29-2
向100mL单口烧瓶中加入29-1(100mg，0.16mmol)、Zn(CN)2(28.28mg，0.24mmol)、Pd2(dba)3(14.8mg，0.016mmol)、Pd(dppf)Cl2DCM(13.2mg，0.016mmol)，室温(30℃)下向其中加入水/DMF(2/14mL)，升温至110℃(内温)，搅拌反应5小时。LCMS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物78mg。[M+H]+534.2648。Add 29-1 (100mg, 0.16mmol), Zn(CN) 2 (28.28mg, 0.24mmol), Pd 2 (dba) 3 (14.8mg, 0.016mmol), Pd(dppf)Cl 2 DCM to the 100mL single-neck flask. (13.2 mg, 0.016 mmol), add water/DMF (2/14 mL) to it at room temperature (30°C), raise the temperature to 110°C (internal temperature), and stir for 5 hours. LCMS monitoring showed that the raw materials were completely consumed and the temperature dropped. Dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter, concentrate, and obtain 78 mg of the target compound by column chromatography. [M+H] + 534.2648.
步骤3：化合物29-3的合成Step 3: Synthesis of Compound 29-3
向100mL单口烧瓶中加入29-2(78mg，0.15mmol)、盐酸羟胺(15.3mg，0.22mmol)、碳酸氢钠(24.6mg，0.29mmol)，加入乙醇搅拌反应12小时。LCMS监测显示原料反应完全，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次。合并有机相，无水硫酸钠干燥30min，过滤，浓缩得目标物0.12g。[M+H]+679.2788。Add 29-2 (78 mg, 0.15 mmol), hydroxylamine hydrochloride (15.3 mg, 0.22 mmol), and sodium bicarbonate (24.6 mg, 0.29 mmol) to a 100 mL single-neck flask, add ethanol, and stir for 12 hours. LCMS monitoring showed that the reaction of the raw materials was complete. EA (5 mL) diluted the reaction solution, and water (10 mL) was added to wash the organic phase twice. The organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to obtain 0.12g of the target compound. [M+H] + 679.2788.
步骤4：化合物29-4的合成Step 4: Synthesis of compound 29-4
向100mL单口烧瓶中加入29-3(0.12g，0.21mmol)、苯甲酰氯(32.74mg，0.23mmol)、TEA(23.57mg，0.23mmol)、甲苯(3mL)，0℃搅拌反应1小时，升温至回流搅拌反应12小时。LC-MS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得目标物50mg，收率25％。[M+H]+653.3330。Add 29-3 (0.12g, 0.21mmol), benzoyl chloride (32.74mg, 0.23mmol), TEA (23.57mg, 0.23mmol), and toluene (3mL) to a 100mL single-neck flask, stir and react at 0°C for 1 hour, and raise the temperature. The reaction was stirred under reflux for 12 hours. LC-MS monitoring showed that the raw materials were completely consumed and the temperature dropped. Dilute the reaction solution with EA (5 mL), add water (10 mL) to wash the organic phase twice, combine the organic phases, dry over anhydrous sodium sulfate for 30 minutes, filter and concentrate. Column chromatography (PE/EA 5:1) was used to obtain 50 mg of the target compound with a yield of 25%. [M+H] + 653.3330.
步骤5：化合物29的合成Step 5: Synthesis of Compound 29
向100mL单口烧瓶中加入29-4(50mg)，室温(30℃)下加入盐酸甲醇(3mL)，搅拌反应2-3小时，LCMS监测显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和，加入乙酸乙酯(10mL)并萃取反应液，水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH20:1)并冻干得类白色目标物10mg。HPLC 99.4％，[M+H]+465.2185。1H NMR(500MHz,DMSO-d6)δ8.68(s,1H),8.32–8.25(m,2H),7.76(t,J＝7.6Hz,2H),7.38(d,J＝6.5Hz,1H),7.28–7.23(m,3H),5.39(t,J＝5.1Hz,2H),4.44(s,2H),3.94(s,1H),3.25–3.16(m,3H),2.74(d,J＝15.7Hz,1H),2.08(d,J＝7.4Hz,2H),1.91–1.88(m,1H),1.67–1.61(m,2H)。 Add 29-4 (50 mg) to a 100 mL single-neck flask, add methanol hydrochloride (3 mL) at room temperature (30°C), and stir for 2-3 hours. LCMS monitoring shows that the raw materials are completely consumed. Add saturated sodium bicarbonate solution to the reaction solution to neutralize, add ethyl acetate (10 mL) and extract the reaction solution, wash the organic phase twice with water (10 mL), combine the organic phases, and dry over anhydrous sodium sulfate for 30 minutes. Filter, concentrate, column chromatography (DCM/MeOH20:1) and freeze-dry to obtain 10 mg of off-white target substance. HPLC 99.4%, [M+H] + 465.2185. 1 H NMR (500MHz, DMSO-d 6 ) δ8.68 (s, 1H), 8.32–8.25 (m, 2H), 7.76 (t, J = 7.6Hz, 2H), 7.38 (d, J = 6.5Hz, 1H),7.28–7.23(m,3H),5.39(t,J＝5.1Hz,2H),4.44(s,2H),3.94(s,1H),3.25–3.16(m,3H),2.74(d ,J＝15.7Hz,1H),2.08(d,J＝7.4Hz,2H),1.91–1.88(m,1H),1.67–1.61(m,2H).
实施例30：化合物30的合成
Example 30: Synthesis of Compound 30
按照与实施例29相似的方法合成化合物30。[M+H]+533.14。1H NMR(500MHz,DMSO-d6)δ8.64(s,1H),8.16(dd,J＝7.9,1.6Hz,1H),8.03(dd,J＝8.1,1.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.42–7.33(m,1H),7.27–7.21(m,3H),5.32(t,J＝5.1Hz,1H),4.43–4.35(m,2H),4.04(s,1H),3.15(d,J＝15.8Hz,1H),2.79(d,J＝15.8Hz,1H),1.98(q,J＝6.6,5.1Hz,2H),1.79–1.71(m,1H),1.58(d,J＝13.3Hz,1H)。Compound 30 was synthesized in a similar manner to Example 29. [M+H] + 533.14. 1 H NMR (500MHz, DMSO-d 6 ) δ8.64 (s, 1H), 8.16 (dd, J = 7.9, 1.6 Hz, 1H), 8.03 ( dd, J = 8.1, 1.6 Hz, 1H), 7.67 ( t,J＝8.0Hz,1H),7.42–7.33(m,1H),7.27–7.21(m,3H),5.32(t,J＝5.1Hz,1H),4.43–4.35(m,2H),4.04 (s,1H),3.15(d,J＝15.8Hz,1H),2.79(d,J＝15.8Hz,1H),1.98(q,J＝6.6,5.1Hz,2H),1.79–1.71(m, 1H), 1.58 (d, J = 13.3Hz, 1H).
经由不同的起始原料和相应的试剂，采用与前述实施例29相似的方法合成得到下列目标物。

Using different starting materials and corresponding reagents, the following target substances were synthesized using a method similar to that of Example 29.

实施例40：化合物40的合成
Example 40: Synthesis of Compound 40
步骤1：化合物40-1的合成Step 1: Synthesis of Compound 40-1
于100mL单口瓶中加入原料SM2(3g)，并用50mL DMSO溶解，随后加入Me3SI(3g)，在搅拌下缓慢加入叔丁醇钾(1.65g)。加料完毕后，于25℃下搅拌反应1小时。TLC检测，以PE:EA＝5:1为展开剂，原料无剩余。向反应液中加入水淬灭反应，并加入石油醚萃取，合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩，得白色固体目标产物3g，收率为94.6％。[M+H]+230。Add the raw material SM2 (3g) to a 100mL single-neck bottle and dissolve it with 50mL DMSO. Then add Me 3 SI (3g), and slowly add potassium tert-butoxide (1.65g) under stirring. After the addition was completed, the reaction was stirred at 25°C for 1 hour. TLC test showed that PE:EA=5:1 was used as the developing agent, and there was no remaining raw material. Water was added to the reaction solution to quench the reaction, and petroleum ether was added for extraction. The organic phases were combined, washed with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrate to obtain 3g of the target product as a white solid, with a yield of 94.6%. [M+H] + 230.
步骤2：化合物40-2的合成Step 2: Synthesis of Compound 40-2
将原料40-1(400mg)溶于10mL的7M NH3甲醇溶液中，并将反应液转移至封管中于80℃下搅拌反应16小时。TLC检测，以DCM:MeOH＝10:1为展开剂，原料无剩余。将反应液直接浓缩至干，并用DCM带除残留的NH3，浓缩后静置一段时间，得黄色固体400mg，收率94％。[M+H]+247。Dissolve raw material 40-1 (400 mg) in 10 mL of 7M NH 3 methanol solution, transfer the reaction solution to a sealed tube, and stir for 16 hours at 80°C. TLC detection, using DCM:MeOH=10:1 as the developing agent, there is no remaining raw material. The reaction solution was directly concentrated to dryness, and residual NH 3 was removed with DCM. After concentration, it was allowed to stand for a period of time to obtain 400 mg of yellow solid with a yield of 94%. [M+H] +247 .
步骤3：化合物40-3的合成Step 3: Synthesis of Compound 40-3
于25mL单口瓶中将原料40-2(150mg)溶于无水THF(5mL)中，随后加入三乙胺(82.2mg)及DMAP(10mg)，于25℃下搅拌活化10分钟后。加入的Boc2O(106mg)，并继续在25℃下搅拌反应2小时。LCMS检测原料无剩余，且产物峰为主要信号峰，将反应液加水淬灭，并用DCM萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品。柱层析纯化，以PE:EA＝5:1为展开剂，得黄色油状物170mg，收率81％。[M+H]+347。Dissolve raw material 40-2 (150 mg) in anhydrous THF (5 mL) in a 25 mL single-neck bottle, then add triethylamine (82.2 mg) and DMAP (10 mg), and stir and activate at 25°C for 10 minutes. Boc 2 O (106 mg) was added and the reaction was continued to stir at 25 °C for 2 h. LCMS detected that there was no remaining raw material and the product peak was the main signal peak. The reaction solution was quenched with water and extracted with DCM. The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification by column chromatography, using PE:EA=5:1 as the developing solvent, yielded 170 mg of yellow oil, with a yield of 81%. [M+H] +347 .
步骤4：化合物40-4的合成Step 4: Synthesis of Compound 40-4
于50mL单口瓶中加入原料40-3(170mg)，随后加入无水甲醇(15mL)溶解，并加入的Pd/C(20mg)。于氢气球保护下，在25℃下搅拌反应20小时，LCMS 检测原料无剩余。硅藻土抽滤，收集滤液，浓缩，即得目标产物120mg，为黄色油状物。收率95.2％，[M+H]+257。Add raw material 40-3 (170 mg) to a 50 mL single-neck bottle, then add anhydrous methanol (15 mL) to dissolve, and add Pd/C (20 mg). Under the protection of a hydrogen balloon, stir the reaction at 25°C for 20 hours, LCMS Check that there is no remaining raw material. Filter through diatomaceous earth, collect the filtrate, and concentrate to obtain 120 mg of the target product as a yellow oil. Yield 95.2%, [M+H] + 257.
步骤5：化合物40-5的合成Step 5: Synthesis of Compound 40-5
于50mL单口瓶中加入原料40-4(120mg)及IM15(222mg)并用DMF(10mL)溶解，加入碳酸钾(195mg)后，升温至60℃搅拌反应3小时。LCMS检测原料无剩余，TLC检测以PE:EA＝2:1为展开剂。向反应液中加入水淬灭反应，并用EA萃取，合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品。柱层析纯化，以PE:EA＝2:1为展开剂，得纯化后产物150mg，收率55％。[M+H]+585。Add raw materials 40-4 (120 mg) and IM15 (222 mg) to a 50 mL single-neck bottle and dissolve them in DMF (10 mL). After adding potassium carbonate (195 mg), the temperature is raised to 60°C and stirred for 3 hours. The LCMS test showed that there was no remaining raw material, and the TLC test used PE:EA=2:1 as the developing agent. Water was added to the reaction solution to quench the reaction, and extracted with EA. The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purified by column chromatography, using PE:EA=2:1 as the developing solvent, 150 mg of the purified product was obtained with a yield of 55%. [M+H] +585 .
步骤6：化合物40-6的合成Step 6: Synthesis of Compound 40-6
于50mL单口瓶中加入原料40-5(150mg)，用二氧六环(20mL)及水(2mL)混合溶剂溶解，随后加入的二氯苯硼酸(59mg)、钯催化剂(20mg)及碳酸钾(106mg)，氩气置换三次保护下，升温至90℃下搅拌反应16小时。LCMS检测原料无剩余且有产物峰出现，将反应液直接浓缩至干。柱层析纯化，以PE:EA＝2:1为展开剂，得纯化后产物100mg，收率为65％。[M+H]+603。Add raw material 40-5 (150mg) into a 50mL single-neck bottle, dissolve it in a mixed solvent of dioxane (20mL) and water (2mL), and then add dichlorophenylboronic acid (59mg), palladium catalyst (20mg) and potassium carbonate (106mg), under the protection of argon gas replacement three times, the temperature was raised to 90°C and the reaction was stirred for 16 hours. LCMS detected that there was no remaining raw material and product peak appeared, and the reaction solution was directly concentrated to dryness. Purified by column chromatography, using PE:EA=2:1 as the developing solvent, 100 mg of the purified product was obtained with a yield of 65%. [M+H] +603 .
步骤7：化合物40的合成Step 7: Synthesis of Compound 40
于50mL单口瓶中加入原料40-6(100mg)，随后加入4M HCl甲醇溶液(10mL)溶解原料，并于25℃下搅拌反应2小时。LCMS检测，原料无剩余。将反应液直接浓缩至干，随后加入饱和碳酸钠溶液调节pH＝8～9，并用乙酸乙酯萃取，合并有机相。依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得粗品60mg。将粗品柱层析纯化，以DCM:MeOH＝5:1为展开剂，收集目标化合物，浓缩后用乙腈/水的混合溶剂冻干，得纯化后白色固体目标化合物30mg，收率43.4％。[M+H]+419.6192。1H NMR(500MHz,DMSO-d6)δ8.26(s,1H),7.75(d,J＝7.8Hz,1H),7.66(d,J＝7.7Hz,1H),7.51(t,J＝7.9Hz,1H),4.76(p,J＝3.1Hz,2H),2.51(s,2H),2.29(d,J＝7.3Hz,2H),1.97(t,J＝5.9Hz,2H),1.79(q,J＝14.1Hz,4H)。Add raw material 40-6 (100 mg) into a 50 mL single-neck bottle, then add 4M HCl methanol solution (10 mL) to dissolve the raw material, and stir and react at 25°C for 2 hours. LCMS test showed no remaining raw materials. The reaction solution was directly concentrated to dryness, then saturated sodium carbonate solution was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate, and the organic phases were combined. Wash with water and saturated sodium chloride solution in sequence, dry with anhydrous sodium sulfate, and concentrate to obtain 60 mg of crude product. The crude product was purified by column chromatography, using DCM:MeOH=5:1 as the developing solvent. The target compound was collected, concentrated and lyophilized with a mixed solvent of acetonitrile/water to obtain 30 mg of the purified white solid target compound, with a yield of 43.4%. [M+H] + 419.6192. 1 H NMR (500MHz, DMSO-d 6 ) δ8.26 (s, 1H), 7.75 (d, J = 7.8Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.51 (t, J = 7.9Hz,1H),4.76(p,J＝3.1Hz,2H),2.51(s,2H),2.29(d,J＝7.3Hz,2H),1.97(t,J＝5.9Hz,2H),1.79 (q,J=14.1Hz,4H).
实施例41：化合物41的合成
Example 41: Synthesis of Compound 41
步骤1：化合物41-1的合成 Step 1: Synthesis of Compound 41-1
于25mL单口瓶中加入原料40-1(300mg)并溶解于水(5mL)中，随后缓慢加入浓硫酸(0.5mL)，滴加完毕后于25摄氏度下搅拌反应16小时。LCMS检测有产物峰，用饱和碳酸钠溶液淬灭并调节pH＝10，随后加入EA萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得产物为黄色油状物200mg，收率为62.5％。[M+H]+248。Add raw material 40-1 (300 mg) into a 25 mL single-neck bottle and dissolve it in water (5 mL). Then slowly add concentrated sulfuric acid (0.5 mL). After the dropwise addition is completed, stir and react at 25 degrees Celsius for 16 hours. The product peak was detected by LCMS, which was quenched with saturated sodium carbonate solution and adjusted to pH=10, and then EA was added for extraction. The organic phases were combined, washed with water and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain 200 mg of the product as a yellow oil, with a yield of 62.5%. [M+H] + 248.
步骤2：化合物41-2的合成Step 2: Synthesis of Compound 41-2
于50mL单口瓶中将原料41-1(200mg)溶于无水甲醇(15mL)中，随后加入Pd/C(30mg)，在氢气球保护下于25℃下搅拌反应20小时。LCMS检测，原料无剩余。将反应液用硅藻土过滤，收集滤液浓缩至干即得产物为黄色油状物70mg，收率95％。[M+H]+158。Dissolve raw material 41-1 (200 mg) in anhydrous methanol (15 mL) in a 50 mL single-neck bottle, then add Pd/C (30 mg), and stir and react at 25°C for 20 hours under the protection of a hydrogen balloon. LCMS test showed no remaining raw materials. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected and concentrated to dryness to obtain 70 mg of yellow oily product, with a yield of 95%. [M+H] + 158.
步骤3：化合物41-3的合成Step 3: Synthesis of Compound 41-3
于50mL单口瓶中加入原料41-2(70mg)，随后加入DMF(15mL)溶解，并加入IM15(149mg)、碳酸钾(170mg)，于60℃下搅拌反应16小时。TLC检测原料无剩余，LCMS检测有产物主峰出现，将反应液加水淬灭。EA萃取，浓缩有机相，柱层析纯化，以纯EA为展开剂，得目标产物黄色固体50mg，收率27％。[M+H]+486。Add raw material 41-2 (70 mg) to a 50 mL single-neck bottle, then add DMF (15 mL) to dissolve, add IM15 (149 mg), and potassium carbonate (170 mg), and stir and react at 60°C for 16 hours. TLC detects that there is no remaining raw material, and LCMS detects that the main peak of the product appears. Add water to the reaction solution to quench it. EA was extracted, the organic phase was concentrated, and purified by column chromatography. Pure EA was used as the developing agent to obtain 50 mg of the target product as a yellow solid, with a yield of 27%. [M+H] + 486.
步骤4：化合物41-4的合成Step 4: Synthesis of Compound 41-4
于50mL单口瓶中加入原料41-3(50mg)并用二氧六环(10ml)及水(2mL)的混合溶剂溶解。加入二氯苯硼酸(23mg)、碳酸钾(42mg)、钯催化剂(10mg)，氩气保护下于90℃下搅拌反应4小时。LC-MS检测，原料无剩余。将反应液浓缩至干，柱层析纯化，以纯EA为展开剂，得产物20mg，收率40％。[M+H]+504。Add raw material 41-3 (50 mg) to a 50 mL single-neck bottle and dissolve it in a mixed solvent of dioxane (10 ml) and water (2 mL). Add dichlorophenylboronic acid (23 mg), potassium carbonate (42 mg), and palladium catalyst (10 mg), and stir and react at 90°C for 4 hours under argon protection. LC-MS detected that there was no remaining raw material. The reaction solution was concentrated to dryness and purified by column chromatography. Pure EA was used as the developing agent to obtain 20 mg of product with a yield of 40%. [M+H] +504 .
步骤5：化合物41的合成Step 5: Synthesis of Compound 41
于50mL单口瓶中加入原料41-4(320mg)，随后加入4M HCl甲醇溶液(10mL)溶解，并于25℃下搅拌反应2小时。LCMS检测原料无剩余。将反应液直接浓缩至干，随后加入饱和碳酸钠溶液调节pH＝8～9，并用乙酸乙酯萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得粗品。将粗品柱层析纯化，以纯EA为展开剂，收集目标化合物，浓缩后用乙腈/水的混合溶剂冻干，纯化后得白色固体目标化合物12mg，收率90.4％。[M+H]+420.1989。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),8.25(s,1H),7.72(ddd,J＝16.0,7.9,1.6Hz,2H),7.48(t,J＝7.9Hz,1H),4.71(d,J＝5.0Hz,2H),4.52(t,J＝5.7Hz,1H),4.23(s,1H),2.87(d,J＝5.6Hz,2H),2.33(d,J＝7.1Hz,2H),2.03–1.97(m,2H),1.92(d,J＝8.4Hz,2H),1.47(d,J＝14.0Hz,2H)。 Add raw material 41-4 (320 mg) to a 50 mL single-neck bottle, then add 4M HCl methanol solution (10 mL) to dissolve, and stir for 2 hours at 25°C. LCMS detected that there was no remaining raw material. The reaction solution was directly concentrated to dryness, then saturated sodium carbonate solution was added to adjust the pH to 8-9, and extracted with ethyl acetate. Combine the organic phases, wash with water and saturated sodium chloride solution in sequence, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was purified by column chromatography, and pure EA was used as the developing solvent. The target compound was collected, concentrated and lyophilized with a mixed solvent of acetonitrile/water. After purification, 12 mg of the target compound was obtained as a white solid, with a yield of 90.4%. [M+H] + 420.1989. 1 H NMR (500MHz, DMSO-d 6 ) δ13.34 (s, 1H), 8.25 (s, 1H), 7.72 (ddd, J = 16.0, 7.9, 1.6Hz, 2H), 7.48 (t, J = 7.9 Hz,1H),4.71(d,J＝5.0Hz,2H),4.52(t,J＝5.7Hz,1H),4.23(s,1H),2.87(d,J＝5.6Hz,2H),2.33( d,J＝7.1Hz,2H),2.03–1.97(m,2H),1.92(d,J＝8.4Hz,2H),1.47(d,J＝14.0Hz,2H).
实施例47：化合物47的合成
Example 47: Synthesis of Compound 47
按照与实施例28中化合物28-2相同的方法合成。[M+H]+406.0642。1H NMR(500MHz,DMSO-d6)δ13.62(s,1H),8.47(s,1H),7.73(ddd,J＝31.6,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H)。It was synthesized according to the same method as compound 28-2 in Example 28. [M+H] + 406.0642. 1 H NMR (500MHz, DMSO-d 6 ) δ13.62 (s, 1H), 8.47 (s, 1H), 7.73 (ddd, J = 31.6, 7.8, 1.6Hz, 2H), 7.50 (t, J = 7.9 Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz ,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H).
实施例48：化合物48的合成
Example 48: Synthesis of Compound 48
步骤1：化合物48-1的合成Step 1: Synthesis of Compound 48-1
向100mL圆底烧瓶中加入SM3(20g，270mmol)于250mL圆底烧瓶中，加入EtOH(176mL)溶解。反应物置于0℃冰水浴中，然后滴加酮基丙二酸二乙酯(47g，270mmol)，反应液在25℃反应1.5小时，反应液变成乳白色，然后置于85℃油浴中反应20小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约20小时后显示反应完毕。反应液直接减压旋干,然后硅胶拌样柱层析分离(PE/EA＝20/1～2/1)得黄色固体48-1共计9.1g，收率：20％。Add SM3 (20g, 270mmol) to a 100mL round-bottomed flask, add EtOH (176mL) to a 250mL round-bottomed flask, and dissolve. The reactant was placed in an ice-water bath at 0°C, and then diethyl ketomalonate (47g, 270mmol) was added dropwise. The reaction solution reacted at 25°C for 1.5 hours. The reaction solution turned milky white, and then was placed in an 85°C oil bath for reaction. 20 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 20 hours. The reaction solution was directly spin-dried under reduced pressure, and then separated by silica gel sample column chromatography (PE/EA=20/1～2/1) to obtain a total of 9.1g of yellow solid 48-1, yield: 20%.
步骤2：化合物48-2的合成 Step 2: Synthesis of Compound 48-2
称取48-1(1g，5.49mmol)于100mL圆底烧瓶，加POCl3(5mL)溶解，混合物在110℃反应12小时。TLC监控反应终点(PE/EA＝2/1)，反应约12小时后显示反应完毕。反应液慢慢加入水中淬灭，然后用NaOH调pH至中性。然后用EA进行萃取，有机相旋干得粗品。粗品柱分离(PE/EA＝20/1～5/1)得黄色油状物48-2共计0.3g，收率：30％。1H NMR(500MHz,CDCl3)δ8.45(s,1H),4.50(q,J＝7.1Hz,2H),2.69–2.61(m,3H),1.45(t,J＝7.1Hz,3H)。Weigh 48-1 (1g, 5.49mmol) into a 100mL round-bottomed flask, add POCl 3 (5mL) to dissolve, and react the mixture at 110°C for 12 hours. TLC monitored the reaction end point (PE/EA=2/1), and the reaction was completed after about 12 hours. The reaction solution was slowly added to water to quench, and then the pH was adjusted to neutral with NaOH. Then extract with EA, and spin dry the organic phase to obtain crude product. The crude product was separated by column (PE/EA=20/1～5/1) to obtain a total of 0.3g of yellow oily substance 48-2, yield: 30%. 1 H NMR (500MHz, CDCl 3 ) δ8.45 (s, 1H), 4.50 (q, J = 7.1Hz, 2H), 2.69–2.61 (m, 3H), 1.45 (t, J = 7.1Hz, 3H) .
步骤3：化合物48-3的合成Step 3: Synthesis of Compound 48-3
称取48-2(123mg，0.61mmol)、IM2(200mg，0.61mmol)、DIPEA(394mg，3.05mmol)于100mL圆底烧瓶中，然后加DMF(2mL)溶解，混合物在60℃油浴中反应6小时。TLC监控反应终点(DCM/MeOH＝20/1)，显示反应完毕。反应液加入水中析出黄色固体，抽滤，滤饼旋干得粗品无色油状物48-3粗品201mg,收率：66％。[M+H]+501.25。Weigh 48-2 (123 mg, 0.61 mmol), IM2 (200 mg, 0.61 mmol), and DIPEA (394 mg, 3.05 mmol) in a 100 mL round-bottomed flask, then add DMF (2 mL) to dissolve, and react the mixture in a 60°C oil bath 6 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), indicating that the reaction was completed. The reaction solution was added to water to precipitate a yellow solid, which was filtered with suction, and the filter cake was spin-dried to obtain 201 mg of crude colorless oil 48-3, yield: 66%. [M+H] + 501.25.
步骤4：化合物48-4的合成Step 4: Synthesis of compound 48-4
称取48-3(201mg，0.402mmol)于100mL圆底烧瓶中，然后加DCM(2mL)溶解，分批加入NBS(101mg，0.603mmol)，混合物在25℃反应1小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约1小时后显示反应完毕。反应液加Na2SO3溶液淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/iPrOH＝15/1)无色油状物99mg，收率：52％。[M+H]+475.11。Weigh 48-3 (201 mg, 0.402 mmol) into a 100 mL round-bottomed flask, then add DCM (2 mL) to dissolve, add NBS (101 mg, 0.603 mmol) in batches, and react the mixture at 25°C for 1 hour. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 1 hour. The reaction solution was quenched by adding Na 2 SO 3 solution, then extracted with DCM, and the organic phase was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/iPrOH=15/1), 99 mg of colorless oil, yield: 52%. [M+H] + 475.11.
步骤5：化合物48-5的合成Step 5: Synthesis of Compound 48-5
称取48-4(99mg，0.209mmol)、TEA(25mg，0.25mmol)于100mL圆底烧瓶中，然后加2mL DCM溶解，然后慢慢加入Boc2O(55mg，0.25mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得淡黄色固体64mg 48-5，收率：53％。[M+H]+574.2/577.2。Weigh 48-4 (99 mg, 0.209 mmol) and TEA (25 mg, 0.25 mmol) into a 100 mL round-bottomed flask, then add 2 mL DCM to dissolve, then slowly add Boc 2 O (55 mg, 0.25 mmol), and the mixture is at 25°C. Reaction time is 12 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 12 hours. The reaction solution was quenched with water, then extracted with DCM, and the organic phase was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=20/1) to obtain 64 mg of 48-5 as a light yellow solid, yield: 53%. [M+H] + 574.2/577.2.
步骤6：化合物48-6的合成Step 6: Synthesis of Compound 48-6
称取48-5(390mg，0.678mmol)、三丁基乙烯基锡(322mg，1.017mmol)、Pd(PPh3)4(157mg，0.136mmol)，TEA(0.14g，1.34mmol)于100mL圆底烧瓶中，然后加DMF(5mL)溶解，混合物用氩气置换3次气体后置于110℃油浴中反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品。粗品柱层析分离(DCM/MeOH＝40/1)黄色油状物320mg，收率：90％。[M+H]+523.22。Weigh 48-5 (390mg, 0.678mmol), tributylvinyltin (322mg, 1.017mmol), Pd(PPh 3 ) 4 (157mg, 0.136mmol), TEA (0.14g, 1.34mmol) in a 100mL round bottom flask, then add DMF (5 mL) to dissolve, replace the mixture with argon gas three times, and then place it in a 110°C oil bath for reaction for 12 hours. TLC monitored the reaction end point (DCM/MeOH=40/1), and the reaction was completed after about 12 hours. The reaction solution was suction-filtered through diatomaceous earth, and the filtrate was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=40/1) and 320 mg of yellow oil was obtained, yield: 90%. [M+H] + 523.22.
步骤7：化合物48-7的合成Step 7: Synthesis of Compound 48-7
称取48-6(320mg，0.612mmol)、K2OsO4·2H2O(22.5mg，0.0612mmol)、NMO(144mg，0.612mmol)于100mL圆底烧瓶中，然后加丙酮(3mL)和H2O(3mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)， 反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品中间体([M+H]+557.29)。中间体溶于THF(2mL)和H2O(2mL)，然后加入NaIO4(132mg，0.619mmol)，混合物在25℃反应2小时。TLC监控反应终点(DCM/MeOH＝10/1)，反应约2小时后显示反应完毕。反应液加水淬灭，然后用DCM/MeOH＝20/1萃取，有机相旋干得粗品无色油状物147mg。[M+H]+525.24。Weigh 48-6 (320mg, 0.612mmol), K 2 OsO 4· 2H 2 O (22.5mg, 0.0612mmol), and NMO (144mg, 0.612mmol) into a 100mL round-bottomed flask, then add acetone (3mL) and H 2 O (3 mL) was dissolved, and the mixture was reacted at 25°C for 12 hours. TLC monitors the reaction endpoint (DCM/MeOH=20/1), The reaction was completed after about 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was spin-dried to obtain the crude intermediate ([M+H] + 557.29). The intermediate was dissolved in THF (2 mL) and H 2 O (2 mL), then NaIO 4 (132 mg, 0.619 mmol) was added, and the mixture was reacted at 25°C for 2 hours. TLC monitored the reaction end point (DCM/MeOH=10/1), and the reaction was completed after about 2 hours. The reaction solution was quenched by adding water, then extracted with DCM/MeOH=20/1, and the organic phase was spin-dried to obtain 147 mg of crude colorless oil. [M+H] + 525.24.
步骤8：化合物48-8的合成Step 8: Synthesis of Compound 48-8
称取48-7(20mg，0.038mmol)、NH2OH.HCl(11mg，0.152mmol)于100mL圆底烧瓶中，然后加EtOH(1mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得黄色固体12mg，收率：60％。[M+H]+540.27。Weigh 48-7 (20 mg, 0.038 mmol) and NH 2 OH.HCl (11 mg, 0.152 mmol) into a 100 mL round-bottomed flask, then add EtOH (1 mL) to dissolve, and react the mixture at 25°C for 12 hours. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 12 hours. The reaction solution was quenched with water, then extracted with DCM, and the organic phase was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=20/1) to obtain 12 mg of yellow solid, yield: 60%. [M+H] + 540.27.
步骤9：化合物48-9的合成Step 9: Synthesis of Compound 48-9
称取48-8(20mg，0.037mmol)于25mL圆底烧瓶中，加MeOH(3mL)和H2O(0.6mL)溶解，然后加入苯乙炔(6mg，0.0556mmol)、PhI(AcO)2(24mg，0.074mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得无色油状物7mg，收率：30％。[M+H]+640.40。Weigh 48-8 (20 mg, 0.037 mmol) in a 25 mL round bottom flask, add MeOH (3 mL) and H 2 O (0.6 mL) to dissolve, then add phenylacetylene (6 mg, 0.0556 mmol), PhI(AcO) 2 ( 24 mg, 0.074 mmol), and the mixture was reacted at 25°C for 12 hours. TLC monitored the reaction end point (DCM/MeOH=40/1), and the reaction was completed after about 12 hours. The reaction solution was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=20/1) to obtain 7 mg of colorless oil, yield: 30%. [M+H] + 640.40.
步骤10：化合物48-10的合成Step 10: Synthesis of compound 48-10
称取48-9(20mg，0.033mmol)于25mL圆底烧瓶中，加4M HCl/MeOH(1mL)溶解，混合物在25℃反应1小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约1小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝25/1)得白色固体15mg,收率:79％。[M+H]+598.31。Weigh 48-9 (20 mg, 0.033 mmol) into a 25 mL round-bottomed flask, add 4 M HCl/MeOH (1 mL) to dissolve, and react the mixture at 25°C for 1 hour. TLC monitored the reaction end point (DCM/MeOH=20/1), and the reaction was completed after about 1 hour. The reaction solution was quenched with water, then extracted with DCM, and the organic phase was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=25/1) to obtain 15 mg of white solid, yield: 79%. [M+H] + 598.31.
步骤11：化合物48的合成Step 11: Synthesis of Compound 48
称取48-10(20mg，0.033mmol)于25mL圆底烧瓶中，加THF(1mL)溶解，然后加入LiAlH4(2.4mg，0.066mmol)，于25℃反应1小时。TLC监控反应终点(DCM/MeOH＝10/1)，反应约1小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝10/1)得白色固体7mg，收率：58％。[M+H]+498.25。1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝7.0Hz,2H),7.60–7.51(m,4H),7.08(d,J＝8.1Hz,1H),6.91(d,J＝2.1Hz,1H),6.71(dd,J＝8.1,2.4Hz,1H),5.24(t,J＝4.5Hz,1H),4.60(d,J＝4.1Hz,2H),3.86(dd,J＝15.6,11.9Hz,3H),3.73(s,3H),3.19–3.08(m,2H),2.98(d,J＝15.3Hz,1H),2.71(s,3H),2.55(d,J＝15.3Hz,1H),1.96–1.88(m,1H),1.79(td,J＝12.7,3.8Hz,1H),1.55(d,J＝12.5Hz,1H),1.15(d,J＝13.0Hz,1H)。Weigh 48-10 (20 mg, 0.033 mmol) into a 25 mL round-bottomed flask, add THF (1 mL) to dissolve, then add LiAlH 4 (2.4 mg, 0.066 mmol), and react at 25°C for 1 hour. TLC monitored the reaction end point (DCM/MeOH=10/1), and the reaction was completed after about 1 hour. The reaction solution was spin-dried to obtain crude product. The crude product was separated by column chromatography (DCM/MeOH=10/1) to obtain 7 mg of white solid, yield: 58%. [M+H] + 498.25. 1 H NMR (500MHz, DMSO-d 6 ) δ7.95 (d, J＝7.0Hz, 2H), 7.60–7.51 (m, 4H), 7.08 (d, J＝8.1Hz, 1H), 6.91 (d, J＝2.1Hz,1H),6.71(dd,J＝8.1,2.4Hz,1H),5.24(t,J＝4.5Hz,1H),4.60(d,J＝4.1Hz,2H),3.86(dd, J＝15.6,11.9Hz,3H),3.73(s,3H),3.19–3.08(m,2H),2.98(d,J＝15.3Hz,1H),2.71(s,3H),2.55(d,J ＝15.3Hz,1H),1.96–1.88(m,1H),1.79(td,J＝12.7,3.8Hz,1H),1.55(d,J＝12.5Hz,1H),1.15(d,J＝13.0Hz ,1H).
经由不同的起始原料和相应的试剂，采用与前述实施例48相似的方法合成得到下列目标物。
Using different starting materials and corresponding reagents, the following target substances were synthesized using a method similar to the aforementioned Example 48.
实施例56：化合物56的合成
Example 56: Synthesis of Compound 56
称取48-4(56mg)、IM6(50mg)、Pd(pph3)4(25mg)、Na2CO3(22.3mg)于100mL圆底烧瓶中，加入DME/H2O(2/0.5mL)溶解。混合物用氩气置换3次气体后于100℃油浴中反应4小时。TLC监控反应(DCM/MeOH＝20/1)，显示反应完毕。反应液用甲醇稀释后，硅藻土抽滤，滤液旋干得粗品。粗品薄层制备分离(DCM/MeOH＝20/1)得白色固体21mg，收率：26％。[M+H]+622.28。 Weigh 48-4 (56mg), IM6 (50mg), Pd(pph 3 ) 4 (25mg), and Na 2 CO 3 (22.3mg) into a 100mL round-bottomed flask, and add DME/H 2 O (2/0.5mL ) dissolve. The mixture was replaced with argon three times and reacted in an oil bath at 100°C for 4 hours. TLC monitored the reaction (DCM/MeOH=20/1) and showed that the reaction was complete. After the reaction solution was diluted with methanol, it was suction-filtered through diatomaceous earth, and the filtrate was spin-dried to obtain a crude product. The crude product was separated by thin layer preparation (DCM/MeOH=20/1) to obtain 21 mg of white solid, yield: 26%. [M+H] + 622.28.
实施例57：化合物57的合成
Example 57: Synthesis of Compound 57
称取化合物56(20mg)于100mL圆底烧瓶中，加THF(2mL)溶解，然后分批加入LiAlH4(20mg)。混合物在室温反应12小时。TLC监控反应(DCM/MeOH＝20/1)，显示反应完毕。反应液加饱和NH4Cl溶液淬灭，然后用(DCM/MeOH＝20/1)进行萃取，有机相旋干得粗品。粗品薄层制备分离(DCM/MeOH＝20/1)得白色固体7mg，收率：46％。[M+H]+580.26。Weigh compound 56 (20 mg) into a 100 mL round-bottomed flask, add THF (2 mL) to dissolve, and then add LiAlH 4 (20 mg) in batches. The mixture was reacted at room temperature for 12 hours. TLC monitored the reaction (DCM/MeOH=20/1) and showed that the reaction was complete. The reaction solution was quenched by adding saturated NH 4 Cl solution, then extracted with (DCM/MeOH=20/1), and the organic phase was spin-dried to obtain a crude product. The crude product was separated by thin layer preparation (DCM/MeOH=20/1) to obtain 7 mg of white solid, yield: 46%. [M+H] + 580.26.
实施例58：SHP2酶活测试Example 58: SHP2 enzyme activity test
为了测试化合物对SHP2-PTP酶活性的抑制作用，使用DiFMUP为替代底物的终点荧光酶法测定SHP2的催化活性，以确定化合物的IC50值。脱磷反应在黑色、384孔浅聚苯乙烯板上进行。总反应体积设为24μL/孔。为了使DMSO的浓度保持在较低的水平，将化合物从10mM开始用DMSO进行4倍梯度稀释，共计8个浓度。然后25倍稀释至反应缓冲液(60mM HEPES pH 7.2、75mM NaCl、75mM KCl、1mM EDTA、0.02％BSA、5mM DTT)，得到不同浓度的化合物溶液。0.5nM SHP2(购自美国Signalchem,p38-20G-10)与1μM p-IRS1肽(吉尔生化，86703)预孵育5到10分钟激活酶，然后加入不同浓度的化合物溶液或DMSO作为对照。在室温下反应30分钟，然后加入100μM DiFMUP(购自美国Invitrogen，D6567-5mg)底物，室温反应30分钟后，加入160μM的bpV(phen)(购自美国Sigma，SML0889-5mg)终止反应。反应结束后，将板子转移到Spectramax光谱仪上进行读板，激发波长为350nm，发射波长为450nm，通过监测反应产物DiFMUP在室温下积累的荧光信号变化来测定酶的催化速度。然后通过基于对照的归一化拟合来推断IC50值，绘制抑制剂剂量-反应曲线，数据如表4所示。结果显示本申请所涉及的化合物对SHP2酶活有很强的抑制效果。In order to test the inhibitory effect of the compound on SHP2-PTPase activity, the catalytic activity of SHP2 was determined using the end-point fluorescent enzymatic method with DiFMUP as the alternative substrate to determine the IC 50 value of the compound. Dephosphorization reactions were performed on black, 384-well light polystyrene plates. The total reaction volume was set to 24 μL/well. In order to keep the concentration of DMSO at a low level, compounds were diluted 4-fold with DMSO starting from 10 mM, for a total of 8 concentrations. Then dilute 25 times into the reaction buffer (60mM HEPES pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.02% BSA, 5mM DTT) to obtain compound solutions of different concentrations. 0.5 nM SHP2 (purchased from Signalchem, USA, p38-20G-10) was pre-incubated with 1 μM p-IRS1 peptide (Gill Biochemical, 86703) for 5 to 10 minutes to activate the enzyme, and then different concentrations of compound solutions or DMSO were added as a control. React at room temperature for 30 minutes, then add 100 μM DiFMUP (purchased from Invitrogen, USA, D6567-5mg) substrate, and after reacting at room temperature for 30 minutes, add 160 μM bpV (phen) (purchased from Sigma, USA, SML0889-5mg) to terminate the reaction. After the reaction is completed, the plate is transferred to a Spectramax spectrometer for plate reading. The excitation wavelength is 350nm and the emission wavelength is 450nm. The catalytic speed of the enzyme is measured by monitoring the changes in the fluorescence signal accumulated by the reaction product DiFMUP at room temperature. The IC50 values were then inferred by normalized fitting based on the control, and inhibitor dose-response curves were drawn, with the data shown in Table 4. The results show that the compounds involved in this application have a strong inhibitory effect on SHP2 enzyme activity.
表4

Table 4

工业应用性Industrial applicability
本发明提供一种SHP2抑制剂化合物，其可以用于抑制SHP2活性，并且/或者在受试者中治疗、预防或缓和由SHP2介导的疾病。因而，可将其制成相应的药物，适于工业应用。The present invention provides a SHP2 inhibitor compound that can be used to inhibit SHP2 activity and/or treat, prevent or alleviate diseases mediated by SHP2 in a subject. Therefore, it can be made into corresponding drugs and suitable for industrial applications.
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。 Although the present invention has been described in detail herein, the present invention is not limited thereto. Those skilled in the art can make modifications according to the principles of the present invention. Therefore, any modifications made according to the principles of the present invention should be understood to fall within protection scope of the present invention.

Claims (26)

  1. 一种SHP2抑制剂，其为式I的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
    A SHP2 inhibitor which is a compound of formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:
    其中，in,
    A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl, oxadiazolyl, oxazolyl and isoxazolyl;
    B为含氮不饱和单环或双环，优选地选自吡嗪、吡唑并嘧啶酮、和吡唑并吡嗪；B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine, pyrazolopyrimidinone, and pyrazolopyrazine;
    m和n各自独立地为0、1或2；m and n are each independently 0, 1 or 2;
    R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代；R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group;
    R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6 One-membered heterocycloalkyl, 5- or 6-membered heterocycloalkyl C1-6 alkyl, and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
    R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
    R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  2. 如权利要求1所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地，R1和R1'一起形成当存在R6时，R6选自卤素和C1-6烷氧基。The SHP2 inhibitor of claim 1, wherein R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably, R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen and C1-6 alkoxy.
  3. 如权利要求1或2所述的SHP2抑制剂，其中A选自苯基、咪唑并[4,5-b]吡啶基、[1,2,4]噁二唑-3-基、和异噁唑-3-基；更优选地，A选自苯基、 且n为1或2。The SHP2 inhibitor of claim 1 or 2, wherein A is selected from phenyl, imidazo[4,5-b]pyridyl, [1,2,4]oxadiazol-3-yl, and isoxadiazol-3-yl. Azol-3-yl; more preferably, A is selected from phenyl, and n is 1 or 2.
  4. 如权利要求1或2所述的SHP2抑制剂，其中B选自且m为2、且m为1、和且m为0。The SHP2 inhibitor of claim 1 or 2, wherein B is selected from And m is 2, And m is 1, and And m is 0.
  5. 如权利要求1所述的SHP2抑制剂，其中The SHP2 inhibitor of claim 1, wherein
    R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
    R2和R2'各自为H，或连接在一起形成亚乙基；R 2 and R 2 ' are each H, or are joined together to form ethylene;
    R3选自H、羟基、和氟；R 3 is selected from H, hydroxyl, and fluorine;
    R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuranyl, Tetrahydropyranyl, morpholin-4-ethyl, and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R6 ;
    R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；R 5 is each independently selected from C1-C2 alkyl, C1-C2 hydroxyalkyl and C1-C2 alkoxycarbonyl;
    R6各自独立地选自氟、氯、氨基和C1-3烷氧基。Each R 6 is independently selected from fluorine, chlorine, amino and C1-3 alkoxy.
  6. 如权利要求1或2所述的SHP2抑制剂，其中R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。The SHP2 inhibitor of claim 1 or 2, wherein R 2 and R 2 ' are each H; R 3 is H; R 6 is each independently selected from halogen and C1-6 alkoxy.
  7. 如权利要求1所述的SHP2抑制剂，其为式Ia的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
    The SHP2 inhibitor of claim 1, which is a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrugs:
  8. 如权利要求7所述的SHP2抑制剂，其中The SHP2 inhibitor of claim 7, wherein
    A选自苯基、和咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基； A is selected from phenyl, and imidazopyridyl, oxadiazolyl, oxazolyl and isoxazolyl;
    n为1或2；n is 1 or 2;
    R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group;
    R3为H；R 3 is H;
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle alkyl;
    R5为C1-C4烷基；R 5 is C1-C4 alkyl;
    R6选自卤素和C1-6烷氧基。R 6 is selected from halogen and C1-6 alkoxy.
  9. 如权利要求7或8所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选地选自 The SHP2 inhibitor of claim 7 or 8, wherein A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably selected from
  10. 如权利要求7或8所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素或C1-6烷氧基取代，更优选地被氟或甲氧基取代。The SHP2 inhibitor of claim 7 or 8, wherein R1 and R1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally replaced by halogen or C1-6 alkoxy Substituted, more preferably by fluorine or methoxy.
  11. 如权利要求1或7所述的SHP2抑制剂，其中所述化合物选自：

    The SHP2 inhibitor of claim 1 or 7, wherein said compound is selected from:

  12. 如权利要求1所述的SHP2抑制剂，其为式Ib的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
    The SHP2 inhibitor of claim 1, which is a compound of formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrugs:
  13. 如权利要求12所述的SHP2抑制剂，其中The SHP2 inhibitor of claim 12, wherein
    A选自苯基、咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；A is selected from phenyl, imidazopyridyl, oxadiazolyl, oxazolyl and isoxazolyl;
    n为1或2；n is 1 or 2;
    R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group;
    R3选自H、羟基、和卤素；R 3 is selected from H, hydroxyl, and halogen;
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycle Alkyl C1-6 alkyl, and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
    R6各自独立地选自卤素和C1-6烷氧基。Each R 6 is independently selected from halogen and C1-6 alkoxy.
  14. 如权利要求12或13所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选 咪唑并[4,5-b]吡啶基，更优选 The SHP2 inhibitor of claim 12 or 13, wherein A is imidazopyridyl, preferably Imidazo[4,5-b]pyridyl, more preferably
  15. 如权利要求12或13所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基取代，更优选地被甲氧基取代。The SHP2 inhibitor of claim 12 or 13, wherein R1 and R1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy, More preferably substituted by methoxy.
  16. 如权利要求1或12所述的SHP2抑制剂，其中所述化合物选自：

    The SHP2 inhibitor of claim 1 or 12, wherein said compound is selected from:

  17. 如权利要求1所述的SHP2抑制剂，其为式Ic的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
    The SHP2 inhibitor of claim 1, which is a compound of formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrugs:
  18. 如权利要求17所述的SHP2抑制剂，其中The SHP2 inhibitor of claim 17, wherein
    A选自咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；A is selected from imidazopyridyl, oxadiazolyl, oxazolyl and isoxazolyl;
    n为1或2；n is 1 or 2;
    R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
    R2和R2'各自为H；R 2 and R 2 ' are each H;
    R3为H；R 3 is H;
    R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
    R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
    R6各自独立地选自卤素、氨基和C1-6烷氧基。Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  19. 如权利要求17或18所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选 The SHP2 inhibitor of claim 17 or 18, wherein A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
  20. 如权利要求17或18所述的SHP2抑制剂，其中R5是C1-C4羟基烷基，优选羟甲基。The SHP2 inhibitor of claim 17 or 18, wherein R 5 is C1-C4 hydroxyalkyl, preferably hydroxymethyl.
  21. 如权利要求1或17所述的SHP2抑制剂，其中所述化合物选自：

    The SHP2 inhibitor of claim 1 or 17, wherein said compound is selected from:

  22. 一种药物组合物，其包括根据权利要求1-21中任一项所述的SHP2抑制剂、和药学上可接受的稀释剂或载体、以及任选的其他活性药物成分。A pharmaceutical composition comprising the SHP2 inhibitor according to any one of claims 1-21, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.
  23. 根据权利要求1-21中任一项所述的SHP2抑制剂，用于抑制SHP2活性的用途。The SHP2 inhibitor according to any one of claims 1-21, for use in inhibiting SHP2 activity.
  24. 根据权利要求1-21中任一项所述的SHP2抑制剂，用于治疗、预防或缓和由SHP2介导的疾病的用途。The SHP2 inhibitor according to any one of claims 1 to 21, for use in treating, preventing or alleviating diseases mediated by SHP2.
  25. 如权利要求24所述的SHP2抑制剂的用途，其中所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。The use of a SHP2 inhibitor as claimed in claim 24, wherein the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
  26. 如权利要求24或25所述的SHP2抑制剂的用途，其中所述疾病是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。 The use of a SHP2 inhibitor as claimed in claim 24 or 25, wherein the disease is selected from the group consisting of juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, Cancers of the breast, esophagus, lung, colon, head, stomach, lymphoma, glioblastoma, pancreatic cancer, or combinations thereof.
PCT/CN2023/089203 2022-05-20 2023-04-19 Shp2 inhibitor and use thereof WO2023221721A1 (en)

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