CN117088887A

CN117088887A - SHP2 inhibitors and uses thereof

Info

Publication number: CN117088887A
Application number: CN202310421094.9A
Authority: CN
Inventors: 李志文; 刘明清; 刘相军
Original assignee: Anhui Zhongke Tuotuo Pharmaceutical Science Research Co ltd
Current assignee: Anhui Zhongke Tuotuo Pharmaceutical Science Research Co ltd
Priority date: 2022-05-20
Filing date: 2023-04-19
Publication date: 2023-11-21
Also published as: WO2023221721A1

Abstract

The present invention relates to an inhibitor of SHP2 comprising a compound of formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof. The invention also relates to a pharmaceutical composition comprising the SHP2 inhibitor and application of the SHP2 inhibitor in preparing medicines for inhibiting SHP2 activity or treating, preventing or alleviating SHP2 mediated diseases.

Description

SHP2 inhibitors and uses thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an SHP2 inhibitor and application thereof.

Background

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the gene PTPN11, and can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases, phospholipids and the like), thereby regulating downstream signals, and is the only verified protooncoprotein in the Protein Tyrosine Phosphatase (PTP) family at present. SHP2 typically forms a complex with growth factor receptor binding protein 2 (GRB 2), GRB 2-related binding protein (GAB 1), and signaling molecule protein (SOS), 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 generally disrupt the N-SH2/PTP interdomain interactions in the closed conformation, bias SHP2 toward the open conformation, and increase activation of the downstream RAS/MAPK; activation of this signal will lead to the development of a variety of hematological malignancies. This demonstrates that PTPN11 is a true oncogene. As intracellular response signal molecules for various cytokines, growth factors, and other extracellular stimuli, SHP2 is widely expressed in various cells of the body, and is involved in important cell vital activities including cell proliferation, activation, migration, differentiation, and the like. SHP 2-mediated RAS-MAPK signaling activation and its negative regulation of JAK-STAT signaling make SHP2 an important participant in oncogenic or oncostatic signaling pathways.

The function-acquired SHP2 mutations result in Noonan syndrome resulting from increased phosphatase activity, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) and various solid tumors (e.g., lung adenocarcinoma, colon carcinoma, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Thus, SHP2 is a potential therapeutic target for a variety of cancers, and the development of SHP2 inhibitors has attracted increasing attention. Therefore, the discovery and search of SHP2 inhibitors with better potency is a popular target in industry and academia. Currently, no SHP2 inhibitors are commercially available, and thus there is still a clinical need to explore high-activity SHP2 inhibitors.

Disclosure of Invention

It is an object of the present invention to provide a novel class of SHP2 enzyme inhibitors useful in the treatment of diseases such as cancer.

In one aspect, the invention relates to a compound that is an inhibitor of Src homology 2 containing protein tyrosine phosphatase 2 (SHP 2), or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof, said compound being represented by formula I:

Wherein,

a is aryl or heteroaryl, preferably selected from phenyl, imidazopyridinyl (e.g. imidazo [4, 5-b)]Pyridyl, especially) Oxadiazolyl (e.g. [1,2,4 ]]Oxadiazol-3-yl, in particular) Oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, in particular +.>)；

B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazines (e.g) Pyrazolopyrimidinones (e.g.)>) And pyrazolopyrazines (e.g.)>)；

m and n are each independently 0, 1 or 2;

R ₁ and R is ₁ ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxy, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R ₁ And R is ₁ 'together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1 to 3R' s ₆ Substitution;

R ₂ and R is ₂ ' each is H, or linked together to form a C2-4 alkylene group;

R ₃ selected from H, hydroxy, and halogen;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5-or 6 membered heterocycloalkyl C1-6 alkyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazolyl;

R ₅ each independently selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxycarbonyl;

R ₆ Each independently selected from the group consisting of halogen, amino, and C1-6 alkoxy.

Preferably, R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution; more preferably, R ₁ And R is ₁ ' together form When R is present ₆ When R is ₆ Selected from halogen and C1-6 alkoxy. Further preferably, R ₂ And R is ₂ ' each is H; r is R ₃ Is H; r is R ₆ Each independently selected from halogen and C1-6 alkoxy.

In other preferred embodiments, R ₁ And R is ₁ ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxy, C1-3 hydroxyalkyl, C1-3 alkylamido, and oxo, or R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution; r is R ₂ And R is ₂ ' each is H, or linked together to form ethylene; r is R ₃ Selected from H, hydroxy, and fluoro; r is R ₄ Each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4 ylethyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazolyl; r is R ₅ Each independently selected from the group consisting of C1-C2 alkyl, C1-C2 hydroxyalkyl, and C1-C2 alkoxycarbonyl; r is R ₆ Each independently selected from fluorine, chlorine, amino and C1-3 alkoxy.

In a preferred aspect, the present invention relates to a compound as an inhibitor of SHP2, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof, said compound being of formula Ia:

wherein A, n, R ₁ And R is ₁ '、R ₂ And R is ₂ '、R ₃ 、R ₄ And R is ₅ As defined above.

Preferably, A is selected from phenyl, imidazopyridinyl (e.g. imidazo [4, 5-b)]Pyridyl, especially) Oxadiazolyl (e.g. [1,2,4 ]]Oxadiazol-3-yl, in particular +.>) Oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, in particular +.>)；

n is 1 or 2;

R ₁ and R is ₁ ' each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxy, or R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution;

R ₂ and R is ₂ ' each is H, or linked together to form a C2-4 alkylene (preferably ethylene);

R ₃ is H;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5-or 6-membered heterocycloalkyl (preferably tetrahydrofuranyl);

R ₅ is C1-C4 alkyl (preferably methyl);

R ₆ Selected from halogen and C1-6 alkoxy.

Further preferred, A is an imidazopyridinyl, preferably imidazo [4,5-b]Pyridyl, more preferably selected from

Still further preferably, R ₁ And R is ₁ ' together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with halogen or C1-6 alkoxy, more preferably with fluoro or methoxy.

In a further preferred aspect, the present invention relates to a compound as an inhibitor of SHP2, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof, said compound being represented by formula Ib:

wherein A, n, R ₁ And R is ₁ '、R ₂ And R is ₂ '、R ₃ And R is ₄ As defined above.

n is 1 or 2;

R ₁ and R is ₁ ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxy, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution of；

R ₃ selected from H, hydroxy, and halogen;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5-or 6-membered heterocycloalkyl (preferably tetrahydrofuranyl or tetrahydropyranyl), 5-or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4 ylethyl), and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazolyl;

R ₆ each independently selected from halogen and C1-6 alkoxy.

Further preferred, A is an imidazopyridinyl, preferably imidazo [4,5-b]Pyridyl, more preferably

Still further preferably, R ₁ And R is ₁ ' together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with a C1-6 alkoxy group, more preferably with a methoxy group.

In other preferred aspects, the invention relates to a compound that is an inhibitor of SHP2, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite, or prodrug thereof, the compound being represented by formula Ic:

wherein A, n, R ₁ And R is ₁ '、R ₂ And R is ₂ '、R ₃ And R is ₅ As defined above.

Preferably, A is selected from imidazopyridinyl (e.g., imidazo [4, 5-b)]Pyridyl, especially) Oxadiazolyl (e.g. [1,2,4 ]]Oxadiazol-3-yl, in particular +.>) Oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, in particular +.>)；

n is 1 or 2;

R ₁ and R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution;

R ₂ and R is ₂ ' each is H;

R ₃ is H;

R ₄ each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, and pyridyl;

R ₅ selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;

Still further preferably, R ₅ Is a C1-C4 hydroxyalkyl group, more preferably a hydroxymethyl group.

In another aspect, the application also provides pharmaceutical compositions comprising a compound of formula I, ia, ib, or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.

In other aspects, the application also relates to methods and uses of compounds of formula I, ia, ib, or Ic, or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites, or prodrugs thereof, for inhibiting SHP2 activity.

In another aspect, the application also relates to methods and uses of compounds of formula I, ia, ib, or Ic, or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites, or prodrugs thereof, for treating, preventing, or alleviating SHP 2-mediated diseases. 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 cancer selected from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.

In other aspects, the application also relates to the use of a compound of formula I, ia, ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof, in the manufacture of a medicament for the treatment, prevention or alleviation of a SHP2 mediated disease. 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 cancer selected from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.

Detailed Description

Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which claimed subject matter belongs.

The present invention employs, unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology within the skill of the art. Unless specifically defined otherwise, nomenclature and laboratory procedures and techniques related to analytical chemistry, synthetic organic chemistry, and chemistry such as medical and pharmaceutical chemistry described herein are known to those skilled in the art. In general, the foregoing techniques and steps may be implemented by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.

The term "alkyl" refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., alkylene). 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, 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, and the like. It is to be understood that references herein to "alkyl" include such alkyl groups in all configurations and conformations that may be present, e.g., references herein to "propyl" include n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and references to "pentyl" include n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl, and the like.

The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.

The term "alkoxyalkyl" refers to an alkyl group as defined herein substituted with an alkoxy group as defined herein.

The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl includes groups having 3 to 12 ring atoms. Cycloalkyl groups may be monovalent or divalent (e.g., cycloalkylene) depending on the structure. In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, 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 adamantyl.

The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" means that the alkyl groups defined herein are substituted with cycloalkyl groups defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

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. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. The aryl group may be optionally substituted. The term "aryl" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl") groups (e.g., pyridine). The term includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

The term "aryl" as used herein means that each of the atoms making up the ring in the aromatic ring is a carbon atom. The aryl ring may 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, phenanthryl, anthracyl, fluorenyl, and indenyl. Depending on the structure, the aryl group may be a monovalent group or a divalent group (i.e., arylene).

The term "aryloxy" refers to an-O-aryl group, wherein aryl is as defined herein.

The term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An "heteroaryl" moiety containing N means that at least one backbone atom in the ring of the aromatic group is a nitrogen atom. Depending on the structure, the heteroaryl group may be a monovalent group or a divalent group (i.e., heteroarylene). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, furopyridinyl, and the like.

The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.

The term "alkyl (heteroaryl)" or "heteroarylalkyl" means that an alkyl group as defined herein is substituted with a heteroaryl group as defined herein.

The term "heteroalkyl" as used herein means that one or more of the backbone chain atoms in the alkyl groups defined herein are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or where the heteroalkyl group is attached to the remainder of the molecule.

The term "heterocycloalkyl" or "heterocyclyl" as used herein means that one or more of the atoms making up the ring in the non-aromatic ring is a heteroatom selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring may be a single ring or multiple rings of three, four, five, six, seven, eight, nine or more than nine atoms. The heterocycloalkyl ring may be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1, 3-dioxanes, 1, 4-dioxanes, piperazines, 1, 3-oxathiolanes, 1, 4-oxathiolanes, tetrahydro-1, 4-thiazines, 2H-1, 2-oxazines, maleimides, succinimides, barbituric acid, thiobarbituric acid, dioxopiperazines, hydantoins, dihydropyrimidines, morpholines, trioxane, hexahydro-1, 3, 5-triazines, tetrahydrothiophenes, tetrahydrofurans, pyrrolines, pyrrolidines, imidazolidines, pyrazolines, pyrazolidines, imidazolines, imidazoles, 1, 3-dioxoles, 1, 3-dioxanes, 1, 3-dithianes, 1, 3-dithiazolines, 1, 3-oxazanes, 3-oxazalidines, isoxazolines, oxazalidines, and thiazoles. Depending on the structure, the heterocycloalkyl group may be a monovalent group or a divalent group (i.e., heterocycloalkylene).

The term "alkyl (heterocycloalkyl)" or "heterocycloalkyl" means that an alkyl group as defined herein is substituted with a heterocycloalkyl group as defined herein.

The term "alkoxy (heterocycloalkyl)" or "heterocycloalkylalkoxy" means that an alkoxy group as defined herein is substituted with a heterocycloalkyl group as defined herein.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The terms "haloalkyl", "haloalkoxy" and "haloalkylalkyl" include structures of alkyl, alkoxy or heteroalkyl groups in which at least one hydrogen is replaced with a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are the same or different from each other.

The term "oxadiazolyl" is meant to include the isomeric forms of oxadiazolyl, including 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl and 1,3, 4-oxadiazolyl.

The term "oxazolyl" is meant to include oxazolyl in the form of isomers including 1, 2-oxazolyl (isoxazolyl), 1, 3-oxazolyl, and the like.

The term "hydroxy" refers to an-OH group.

The term "cyano" refers to a-CN group.

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).

The term "amino" refers to-NH ₂ A group.

The term "aminoacyl" refers to-CO-NH ₂ A group.

The term "alkylaminoacyl" refers to a-CO-NH-R group, wherein R is an alkyl group as defined herein.

The term "amide" or "amido" refers to-NR-CO-R ', wherein R and R' are each independently hydrogen or alkyl.

The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, specifically to the group-NRR ', wherein R and R ' are each independently selected from hydrogen or lower alkyl, provided that-NRR 'not-NH ₂ . "alkylamino" includes the amino groups wherein-NH ₂ A group of a compound having at least one alkyl group attached to the nitrogen. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "dialkylamino" includes the radical wherein-NH ₂ A group linking at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

The terms "arylamino" and "diarylamino" refer to amino substituents that are further substituted with one or two aryl groups, specifically the group-NRR ', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, where N is attached to at least one or two aryl groups, respectively.

The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

The term "aralkylamino" herein refers to the group-NRR 'where R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

The term "heterocyclylalkylamino" means that an amino group as defined herein is substituted with a heterocycloalkyl group as defined herein.

The term "alkylaminoalkyl" means that an alkyl group as defined herein is substituted with an alkylamino group as defined herein.

The term "aminoalkyl" refers to an alkyl substituent that is further substituted with one or more amino groups.

The term "aminoalkoxy" refers to an alkoxy substituent that is further substituted with one or more amino groups.

The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent that is further substituted with one or more hydroxy groups.

The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

The term "acyl" refers to a monovalent radical of the general formula R-M (O) -, where M is typically C, remaining after removal of the hydroxyl group from an organic or inorganic oxyacid.

The term "carbonyl" is an organofunctional group (c=o) formed by the double bond connection of two atoms of carbon and oxygen.

The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group that is further substituted with one alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.

The term "arylcarbonyl" means that the carbonyl group defined herein is substituted with an aryl group defined herein.

The term "alkoxycarbonyl" refers to a carbonyl group that is further substituted with an alkoxy group.

The term "heterocycloalkylcarbonyl" refers to a carbonyl group that is further substituted with one heterocycloalkyl group.

The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl", "heteroarylaminocarbonyl" refer to the substitution of a carbonyl group as defined herein with an alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino group, respectively, as defined herein.

The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group that is further substituted with one alkylcarbonyl group.

The term "alkylcarbonyloxy" or "alkanoylalkoxy" refers to an alkoxy group that is further substituted with one alkylcarbonyl group.

The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group that is further substituted with a heterocycloalkylcarbonyl group.

The term "mercapto" refers to a-SH group. The term "alkylthio" means that a mercapto group as defined herein is substituted with an alkyl group as defined herein.

The term "sulfonyl" or "sulfonyl" refers to a functional group of a sulfonic acid after loss of hydroxyl groups, in particular, -S (=o) ₂ -a group.

The term "sulfoxide group" or "sulfinyl group" refers to-S (=o) -.

The term "aminosulfonyl" or "aminosulfonyl" refers to-S (=o) ₂ -NH ₂ A group.

The term "alkyl sulfoxide group" or "alkylsulfinyl" refers to alkyl-S (=o) -.

The term "alkylsulfonyl" or "alkylsulfonyl" refers to-S (=o) ₂ -R, wherein R is alkyl.

The term "alkylamino sulfone" means that the sulfone group defined herein is substituted with an alkylamino group defined herein.

The terms "alkylsulfonylamino" or "alkylsulfonylamino", and "cycloalkylsulfonylamino" or "cycloalkylsulfonylamino" mean that the amino group defined herein is substituted by an alkylsulfonyl or cycloalkylsulfonylamino group defined herein, i.e. -NH-S (=o) ₂ -R, wherein R is alkyl and cycloalkyl, respectively.

The terms "cycloalkyl sulfone" and "cycloalkyl sulfonyl" refer to-S (=o) ₂ -R, wherein R is cycloalkyl.

The term "quaternary ammonium group" means-N ⁺ RR 'R ", wherein R, R' and R" are each independently selected from alkyl groups having 1-8 carbon atoms.

The term "optional" means that one or more of the subsequently described events may or may not occur, and that both events occurring and events that do not occur are included. The term "optionally substituted" or "substituted" means that the mentioned groups may be substituted with one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkyl, aminoacyl, amino protecting groups, and the like. Among them, the amino protecting group is preferably selected from pivaloyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl and the like.

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 the appropriate 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 proportion of the solvent molecules in the crystalline solid state, forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alkoxide. Hydrates are formed by binding one or more water molecules to one molecule of the substance, wherein the water maintains its molecular state H ₂ O。

A "metabolite" of a compound disclosed herein is a derivative of a 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 particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, enzymes can produce specific structural transformations into compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while the enzyme phosphoglucomutase 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 compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both of these methods are known in the art. In some embodiments, the metabolites of the compounds are formed by an oxidation process and correspond to the corresponding hydroxyl containing compounds. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

The term "modulate" as used herein refers to directly or indirectly interacting with a target to alter 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.

The term "prodrug" or "prodrug" refers to derivatives that may not possess pharmacological activity, but in some cases may be administered orally or parenterally and thereafter metabolized in the body to form the compounds of the invention that possess pharmacological activity. Non-limiting examples of prodrugs include: esters, carbonates, half esters, phosphates, nitro esters, sulfates, sulfoxides, amides, carbamates, nitrogen containing compounds, phosphamides, glycosides, ethers, acetals, ketals and the like.

An "effective amount" refers to an amount of a drug or pharmaceutical formulation that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject that does not receive the amount. Also included within the scope of the term are amounts effective to enhance normal physiological function.

The term "treating" as used herein refers to alleviating at least one symptom of a disease, disorder, or condition. The term includes administration and/or application of one or more compounds described herein to a subject to provide management or treatment of a condition. "treatment" for purposes of this disclosure may, but need not, provide a cure; rather, "treatment" may be a form of management of a condition. When the compounds described herein are used to treat unwanted proliferating cells (including cancers), the "treatment" includes partial or complete destruction of the unwanted proliferating cells, but with minimal impact on the destruction of normal cells. The desired processing mechanism for deleterious rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

The term "preventing" as used herein includes co-preventing or slowing the onset of clinically significant disease progression or preventing or slowing the onset of preclinical significant disease stage in an at risk individual. This includes prophylactic treatment of individuals at risk of developing the disease.

The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from administration of a compound of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffer from the disorders or related conditions as described herein. The term "non-human animal" includes vertebrates, e.g., 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, and the like.

GI as used herein ₅₀ Refers to the concentration of drug required to inhibit 50% of cell growth, i.e., the concentration of drug at which 50% of cell (e.g., cancer cell) growth is inhibited or controlled.

IC as used herein ₅₀ Refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum effect in the analysis of the measured effect.

EC as used herein ₅₀ Refers to the dosage, concentration or amount of a test compound that causes a dose-dependent response that induces, stimulates or enhances 50% of the maximum expression of a particular response by a particular test compound.

Kinase inhibitors of the invention

The present invention relates to an SHP2 inhibitor comprising a compound as described by formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:

wherein,

B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazines (e.g) Pyrazolopyrimidinones (e.g.) >) And pyrazolopyrazines (e.g.)>)；

m and n are each independently 0, 1 or 2;

R ₃ selected from H, hydroxy, and halogen;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5-or 6 membered heterocycloalkyl C1-6 alkyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazoleA base;

Preferably, R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution; more preferably R ₁ And R is ₁ ' together form When R is present ₆ When R is ₆ Selected from halogen (e.g., fluorine) and C1-6 alkoxy (e.g., methoxy).

Further preferably, R ₂ And R is ₂ ' each is H; r is R ₃ Is H; r is R ₆ Each independently selected from halogen and C1-6 alkoxy.

In a preferred aspect, the present invention relates to an SHP2 inhibitor comprising a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:

Preferably, A is selected from phenyl, and imidazopyridinyl (e.g., imidazo [4,5-b]Pyridyl, especially) Oxadiazolyl (e.g. [1,2,4 ]]Oxadiazol-3-yl, in particular +.>) Oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, in particular +.>)；

n is 1 or 2;

R ₃ is H;

R ₅ is C1-C4 alkyl (preferably methyl);

R ₆ selected from halogen and C1-6 alkoxy.

Further preferred, A is an imidazopyridinyl group, in particular imidazo [4,5-b]Pyridyl, more particularly selected fromFurther preferably, R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with a halogen (e.g., fluoro) or a C1-6 alkoxy (e.g., methoxy).

Particularly preferably, the present invention relates to a compound represented by formula I or formula Ia as set forth in table 1 below, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof.

TABLE 1

In a further preferred aspect, the present invention relates to an inhibitor of SHP2 comprising a compound according to formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:

Preferably, A is selected from phenyl, imidazopyridinyl (e.g. imidazo [4, 5-b)]Pyridyl, especially) And oxadiazolyl (e.g. [1,2,4 ]]Oxadiazol-3-yl, in particular +.>) Oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, in particular +.>)；

n is 1 or 2;

R ₁ and R is ₁ ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxy, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution;

R ₃ Selected from H, hydroxy, and halogen;

R ₆ each independently selected from halogen and C1-6 alkoxy.

Further preferred, A is an imidazopyridinyl group, in particular imidazo [4,5-b]Pyridyl, more particularlyFurther preferably, R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with a C1-6 alkoxy group (e.g., methoxy).

Particularly preferably, the present invention relates to a compound represented by formula I or formula Ib as set forth in table 2 below, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof.

TABLE 2

In other preferred aspects, the invention relates to an inhibitor of SHP2 comprising a compound of formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:

n is 1 or 2;

R ₂ and R is ₂ ' each is H;

R ₃ is H;

R ₅ selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;

Further preferred, A is an imidazopyridinyl group, in particular imidazo [4,5-b]Pyridyl, more particularlyFurther preferably, R ₅ Is a C1-C4 hydroxyalkyl group, in particular hydroxymethyl.

Particularly preferably, the present invention relates to a compound represented by formula I or formula Ic as set forth in table 3 below, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof.

TABLE 3 Table 3

Any combination of the above groups for each variable is also contemplated herein. It will be appreciated that: substituents and substitution patterns on the compounds provided herein can be selected by one of skill in the art to provide compounds that are chemically stable and that can be synthesized using techniques known in the art and set forth herein.

Pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites or prodrugs of such compounds are also described herein.

In additional or further embodiments, the compounds described herein are metabolized in vivo to produce metabolites in organisms in need thereof, which are then used to produce desired effects, including desired therapeutic effects.

The compounds described herein may be formulated 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, and the like; or with an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, 2-naphthalenesulfonic acid, t-butylacetic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, and the like; (2) A base addition salt, which is formed when an acidic proton in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth metal ion (e.g., magnesium or calcium), or aluminum ion; or with organic or inorganic bases, acceptable organic bases including ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

The corresponding counterions of the 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 spectroscopy, mass spectrometry, or any combination thereof.

Recovering the salt using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of aqueous solutions.

Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis. Various spectroscopic techniques are used including, but 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 (Raman) microscopy.

The pharmaceutical use of the invention

The compound of the formula I, ia, ib or Ic or pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof can inhibit the activity of SHP2, thereby achieving the aim of treating, preventing or alleviating the diseases mediated by SHP 2. In a preferred aspect of the present invention,

Accordingly, the present application contemplates the use of a compound of formula I, ia, ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof, in the manufacture of a medicament for inhibiting SHP2 activity, or for treating, preventing or alleviating a disorder mediated by SHP 2.

Preferably, the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.

More preferably, the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.

In embodiments of the present application, a medicament comprising a compound of the present application may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration. The amount of a given drug in treating a patient according to the present application will depend on a number of factors, such as the particular dosage regimen, the type of disease or disorder and its severity, the uniqueness of the subject or host in need of treatment (e.g., body weight), but depending on the particular circumstances, including, for example, the particular drug employed, the route of administration, the disorder being treated, and the subject or host being treated, the dosage administered can be routinely determined by methods known in the art. Generally, for dosages used in adult treatment, the dosage administered is typically in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day. The desired dosage may conveniently be presented as a single dose, or as divided doses administered simultaneously (or in short time periods) or at appropriate intervals, for example two, three, four or more divided doses per day. It will be appreciated by those skilled in the art that, although the above dosage ranges are given, the specific effective amount may be suitably adjusted depending on the patient's condition in combination with a physician's diagnosis.

Preparation of the Compounds

The 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. In addition, the solvents, temperatures, and other reaction conditions set forth herein may vary according to the skill in the art. As a further guidance, the following synthetic methods may also be used.

The reactions may be used sequentially to provide the compounds described herein; or they may be used to synthesize fragments that are subsequently added by methods described herein and/or known in the art.

In certain embodiments, provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of use thereof. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds can be synthesized using a method similar to that described below, by using appropriate alternative starting materials.

The starting materials for the synthesis of the compounds described herein may be synthesized or may be obtained from commercial sources. Commercially available starting materials were not further purified unless otherwise indicated. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and starting materials known to those skilled in the art. The general methods of preparing the compounds disclosed herein may be from reactions known in the art, and the reactions may be modified by reagents and conditions deemed appropriate by one of skill in the art to incorporate various moieties in the molecules provided herein.

If desired, the reaction product may be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and profile data.

Column chromatography adopts silica gel (200-300 mesh) produced by Qingdao chemical Co., ltd.) and thin layer chromatography adopts silica gel plate produced by Qingdao chemical Co., ltd., nuclear magnetic resonance chromatograph uses Bruce nuclear magnetic resonance spectrometer, and liquid chromatography-mass spectrometry (LCMS) uses Agilent 1200 series liquid phase mass spectrometer.

The following abbreviations are used in the synthesis of the examples:

DCM: dichloromethane (dichloromethane)

ACN: acetonitrile

DIEPA: n, N-diisopropylethylamine

DME: ethylene glycol dimethyl ether

DMF: n, N-dimethylformamide

DMAc: dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMSO: dimethyl sulfoxide

EA: acetic acid ethyl ester

LCMS: liquid chromatography-mass spectrometry combination

TEA: triethylamine

PE: petroleum ether

TFA: trifluoroacetic acid

Ti(OEt) ₄ : titanic acid tetraethyl ester

TLC: thin layer chromatography

DAST: diethylaminosulfur trifluoride

THP: tetrahydropyrane

DHP:3, 4-dihydro-2H-pyranes

NIS: n-iodosuccinimide

NBS N-bromosuccinimide

NMO: n-methylmorpholine N-oxide

LDA: lithium diisopropylamide

Ar: argon gas.

Synthesis of intermediate compound IM 1:

step 1: synthesis of Compound IM1-3

The compound IM1-1 (10 g) and IM1-2 (19.8 g) were dissolved in DMF at room temperature and cooled to 0deg.C, N ₂ Protection sodium hydride (9 g) was added thereto in portions. After the addition, the reaction is carried out for 30 to 40 minutes by heat preservation and stirring, the temperature is raised to 60 ℃, and the reaction is carried out for 12 to 16 hours by stirring. LCMS monitoring showed the disappearance of starting material, cooling to 0 ℃, and dropwise adding water thereto to quench the reaction. The EA extraction reaction solution was added twice, the organic phase was washed twice, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and separated by column chromatography to obtain 3.83g of the target substance.

Step 2: synthesis of Compound IM1-4

The compound IM1-3 (3.83 g) and R-t-butylsulfinamide (4 g) were dissolved in tetraethyl titanate at room temperature, and the temperature was raised to 90℃and the reaction was stirred for 12-16 hours. LCMS monitoring showed complete reaction, cooling to room temperature, adding water to the reaction, EA extracting the reaction twice, washing the organic phase twice, drying over anhydrous sodium sulfate for 30 min, filtering, concentrating to give the target 3.1g.

Step 3: synthesis of Compound IM1-5

Compound IM1-4 (3.1 g) was dissolved in THF at room temperature, sodium borohydride (0.33 g) was added in portions, and the reaction was stirred at room temperature for 12-14 hours. LCMS monitoring showed complete reaction, quenching the reaction with saturated aqueous ammonium chloride, EA extraction twice, washing the organic phase twice, drying over anhydrous sodium sulfate for 30 min, filtering, concentrating, and column chromatography to give the target 2.5g.

Step 4: synthesis of Compound IM1

Compound IM1-5 (2.5 g) was dissolved in DCM at room temperature, trifluoroacetic acid (0.66 mL) was added and the reaction stirred at room temperature for 5-7 hours. LCMS monitoring showed complete reaction, concentration under reduced pressure removed solvent and excess trifluoroacetic acid. To this was added a saturated aqueous sodium hydrogencarbonate solution to neutralize the reaction solution, the reaction solution was extracted with EA twice, the organic phase was washed with water twice, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column-chromatographed to give 1.5g of the target substance. [ M+H ]] ⁺ 325.20。

The following intermediates were synthesized with reference to the above procedure:

synthesis of intermediate compound IM 5:

step 1: synthesis of Compound IM5-2

To a 100mL single-necked flask, IM5-1 (2.5 g,10.55 mmol), SM (1.5 g,11.6 mmol) and cesium carbonate (6.86 g,21.1 mmol) were added, and anhydrous DMF was added thereto at room temperature (10 ℃ C.), and the temperature was raised to 60 ℃ C. (internal temperature), followed by stirring and reaction for 1 hour. LCMS monitoring showed complete consumption of starting material, cooling, EA (5 mL) dilution of the reaction, washing the organic phase 2 times with water (10 mL), combining the organic phases, drying over anhydrous sodium sulfate for 30 min, filtering, concentrating to give the target 2.51g.

Step 2-3: synthesis of Compound IM5-4

To a 100mL one-necked flask, IM5-2 (0.7 g,2.11 mmol) was added, TFA (5.0 mL) was added, and iron powder (0.6 g) was added, followed by stirring and reaction for 3 hours. LCMS detection showed complete consumption of starting material, adsorption removal of iron powder with a magnet bar followed by warming to reflux and reaction for 10 hours, LCMS detection showed complete reaction. The solvent was removed by concentration under reduced pressure, the residue was diluted with EA, the reaction solution was neutralized with saturated sodium hydrogencarbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, and the concentrated target was filtered to conduct the next reaction without purification.

Step 4: synthesis of Compound IM5

Into a 100mL single-necked flask, IM5-4 (0.57 g,1.5 mmol), pinacol biborate (0.76 g,3.0 mmol), potassium acetate (0.36 g,3.76 mmol), pd (dppf) Cl were charged ₂ DCM(0.25g,0.3mmol)，N ₂ And replacing for 4-5 times, pumping dioxane at room temperature (30 ℃) under negative pressure, heating to 100 ℃, and stirring for reacting for 12 hours. LCMS monitoring showed complete consumption of starting material, cooling, dilution of the reaction with EA (5 mL), washing the organic phase 2 times with water (10 mL), combining the organic phases, drying over anhydrous sodium sulfate for 30 min, filtering, concentrating to give the title compound as a brown-black oil, 0.6g, 87% yield. [ M+H ]] ⁺ 427.2202。

intermediate compounds IM13, IM14:

synthesis of intermediate compound IM 15:

step 1: synthesis of Compound IM15-2

To a 100mL round bottom flask was added IM15-1 (50 mg), NIS (145 mg), 1mL acetonitrile. The mixture was reacted at 85℃for 2 hours. TLC monitored the end point of the reaction (PE/ea=5/1), indicating the completion of the reaction. The reaction solution was cooled to room temperature and then suction filtered, and the filter cake was dried to give 90mg of yellow solid, yield: 99%. [ M+H ]] ⁺ 280.8。

Step 2: synthesis of Compound IM15

IM15-2 (90 mg) was weighed into a 100mL round bottom flask, dissolved in DCM (1 mL) and then DHP (81 mg), tsOH (16.6 mg) were added and the mixture was reacted at 25℃for 10 min. TLC monitoring of the end of the reaction (PE/EA=20/1) showed that the reaction was complete, and NaHCO was added to the reaction mixture ₃ Quenching. Extraction with DCM and spin-drying of the filtrate gives crude product. Crude column chromatography (PE/ea=20/1) gave 40mg of white solid, yield: 34%. [ M+H ]] ⁺ 364.9。

Synthesis of intermediate compound IM 16:

step 1: synthesis of Compound IM16-2

IM16-1 (1.0 g,5.3 mmol) was weighed into a 100mL round bottom flask, dissolved in DCM (5.0 mL) and then DHP (0.49 g,5.82 mmol), tsOH (91 mg,0.53 mmol) was added and the mixture reacted at 25℃for 20 min. TLC monitored the end point of the reaction (PE/ea=20/1), indicating the completion of the reaction. NaHCO is added into the reaction solution ₃ Quench and then extract with DCM and spin dry the filtrate to give crude. Crude column chromatography (PE/ea=20/1) gave 900mg of white solid, yield: 34%. [ M+H ]] ⁺ 274.12。

Step 2: synthesis of Compound IM16-3

Compound IM16-2 (900 mg,3.3 mmol) and sodium hydroxide (0.53 g,13.2 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, the temperature was raised to 80-90℃and the reaction was stirred for 12-16 hours, and LCMS monitoring showed complete reaction. Cooling to room temperature, adding water into the reaction solution, extracting the reaction solution by EA for two times, washing the organic phase by water for two times, drying by anhydrous sodium sulfate for 30 minutes, filtering, and concentrating to obtain 0.7g of target substance.

Step 3: synthesis of Compound IM16-4

Compound IM16-3 (0.7 g,2.74 mmol), K was taken at room temperature ₂ CO ₃ (0.76 g,5.50 mmol) was dissolved in THF and methyl iodide (0.5 g,3.57 mmol) was added and the reaction stirred at 55-60℃for 12-14 hours, LCMS monitoring indicated complete reaction. Adding saturated ammonium chloride aqueous solution to quench The reaction solution was quenched, extracted with EA twice, the organic phase was washed twice, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column chromatographed to give 0.85g of the target.

Step 4: synthesis of Compound IM16

To a 100mL round bottom flask was added IM16-4 (0.85 g,3.16 mmol), NIS (0.78 g,3.48 mmol), ACN (6.0 mL). The mixture was reacted at 85℃for 2 hours. TLC monitored the end point of the reaction (PE/ea=5/1), indicating the completion of the reaction. The reaction solution was cooled to room temperature and then suction filtered, and the filter cake was dried by spinning to give 90mg of yellow solid. [ M+H ]] ⁺ 395.60。

EXAMPLE 1 Synthesis of Compound 1

Step 1: synthesis of Compound 1-1

Compound IM16 (200 mg) was weighed into a 50mL round bottom flask, IM18 (234.4 mg), csF (210.2 mg) were added, and anhydrous DMAc (2 mL) was added at room temperature to dissolve, and the reaction was stirred in an oil bath at 80 ℃ for 1 hour, and the reaction end point was monitored by TLC (developer: meOH/dcm=1/20). Ethyl acetate is added into the reaction liquid, the mixture is washed twice with water and once with saturated saline, the organic phase is dried with anhydrous sodium sulfate, and the mixture is subjected to sample column chromatography after decompression spin drying, so that the total of 430mg of intermediate 1-1 is obtained, and the yield is 99%. Mass spectrometry: [ M+H ]] ⁺ 645.29。

Step 2: synthesis of Compounds 1-2

Compound 1-1 (430 mg) was weighed into a 100mL round bottom flask, dichlorobenzoboric acid (148.1 mg) was added, pd (dppf) Cl was added at room temperature ₂ (74.8 mg), potassium phosphate (178.8 mg), dioxane (5 mL) and water (0.5 mL), were replaced with argon three times, and then placed in an oil bath at 100℃to stir and react for 16 hours. TLC monitored the end point of the reaction (developer: meOH/dcm=1/12.5). Performing sample column chromatography after decompressing and spin-drying the reaction liquid to obtain 300mg of intermediate 1-2 in total, and obtaining the product with the yield of 65 percent and [ M+H ]] ⁺ 683.23。

Step 3: synthesis of Compound 1

Weigh Compounds 1-2 (300 mg) in a 100mL round bottom flask, add at room temperatureMethanol (10 mL) was added, and a hydrochloric acid/methanol solution (4N, 10 mL) was slowly added with stirring, and the reaction was stirred at room temperature for 16 hours. LCMS monitored the reaction endpoint, the reaction solution was dried under reduced pressure, neutralized with saturated aqueous sodium carbonate, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. After spin drying, the mixture is separated and purified by a preparation plate, and 70mg of a final product is obtained, and the yield is 32%. Mass spectrometry: [ M+H ]] ⁺ 495.19； ¹ H NMR(DMSO-d ₆ ,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)。

Example 2: synthesis of Compound 2

Step 1: synthesis of Compound 2-1

IM16 (100 mg,0.25 mmol), IM13 (69 mg,0.30 mmol), DIPEA (66 mg,0.50 mmol) were weighed into a 100mL round bottom flask and then dissolved in DMF (2 mL) and the mixture was reacted in an oil bath at 60℃for 6 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) indicating the reaction was complete. Adding the reaction solution into water to separate out yellow solid, suction filtering, and spin-drying filter cake to obtain crude colorless oily 2-1 crude product 110mg with yield of 74%, [ M+H ] ] ⁺ 587.21。

Step 2: synthesis of Compound 2-2

2-1 (110 mg,0.19 mmol), tributylvinyltin (322 mg,0.28 mmol), pd (PPh) were weighed out ₃ ) ₄ (43.4 mg,0.038 mmol) TEA (38 mg,0.37 mmol) was placed in a 100mL round bottom flask, then DMF (5 mL) was added for dissolution, and the mixture was replaced 3 times with argon and then placed in an oil bath at 110℃for reaction for 12 hours. TLC monitored the end of the reaction (DCM/meoh=40/1) and after about 12 hours the reaction was complete. The reaction solution is filtered by diatomite, and the filtrate is dried by spin to obtain a crude product. Crude product was isolated by column chromatography (DCM/meoh=40/1) to give 80mg of yellow oil, yield: 88%. [ M+H ]] ⁺ 487.61。

Step 3: synthesis of Compound 2-3

Weighing 2-2 (80 mg,0.16 mmol), K ₂ OsO _4· 2H ₂ O(5.5mg，0.016mmol)、NaIO ₄ (35 mg,0.16 mmol) in a 100mL round bottom flask followed by THF (2 mL) and H ₂ O (2 mL) was dissolved and the mixture was reacted at 25℃for 12 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) and after about 12 hours the reaction was complete. The reaction solution was quenched with aqueous sodium bisulphite, extracted with EA, and the organic phase was dried by spinning to give 90mg of crude product, which was carried on to the next step directly without purification. [ M+H ]] ⁺ 488.6。

Step 4: synthesis of Compounds 2-4

Weighing 2-3 (90 mg,0.18 mmol) of hydroxylamine hydrochloride NH ₂ OH HCl (14.1 mg,0.21 mmol) was dissolved in 100mL round bottom flask and the mixture was reacted at 25℃for 12 hours with EtOH (1 mL). TLC monitored the end of the reaction (DCM/meoh=20/1) and after about 12 hours the reaction was complete. The reaction was quenched with water, extracted with DCM and the organic phase was dried by spinning to give the crude product. Crude product was chromatographed (DCM/meoh=20/1) to give 60mg of yellow solid, [ m+h ] ⁺ 503.3。

Step 5: synthesis of Compounds 2-5

2-4 (60 mg,0.12 mmol) was weighed into a 25mL round bottom flask, added MeOH (3 mL) and H ₂ O (0.6 mL) was dissolved, followed by the addition of phenylacetylene (6 mg,0.24 mmol), phI (AcO) ₂ (57.6 mg,0.18 mmol) and the mixture was reacted at 25℃for 12 hours. TLC monitored the end of the reaction (DCM/meoh=40/1) and after about 12 hours the reaction was complete. The reaction solution is dried by spin to obtain a crude product. Crude product was chromatographed (DCM/MeOH=20/1) to give 31mg of a colorless oil, [ M+H ]] ⁺ 604.30。

Step 6: synthesis of Compound 2

Compounds 2-5 (31 mg) were weighed into a 100mL round bottom flask, methanol (4 mL) was added at room temperature, hydrochloric acid/methanol solution (4N, 4 mL) was slowly added with stirring, and the reaction was stirred at room temperature for 16 hours. LCMS monitored the reaction endpoint, the reaction solution was dried under reduced pressure, neutralized with saturated aqueous sodium carbonate, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. After spin drying, the mixture was separated and purified by a preparation plate to obtain 10mg of the final product. Mass spectrometry: [ M+H ]420.2.

Example 3: synthesis of Compound 3

Step 1: synthesis of Compound 3-1

The synthesis of reference compound 2-1 was obtained via synthesis of intermediates IM16 and IM13, mass spectrum [ M+H ]587.2.

Step 2: synthesis of Compound 3-2

To a 100mL single-necked flask, 3-1 (100 mg,0.16 mmol) and Zn (CN) were added ₂ (28.28mg，0.24mmol)、Pd ₂ (dba) ₃ (14.8mg，0.016mmol)、Pd(dppf)Cl ₂ DCM (13.2 mg,0.016 mmol) was added thereto water/DMF (2/14 mL) at room temperature (30 ℃ C.), warmed to 110 ℃ C. (inner temperature) and stirred for 5 hours. LCMS monitoring showed complete consumption of starting material, cooling. EA (5 mL) was added to the reaction solution, water (10 mL) was added to wash the organic phase 2 times, the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column chromatographed to give 78mg of the target substance. [ M+H ]] ⁺ 486.3。

Step 3: synthesis of Compound 3-3

To a 100mL one-necked flask, 3-2 (78 mg,0.15 mmol), hydroxylamine hydrochloride (15.3 mg,0.22 mmol) and sodium hydrogencarbonate (24.6 mg,0.29 mmol) were added, and the mixture was reacted with ethanol under stirring for 12 hours. LCMS monitoring showed complete reaction of starting material, dilution of reaction with EA (5 mL) and washing of the organic phase 2 times with water (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to give 0.1g of the target. [ M+H ]] ⁺ 519.3。

Step 4: synthesis of Compounds 3-4

To a 100mL single-necked flask, 3-3 (0.10 g,0.19 mmol), benzoyl chloride (32.74 mg,0.23 mmol), TEA (23.57 mg,0.23 mmol) and toluene (3 mL) were added, and the mixture was stirred at 0℃for 1 hour, and the temperature was raised to reflux and the mixture was stirred for 12 hours. LC-MS monitoring shows complete consumption of the raw materials and cooling. EA (5 mL) diluted reaction, water (10 mL) was added to wash the organic phase 2 times, the organic phases were combined, and anhydrous sulfur The sodium acid is dried for 30 minutes, filtered and concentrated. Column chromatography (PE/EA 5:1) to give 50mg of target substance, [ M+H ]] ⁺ 605.3。

Step 5: synthesis of Compound 3

To a 100mL single-necked flask, 3-4 (50 mg) was added, methanol hydrochloride (3 mL) was added at room temperature (30 ℃ C.), and the reaction was stirred for 2-3 hours, and LCMS monitoring showed complete consumption of the starting material. To the reaction solution was added a saturated sodium hydrogencarbonate solution for neutralization, ethyl acetate (10 mL) was added and the reaction solution was extracted, and the organic phase was washed with water (10 mL) 2 times, and the organic phases were combined and dried over anhydrous sodium sulfate for 30 minutes. Filtration, concentration, column chromatography (DCM/MeOH 20:1) and lyophilization gave 8mg of the off-white target. Mass spectrometry: [ M+H ]421.2.

The following targets were synthesized by a similar method to the previous example 1 via different starting materials and corresponding reagents.

Example 7: synthesis of Compound 7

Step 1: synthesis of Compound 7-1

Into a 250mL three-necked flask, THF (80 mL) and SM2 (3 g) were added, stirring was started, ar was replaced three times, then the temperature was lowered to-40℃and methylmagnesium bromide (dissolved in THF,1.0mol/L,63 mL) was slowly added dropwise, and after stirring was continued at-40℃for about 30 minutes, the mixture was allowed to react at room temperature. TLC monitored the end of the reaction (PE/ea=5/1) and after about 2 hours the reaction was complete. The reaction solution was slowly added to about 100mL of saturated ammonium chloride solution, the solution was separated, the organic phase was washed with water 2 times, saturated brine was washed 1 time, dried over anhydrous sodium sulfate, filtered, EA was used to wash the cake, and the filtrate was concentrated to dryness in vacuo to give 2.59g of the product, yield: 80%. [ M+H ] ] ⁺ 232。

Step 2: synthesis of Compound 7-2

To a 50mL single-necked flask, 7-1 (0.5 g), pd/C (50 mg) and 10mL of methanol were added, and the mixture was stirred and then, after three hydrogen substitutions, reacted overnight at room temperature. The LC-MS monitored the end point of the reaction and showed the reaction was complete after about 16 hours. The Pd/C was removed by filtration through celite, the filter cake was washed 2 times with methanol, the washes were combined and concentrated in vacuo to dryness to give 0.43g of crude product. [ M+H ]] ⁺ 142。

Step 3: synthesis of Compound 7-3

To a 10mL reaction tube were added 7-2 (100 mg), IM16 (43 mg), potassium carbonate (173 mg) and DMF (2 mL), and the mixture was stirred and heated to 60℃to react. LC-MS monitored the end point of the reaction and showed the reaction was complete after about 2 hours. After cooling to room temperature, water was added and quenched, the mixture was extracted 3 times with DCM, the organic phase was washed 3 times with water, 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with DCM, and the combined washings were concentrated to dryness in vacuo to give 70mg of crude product. [ M+H ]] ⁺ 500。

Step 4: synthesis of Compound 7-4

7-3 (70 mg), dichlorobenzoboric acid (33 mg), pdCl were added to a 10mL vial ₂ (dppf) (23 mg), potassium carbonate (58 mg), dioxane (2 mL) and water (0.5 mL) were stirred and then heated to 90℃for reaction. TLC monitored the end of the reaction (PE/ea=1/1), and after about 2 hours the reaction was complete. Cooling to room temperature, quenching with water, extracting with DCM for 3 times, washing the organic phase with saturated saline for 1 time, and drying with anhydrous sodium sulfate The mixture was dried, filtered and the filter cake washed with DCM. The combined washes were concentrated to dryness in vacuo and column chromatographed (PE/ea=1/1) to give 31mg of product, yield: 43%. [ M+H ]] ⁺ 518。

Step 5: synthesis of Compound 7 of interest

To a 25mL reaction flask were added 7-4 (31 mg) and TFA (5 mL), and the reaction was stirred at room temperature. LC-MS monitored the end point of the reaction and showed the reaction was complete after about 2 hours. TFA was removed by concentration in vacuo, aqueous sodium carbonate was added, extracted three times with DCM, washed once with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filter cake washed with DCM, and column chromatographed (PE/EA=1/1) to give 12mg of product in 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)。

Example 15: synthesis of Compound 15:

this compound, [ M+H ]390.2 was synthesized via the intermediate IM15, IM13, by the method of synthesis as described in reference to example 2.

Example 19: synthesis of Compound 19

Step 1: synthesis of Compound 19-1

Into a 250mL three-necked flask, THF (80 mL) and SM2 (3 g) were added, stirring was started, ar gas was replaced three times, then the temperature was lowered to-40℃and methylmagnesium bromide (dissolved in THF,1.0mol/L,63 mL) was slowly added dropwise, and after stirring was continued at-40℃for about 30 minutes, the mixture was allowed to react at room temperature. TLC monitored the end of the reaction (PE/ea=5/1) and after about 2 hours the reaction was complete. The reaction solution was slowly added to about 100mL of saturated ammonium chloride solution, the solution was separated, the organic phase was washed with water 2 times, saturated brine was washed 1 time, dried over anhydrous sodium sulfate, filtered, EA was used to wash the cake, and the filtrate was concentrated to dryness in vacuo to give 2.59g of the product, yield: 80%. [ M+H ] ] ⁺ 232。

Step 2: synthesis of Compound 19-2

To a 100mL single-necked flask, 19-1 (1.65 g) and 50mL of acetonitrile were added, stirring was turned on, concentrated sulfuric acid (7 mL) was slowly added dropwise under an ice bath, the ice bath was removed after the addition was completed, and the flask was left to stand at room temperature for reaction. LCMS monitored the progress of the reaction and showed the reaction was complete after about 3 hours of reaction. Placing the reaction solution in ice bath, slowly adding saturated sodium carbonate aqueous solution to adjust pH to alkaline, extracting with EA for three times, mixing organic phases, washing with water for 3 times, washing with saturated saline water for 1 time, drying with anhydrous sodium sulfate, filtering, washing filter cake with EA for two times, mixing the filtrates, and vacuum-washingConcentrating to dry to obtain crude product 0.86g, [ M+H ]] ⁺ 273。

Step 3: synthesis of Compound 19-3

To a 50mL single-necked flask, 19-2 (220 mg), pd/C (25 mg) and methanol (5 mL) were added, and the mixture was stirred and then replaced with hydrogen three times, followed by overnight reaction at room temperature. LC-MS monitored the end point of the reaction and showed the reaction was complete after about 5 hours. Filtering with diatomite to remove Pd/C, washing the filter cake with methanol for 2 times, mixing the washing filtrates, vacuum concentrating to dry to obtain 165mg of crude product, [ M+H ]] ⁺ 183。

Step 4: synthesis of Compound 19-4

To a 25mL single-necked flask, 19-3 (109 mg), IM15 (66 mg), potassium carbonate (124 mg) and DMF (3 mL) were added, and the mixture was stirred and heated to 60℃to react. The LC-MS monitored the end point of the reaction and showed the reaction was complete after about 16 hours. After cooling to room temperature, water was added and quenched, DCM was extracted 3 times, the organic phase was washed 3 times with water, 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered and the filter cake was washed with DCM. The combined washes were concentrated in vacuo to dryness and then column chromatographed (PE/ea=1/3) to give 56mg of product in 37% yield. [ M+H ] ] ⁺ 511。

Step 5: synthesis of Compound 19-5

19-4 (56 mg), dichlorobenzoboric acid (23 mg), pdCl were added to a 10mL vial ₂ (dppf) (16 mg), potassium carbonate (42 mg), dioxane (2 mL) and water (0.5 mL) were reacted at 90℃with stirring after argon substitution, and the reaction was terminated by monitoring the reaction time with LC-MS and indicating the completion of the reaction after about 16 hours. After cooling to room temperature, water was added, extraction was performed 3 times with DCM, the organic phase was washed 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered and the filter cake was washed with DCM. The combined washes were concentrated to dryness in vacuo and column chromatographed (PE/ea=1/2) to give 23mg of product, yield: 39%. [ M+H ]] ⁺ 529。

Step 6: synthesis of Compound 19

To a 25mL single-necked flask, 19-5 (23 mg) and TFA (5 mL) were added, and the reaction was stirred at room temperature. The LC-MS monitored the end point of the reaction and showed the reaction was complete after about 14 hours. Concentrating in vacuo to remove TFA, adding aqueous sodium carbonate solution, extracting with DCM three times, washing with saturated sodium bicarbonate solution once, drying over anhydrous sodium sulfate, filtering, and filteringThe cake was washed with DCM. Column chromatography (PE/ea=1/2) gives 16mg 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)。

Example 20: synthesis of Compound 20

Step 1: synthesis of Compound SM1

SM1-1 (5.0 g) and methylene chloride (5 mL) were added to a 100mL single-necked flask, and anhydrous trifluoroacetic acid (2 mL) was added thereto at room temperature (30 ℃ C.) to stir the reaction for 1 hour, and LCMS monitoring showed complete consumption of the starting material. Dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, the organic phases were washed 2 times with water (10 mL), combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated, and column chromatography (PE/EA 5:1) gave 4.0g of a pale yellow target compound in 81% yield.

Step 2: synthesis of Compound 20-1

To a 100mL single-necked flask, SM1 (71.7 mg), IM15 (0.1 g), and potassium carbonate (77.1 mg) were added, and thereto was added anhydrous DMF at room temperature (30 ℃ C.), and the mixture was warmed to 60 ℃ C. (internal temperature) and reacted for 5 hours with stirring, and TLC monitoring (PE/EA 5:1) showed complete consumption of the starting material. The reaction mixture was cooled, diluted with EA (5 mL), washed with water (10 mL) 2 times, the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column chromatographed (PE/EA 5:1) to give 0.1g of the pale yellow target compound in 83% yield.

Step 3: synthesis of Compound 20-2

Into a 100mL one-necked flask, dichlorobenzoboric acid (50.51 mg), 20-1 (0.1 g), potassium phosphate (60.98 mg), pd (dppf) Cl were charged ₂ (5.4mg)，N ₂ And replacing for 4-5 times, pumping dioxane/water mixed solvent under negative pressure at room temperature (30 ℃), heating to 80-85 ℃ (internal temperature), and stirring for reacting for 5 hours. TLC monitoring (PE/EA 5:1) shows the originalComplete consumption, cooling, EA (5 mL) diluted reaction, water (10 mL) was added to wash the organic phase 2 times, the organic phases were combined, dried over anhydrous sodium sulfate for 30 min, filtered, and concentrated. Column chromatography (PE/EA 2:1) gave 0.09g of the pale yellow target with a yield of 90%. [ M+H ]] ⁺ 472。

Step 4: synthesis of Compound 20-3

To a 100mL single-necked flask, 20-2 (90 mg) was added, and a methanol solution of hydrochloric acid was added at room temperature (30 ℃ C.) and the reaction was stirred for 2-3 hours, and TLC monitoring (PE/EA 5:1) showed complete consumption of the starting material. To the reaction solution was added saturated sodium bicarbonate solution to neutralize the reaction solution, EA (5 mL) was added to extract the reaction solution twice, the organic phase was washed with water (10 mL) 1 time, and the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated. Column chromatography (DCM/MeOH 20:1) and lyophilization gave the off-white target 30mg in 40.5% yield. [ 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＝7.9Hz,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)。

Step 5: synthesis of Compound 20

To a 100mL single-necked flask was added 20-3 (30 mg), THF (2 mL) was added at room temperature (30 ℃ C.), sodium borohydride (5 mg) was added and the reaction was stirred for 2-3 hours, and TLC monitoring (PE/EA 5:1) showed complete consumption of starting material. The reaction mixture was quenched by adding a saturated ammonium chloride solution. Water and EA (5 mL) were added to extract the reaction twice, the organic phase was washed 2 times with water (10 mL), the organic phases were combined, dried over anhydrous magnesium sulfate for 30 min, filtered, and concentrated. Column chromatography (DCM/MeOH 10:1) and lyophilization gave the off-white target 9mg in 30% yield. [ 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＝7.9Hz,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)。

Example 21: synthesis of Compound 21

Step 1: synthesis of Compound SM1

Reference is made to the synthesis of intermediate SM1 of example 20 above.

Step 2: synthesis of Compound 21-1

To a 100mL single-necked flask, SM1 (0.36 g), IM15 (0.5 g), and potassium carbonate (0.39 g) were added, and anhydrous DMF was added thereto at room temperature (30 ℃ C.), and the mixture was warmed to 60 ℃ C. (internal temperature) and reacted for 5 hours with stirring, and TLC monitoring (PE/EA 5:1) showed complete consumption of the starting material. The reaction mixture was cooled, diluted with EA (5 mL), washed with water (10 mL) 2 times, the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column chromatographed (PE/EA 5:1) to give 0.45g of the pale yellow target compound in 62% yield.

Step 3: synthesis of Compound 21-2

Into a 100mL single-necked flask, dichlorobenzoboric acid (45.45 mg), 21-1 (90 mg), potassium carbonate (55.12 mg), pd (dppf) Cl were charged ₂ DCM(0.51mg)，N ₂ And (3) replacing for 4-5 times, pumping dioxane/water mixed solvent under negative pressure at room temperature (30 ℃), heating to 80-85 ℃ (internal temperature), stirring and reacting for 5 hours, and monitoring by TLC (PE/EA 5:1) to show that the raw material consumption is complete. The reaction was cooled, diluted with EA (5 mL), and the organic phases were washed 2 times with water (10 mL), combined, dried over anhydrous sodium sulfate for 30 min, filtered, and concentrated. Column chromatography (PE/EA 5:1) afforded 78mg of the pale yellow target with 96% yield. [ M+H ]] ⁺ 472.1312。

Step 4. Synthesis of intermediate 21-3

KOH (10.8 mg) and methanol (2 mL) were added to a 250mL three-necked flask and stirred at 0 ℃. 21-2 methanol solution (1 mL) was added dropwise thereto, and after completion of the dropwise addition, the reaction was continued for 25 minutes with the addition of iodobenzene acetate (20.84 mg) and the reaction was continued for 3-4 hours. LCMS monitoring showed reaction was complete. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution to extract the reaction solution twice, the organic phase was washed with water (10 mL) 1 time, and the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and used directly in the next step without further purification. [ M+H ]] ⁺ 534.1670。

Step 5 Synthesis of Compound 21

To a 100mL single-necked flask, 21-3 (90 mg) was added, and methylene chloride was added at room temperature (30 ℃ C.) to dissolve, and trifluoroacetic acid (2 mL) was added, and the reaction was stirred for 2-3 hours, and TLC monitoring (PE/EA 1:1) showed complete consumption of starting material. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure, ethyl acetate (10 mL) was added to the reaction solution, the reaction solution was neutralized with saturated sodium hydrogencarbonate solution and extracted, the organic phases were washed with water (10 mL) 1 time, the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated. Column chromatography (DCM/MeOH 10:1) and lyophilization gave the off-white target 7mg in 11% yield. [ 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＝7.9Hz,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)。

Example 28: synthesis of Compound 28

Step 1: synthesis of Compound 28-1

To a 50mL three-necked flask, 21-3 (100 mg) and DCM (2 mL) were added and stirred at 0 ℃. DAST (60.33 mg,0.37 mmol) was added dropwise thereto, and after completion of the dropwise addition, the reaction was transferred to room temperature (25 ℃ C.) and reacted for 2 hours. Sampling LCMS monitoring showed complete reaction, concentrating to dryness at room temperature, adding ethyl acetate (10 mL), aqueous sodium bicarbonate (10 mL) to extract the reaction twice, washing the organic phase 1 time with water (10 mL), combining the organic phases, drying over anhydrous sodium sulfate for 30 min, filtering, concentrating. Column chromatography gave 80mg with a yield of 70%. [ M+H ]] ⁺ 536.15。

Step 2: synthesis of Compound 28-2

To a 100mL one-necked flask, 28-1 (80 mg) was added, and methylene chloride was added at room temperature (30 ℃ C.) to dissolve the mixture, and trifluoroacetic acid (2 mL) was added thereto, followed by stirring for 2-3 hours. TLC monitoring (PE/EA 1:1)Indicating complete consumption of raw materials. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure, ethyl acetate (10 mL) was added to the reaction solution, the reaction solution was neutralized with saturated sodium hydrogencarbonate solution and extracted, the organic phase was washed with water (10 mL) 1 time, and the organic phases were combined and dried over anhydrous sodium sulfate for 30 minutes. Filtration, concentration, column chromatography (DCM/MeOH 10:1) and lyophilization gave 60mg of the off-white target in 54% yield. [ 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＝7.9Hz,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)。

Step 3: synthesis of Compound 28-3

To a 100mL single-necked flask, 28-2 (0.16 g), t-butylsulfinamide (57.14 mg) and tetraethyltitanate (0.58 g, 33%) were added, and thereto was added anhydrous THF at room temperature (25 ℃ C.), and the temperature was raised to 80 ℃ C. (inner temperature) and the reaction was stirred for 12-16 hours. LCMS monitoring showed complete consumption of starting material, cooling, adding NaBH thereto ₄ The reaction was carried out at 25℃for 5 hours, and monitoring by LCMS showed the reaction to be complete. The reaction was diluted with EA (5 mL), water (10 mL) was added, a large amount of solids precipitated, the mixture was filtered, the organic phase was washed with water 2 times, the organic phases were combined, and dried over anhydrous sodium sulfate for 30 minutes. Filtering and concentrating to obtain 0.1g of target crude product. [ M+H ] ] ⁺ 511.12499。

Step 4: synthesis of Compound 28

28-3 (100 mg) was added to a 100mL single-necked flask, and a methanol solution of hydrochloric acid was added at room temperature (30 ℃ C.) to stir and react for 2-3 hours. TLC monitoring (PE/EA 1:1) showed complete consumption of starting material, concentrating under reduced pressure, adding ethyl acetate (10 mL), neutralizing with saturated sodium bicarbonate solution and extracting the reaction solution, washing the organic phase 1 time with water (10 mL), combining the organic phases, drying over anhydrous sodium sulfate for 30 min. Filtration, concentration, column chromatography (DCM/MeOH 10:1) and lyophilization gave 8mg of the off-white target in 10% yield. [ 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＝7.9Hz,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)。

Example 29: synthesis of Compound 29

Step 1: synthesis of Compound 29-1

The synthesis of reference compound 1-1 was obtained via synthesis of intermediates IM15 and IM18, [ M+H ]635.

Step 2: synthesis of Compound 29-2

29-1 (100 mg,0.16 mmol) and Zn (CN) were charged into a 100mL single-necked flask ₂ (28.28mg，0.24mmol)、Pd ₂ (dba) ₃ (14.8mg，0.016mmol)、Pd(dppf)Cl ₂ DCM (13.2 mg,0.016 mmol) was added thereto water/DMF (2/14 mL) at room temperature (30 ℃ C.), warmed to 110 ℃ C. (inner temperature) and stirred for 5 hours. LCMS monitoring showed complete consumption of starting material, cooling. EA (5 mL) was added to the reaction solution, water (10 mL) was added to wash the organic phase 2 times, the organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated, and column chromatographed to give 78mg of the target substance. [ M+H ] ] ⁺ 534.2648。

Step 3: synthesis of Compound 29-3

To a 100mL one-necked flask, 29-2 (78 mg,0.15 mmol), hydroxylamine hydrochloride (15.3 mg,0.22 mmol) and sodium hydrogencarbonate (24.6 mg,0.29 mmol) were added, and the mixture was reacted with ethanol under stirring for 12 hours. LCMS monitoring showed complete reaction of starting material, dilution of reaction with EA (5 mL) and washing of the organic phase 2 times with water (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered and concentrated to give 0.12g of the target. [ M+H ]] ⁺ 679.2788。

Step 4: synthesis of Compound 29-4

To a 100mL single-necked flask, 29-3 (0.12 g,0.21 mmol), benzoyl chloride (32.74 mg,0.23 mmol), TEA (23.57 mg,0.23 mmol) and toluene (3 mL) were added, and the mixture was stirred at 0℃for 1 hour, and the temperature was raised to reflux and the mixture was stirred for 12 hours. LC-MS monitoring shows that the raw material consumption is complete, and the temperature is reduced. The reaction was diluted with EA (5 mL), the organic phases were washed 2 times with water (10 mL), combined, dried over anhydrous sodium sulfate for 30min, filtered, and concentrated. Column chromatography (PE/EA 5:1) gave 50mg of the target with a yield of 25%. [ M+H ]] ⁺ 653.3330。

Step 5: synthesis of Compound 29

29-4 (50 mg) was added to a 100mL single-necked flask, methanol hydrochloride (3 mL) was added at room temperature (30 ℃ C.), and the reaction was stirred for 2-3 hours, and LCMS monitoring showed complete consumption of the starting material. To the reaction solution was added a saturated sodium hydrogencarbonate solution for neutralization, ethyl acetate (10 mL) was added and the reaction solution was extracted, and the organic phase was washed with water (10 mL) 2 times, and the organic phases were combined and dried over anhydrous sodium sulfate for 30 minutes. Filtration, concentration, column chromatography (DCM/MeOH 20:1) and lyophilization gave the off-white target 10mg. 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)。

Example 30: synthesis of Compound 30

Compound 30 was synthesized according to a procedure similar to example 29. [ M+H ]] ⁺ 533.14。 ¹ HNMR(500MHz,DMSO-d ₆ )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)。

The following targets were synthesized by a similar method to that of example 29 above, via different starting materials and corresponding reagents.

Example 40: synthesis of Compound 40

Step 1: synthesis of Compound 40-1

In a 100mL single-necked flask, starting material SM2 (3 g) was added and dissolved in 50mL DMSO followed by Me ₃ SI (3 g) and potassium tert-butoxide (1.65 g) were added slowly with stirring. After the addition was completed, the reaction was stirred at 25℃for 1 hour. TLC detection with PE: EA=5:1 as developing reagent, no starting material remained. The reaction mixture was quenched with water, extracted with petroleum ether, and the organic phases were combined, washed with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentration gave 3g of the desired product as a white solid in 94.6% yield. [ M+H ]] ⁺ 230。

Step 2: synthesis of Compound 40-2

Raw material 40-1 (400 mg) was dissolved in 10mL of 7M NH ₃ In methanol solution, and the reaction solution was transferred to a lock tube and reacted at 80℃with stirring for 16 hours. TLC detection with DCM: meoh=10:1 as developing reagent, starting material was not left. The reaction was concentrated directly to dryness and the residual NH was removed with DCM ₃ After concentration, the mixture was allowed to stand for a while to give 400mg of yellow solid in 94% yield. [ M+H ]] ⁺ 247。

Step 3: synthesis of Compound 40-3

In a 25mL single-necked flask, the starting material 40-2 (150 mg) was dissolved in anhydrous THF (5 mL), followed by addition of triethylamine (82.2 mg) and DMAP (10 mg), followed by activation by stirring at 25℃for 10 minutes. Added Boc ₂ O (106 mg) and the reaction was stirred at 25℃for 2 hours. LCMS detects no starting material remaining and the product peak is the main signal peak, quench the reaction with water and extract with DCM. The organic phases were combined, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product. Column chromatography purification using PE: ea=5:1 as developing solvent gave 170mg of yellow oil in 81% yield. [ M+H ]] ⁺ 347。

Step 4: synthesis of Compound 40-4

In a 50mL single-necked flask, 40-3 (170 mg) was added followed by dissolution with anhydrous methanol (15 mL) and Pd/C (20 mg) added. The reaction was stirred at 25 ℃ for 20 hours under hydrogen balloon protection, LCMS detects no starting material remaining. Filtering with diatomite, collecting filtrate, and concentrating to obtain 120mg of target product as yellow oily substance. Yield 95.2% [ M+H ]] ⁺ 257。

Step 5: synthesis of Compound 40-5

In a 50mL single flask, 40-4 (120 mg) and IM15 (222 mg) were added and dissolved in DMF (10 mL), and after adding potassium carbonate (195 mg), the temperature was raised to 60℃and the reaction was stirred for 3 hours. LCMS detection starting material did not remain, TLC detection with PE: ea=2:1 as developing agent. The reaction mixture was quenched with water, extracted with EA, the organic phases were combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product. Column chromatography purification, using PE: ea=2:1 as developing solvent, gave 150mg of purified product in 55% yield. [ M+H ] ] ⁺ 585。

Step 6: synthesis of Compound 40-6

In a 50mL single-necked flask, 40-5 (150 mg) was added, and the mixture was dissolved in a mixed solvent of dioxane (20 mL) and water (2 mL), followed by addition of dichlorobenzoboric acid (59 mg), palladium catalyst (20 mg) and potassium carbonate (106 mg), and stirring for reaction at 90℃for 16 hours under the protection of three times of argon substitution. LCMS detects no starting material remaining and product peaks appear, and the reaction was concentrated directly to dryness. Column chromatography purification using PE: ea=2:1 as developing solvent gave 100mg of purified product with a yield of 65%. [ M+H ]] ⁺ 603。

Step 7: synthesis of Compound 40

In a 50mL single-necked flask, 40-6 (100 mg) was added, followed by dissolution of the starting material in 4M HCl methanol solution (10 mL) and reaction stirred at 25℃for 2 hours. LCMS detected no starting material remained. Will beThe reaction solution was concentrated directly to dryness, then saturated sodium carbonate solution was added to adjust ph=8 to 9, and extracted with ethyl acetate, and the organic phases were combined. Washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and concentrating to obtain 60mg of crude product. The crude product was purified by column chromatography using DCM: meoh=5:1 as developing solvent, the target compound was collected, concentrated and lyophilized with acetonitrile/water mixed solvent to give the target compound as a purified white solid 30mg in 43.4% yield. [ 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)。

Example 41: synthesis of Compound 41

Step 1: synthesis of Compound 41-1

In a 25mL single-necked flask, 40-1 (300 mg) was added and dissolved in water (5 mL), followed by slow addition of concentrated sulfuric acid (0.5 mL), and the reaction was stirred at 25℃for 16 hours after the completion of the dropwise addition. LCMS detected a product peak, quenched with saturated sodium carbonate solution and adjusted ph=10, followed by EA extraction. The organic phases were combined, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 200mg of a yellow oil as a product in 62.5% yield. [ M+H ]] ⁺ 248。

Step 2: synthesis of Compound 41-2

In a 50mL single-necked flask, the starting material 41-1 (200 mg) was dissolved in anhydrous methanol (15 mL), followed by addition of Pd/C (30 mg), and the reaction was stirred under hydrogen balloon at 25℃for 20 hours. LCMS detected no starting material remained. The reaction solution was filtered through celite, and the filtrate was collected and concentrated to dryness to give the product as a yellow oily substance 70mg in 95% yield. [ M+H ]] ⁺ 158。

Step 3: synthesis of Compound 41-3

Into a 50mL single-necked flask, raw material 41-2 (70 mg) was addedDMF (15 mL) was then added for dissolution, and IM15 (149 mg), potassium carbonate (170 mg) was added and the reaction stirred at 60℃for 16 hours. TLC detected no starting material remained, LCMS detected the occurrence of a major product peak, and the reaction was quenched with water. EA extraction, concentration of organic phase, column chromatography purification, using pure EA as developing agent, obtaining the target product yellow solid 50mg with a yield of 27%. [ M+H ] ] ⁺ 486。

Step 4: synthesis of Compound 41-4

In a 50mL single-necked flask, raw material 41-3 (50 mg) was added and dissolved in a mixed solvent of dioxane (10 mL) and water (2 mL). Dichlorophenylboronic acid (23 mg), potassium carbonate (42 mg) and palladium catalyst (10 mg) were added thereto, and the mixture was stirred under argon atmosphere at 90℃for 4 hours. LC-MS detection shows that no material remains. The reaction solution was concentrated to dryness, purified by column chromatography using pure EA as a developing solvent to give 20mg of the product in 40% yield. [ M+H ]] ⁺ 504。

Step 5: synthesis of Compound 41

In a 50mL single-necked flask, raw material 41-4 (320 mg) was added, followed by dissolution in 4M HCl in methanol (10 mL) and reaction stirred at 25℃for 2 hours. LCMS detects no starting material remaining. The reaction solution was concentrated directly to dryness, then saturated sodium carbonate solution was added to adjust ph=8 to 9, and extracted with ethyl acetate. The organic phases are combined, washed by water, washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate and concentrated to obtain crude products. Purifying the crude product by column chromatography, collecting the target compound by taking pure EA as a developing agent, concentrating, and freeze-drying by using a mixed solvent of acetonitrile/water to obtain 12mg of the white solid target compound after purification, wherein the yield is 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＝7.9Hz,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)。

Example 47: synthesis of Compound 47

Synthesized in the same manner as in the 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＝7.9Hz,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)。

Example 48: synthesis of Compound 48

Step 1: synthesis of Compound 48-1

SM3 (20 g,270 mmol) was added to a 100mL round bottom flask and dissolved by adding EtOH (176 mL) to a 250mL round bottom flask. The reaction was placed in an ice-water bath at 0℃and then diethyl ketomalonate (47 g,270 mmol) was added dropwise thereto, the reaction solution was reacted at 25℃for 1.5 hours, the reaction solution was milky white, and then placed in an oil bath at 85℃for 20 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) and showed the reaction was complete after about 20 hours. The reaction solution was directly dried under reduced pressure, and then subjected to column chromatography with silica gel (PE/ea=20/1 to 2/1) to obtain 48-1 yellow solid amounting to 9.1g, yield: 20%.

Step 2: synthesis of Compound 48-2

48-1 (1 g,5.49 mmol) was weighed into a 100mL round bottom flask and POCl was added ₃ (5 mL) was dissolved and the mixture was reacted at 110℃for 12 hours. TLC monitored the end of the reaction (PE/ea=2/1) and after about 12 hours the reaction was complete. The reaction solution was quenched by slowly adding water, and then pH was adjusted to neutral with NaOH. Then the EA is used for extraction, and the organic phase is dried by spinning to obtain a crude product. Crude product was isolated by column separation (PE/ea=20/1 to 5/1) to give 48-2 as a yellow oil amounting to 0.3g, 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)。

Step 3: synthesis of Compound 48-3

48-2 (123 mg,0.61 mmol), IM2 (200 mg,0.61 mmol), DIPEA (390 mg,3.05 mmol) were weighed into a 100mL round bottom flask, then DMF (2 mL) was added for dissolution, and the mixture was reacted in an oil bath at 60℃for 6 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) indicating the reaction was complete. Adding the reaction solution into water to separate out yellow solid, carrying out suction filtration, and spin-drying a filter cake to obtain crude colorless oily 48-3 crude 201mg, and obtaining the yield: 66%. [ M+H ]] ⁺ 501.25。

Step 4: synthesis of Compound 48-4

48-3 (201 mg,0.402 mmol) was weighed into a 100mL round bottom flask and dissolved in DCM (2 mL) and NBS (101 mg,0.603 mmol) was added in portions and the mixture reacted at 25℃for 1 hour. TLC monitored the end of the reaction (DCM/meoh=20/1) and showed the reaction was complete after about 1 hour. Na is added into the reaction solution ₂ SO ₃ The solution was quenched and extracted with DCM and the organic phase was dried by spinning to give the crude product. Crude product was isolated by column chromatography (DCM/iproh=15/1) as a colorless oil, 99mg, yield: 52%. [ M+H ]] ⁺ 475.11。

Step 5: synthesis of Compound 48-5

48-4 (99 mg,0.209 mmol), TEA (25 mg,0.25 mmol) were weighed into a 100mL round bottom flask, then dissolved in 2mL DCM, then Boc was slowly added ₂ O (55 mg,0.25 mmol) and the mixture was reacted at 25℃for 12 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) and after about 12 hours the reaction was complete. The reaction was quenched with water, extracted with DCM and the organic phase was dried by spinning to give the crude product. Crude product was chromatographed (DCM/meoh=20/1) to give 64mg 48-5 as a pale yellow solid, yield: 53%. [ M+H ] ] ⁺ 574.2/577.2。

Step 6: synthesis of Compound 48-6

48-5 (390 mg,0.678 mmol), tributylvinyltin (322 mg,1.017 mmol), pd (PPh) ₃ ) ₄ (157 mg,0.136 mmol), TEA (0.14 g,1.34 mmol) was placed in a 100mL round bottom flask, then DMF (5 mL) was added for dissolution, and the mixture was replaced with argon for 3 times and then placed in an oil bath at 110℃for reaction for 12 hours. TLC monitored the end of the reaction (DCM/meoh=40/1) and after about 12 hours the reaction was complete. The reaction solution is filtered by diatomite, and the filtrate is dried by spin to obtain a crude product. Crude product column chromatography320mg of yellow oil was isolated (DCM/MeOH=40/1), yield: 90%. [ M+H ]] ⁺ 523.22。

Step 7: synthesis of Compound 48-7

Weighing 48-6 (320 mg,0.612 mmol), K ₂ OsO _4· 2H ₂ O (22.5 mg,0.0612 mmol), NMO (144 mg,0.612 mmol) was placed in a 100mL round-bottomed flask, then acetone (3 mL) and H were added ₂ O (3 mL) was dissolved and the mixture was reacted at 25℃for 12 hours. TLC monitored the end of the reaction (DCM/meoh=20/1) and after about 12 hours the reaction was complete. The reaction solution is filtered by diatomite, and the filtrate is dried by spin to obtain crude intermediate ([ M+H)] ⁺ 557.29). The intermediate was dissolved in THF (2 mL) and H ₂ O (2 mL) and then NaIO was added ₄ (132 mg,0.619 mmol) and the mixture was reacted at 25℃for 2 hours. TLC monitored the end of the reaction (DCM/meoh=10/1) and after about 2 hours the reaction showed completion. The reaction was quenched with water and extracted with DCM/meoh=20/1 and the organic phase was dried by spinning to give 147mg of crude colorless oil. [ M+H ] ] ⁺ 525.24。

Step 8: synthesis of Compound 48-8

Weighing 48-7 (20 mg,0.038 mmol) and NH ₂ HCl (11 mg,0.152 mmol) was dissolved in 100mL round bottom flask and then EtOH (1 mL) was added and the mixture reacted at 25℃for 12 h. TLC monitored the end of the reaction (DCM/meoh=20/1) and after about 12 hours the reaction was complete. The reaction was quenched with water, extracted with DCM and the organic phase was dried by spinning to give the crude product. Crude product was isolated by column chromatography (DCM/meoh=20/1) to give 12mg of yellow solid, yield: 60%. [ M+H ]] ⁺ 540.27。

Step 9: synthesis of Compound 48-9

48-8 (20 mg,0.037 mmol) was weighed into a 25mL round bottom flask, added MeOH (3 mL) and H ₂ O (0.6 mL) was dissolved, followed by the addition of phenylacetylene (6 mg,0.0556 mmol), phI (AcO) ₂ (24 mg,0.074 mmol) and the mixture was reacted at 25℃for 12 hours. TLC monitored the end of the reaction (DCM/meoh=40/1) and after about 12 hours the reaction was complete. The reaction solution is dried by spin to obtain a crude product. Crude product was isolated by column chromatography (DCM/meoh=20/1) to give 7mg of colorless oil, yield: 30%. [ M+H ]] ⁺ 640.40。

Step 10: synthesis of Compound 48-10

48-9 (20 mg,0.033 mmol) was weighed into a 25mL round bottom flask, dissolved in 4M HCl/MeOH (1 mL) and the mixture was reacted at 25℃for 1 hour. TLC monitored the end of the reaction (DCM/meoh=20/1) and showed the reaction was complete after about 1 hour. The reaction was quenched with water, extracted with DCM and the organic phase was dried by spinning to give the crude product. The crude material was chromatographed (DCM/MeOH=25/1) to give 15mg of a white solid in 79% yield. [ M+H ] ] ⁺ 598.31。

Step 11: synthesis of Compound 48

48-10 (20 mg,0.033 mmol) was weighed into a 25mL round bottom flask, dissolved in THF (1 mL) and then LiAlH was added ₄ (2.4 mg,0.066 mmol) was reacted at 25℃for 1 hour. TLC monitored the end of the reaction (DCM/meoh=10/1) and after about 1 hour the reaction showed completion. The reaction solution is dried by spin to obtain a crude product. Crude product was isolated by column chromatography (DCM/meoh=10/1) to give 7mg 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)。

The following targets were synthesized by a similar method to that of example 48 above, via different starting materials and corresponding reagents.

Example 56: synthesis of Compound 56

Weighing 48-4 (56 mg), IM6 (50 mg), pd (pph) ₃ ) ₄ (25mg)、Na ₂ CO ₃ (22.3 mg) in a 100mL round bottom flask, DME/H was added ₂ O (2/0.5 mL) was dissolved. The mixture was replaced with argon for 3 times and then reacted in an oil bath at 100℃for 4 hours. TLC monitored the reaction (DCM/meoh=20/1) indicating the reaction was complete. After the reaction solution is diluted by methanol, diatomite is filtered, and the filtrate is dried by spin to obtain a crude product. Crude thin layer preparation was isolated (DCM/meoh=20/1) to give 21mg of white solid, yield: 26%. [ M+H ]] ⁺ 622.28。

Example 57: synthesis of Compound 57

Compound 56 (20 mg) was weighed into a 100mL round bottom flask, dissolved in THF (2 mL) and then added in portions to LiAlH ₄ (20 mg). The mixture was reacted at room temperature for 12 hours. TLC monitored the reaction (DCM/meoh=20/1) indicating the reaction was complete. Saturated NH is added into the reaction solution ₄ The Cl solution was quenched and then extracted with (DCM/MeOH=20/1) and the organic phase was dried to give the crude product. Crude thin layer preparation was isolated (DCM/meoh=20/1) to give 7mg of white solid, yield: 46%. [ M+H ]] ⁺ 580.26。

Example 58: SHP2 enzyme activity test

To test compounds for inhibition of SHP 2-PTPase activity, the catalytic activity of SHP2 was assayed using an endpoint fluoroenzyme method using DiFMUP as a surrogate substrate to determine the IC of the compound ₅₀ Values. Dephosphorization was performed on black 384 well shallow polystyrene plates. The total reaction volume was set at 24. Mu.L/well. In order to keep the DMSO concentration at a low level, compounds were diluted 4-fold in gradient from 10mM with DMSO for a total of 8 concentrations. Then diluted 25-fold to reaction buffer (60mM HEPES pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.02% BSA, 5mM DTT) to give compound solutions of different concentrations. 0.5nM SHP2 (available from Signalchem, p 38-20G-10) and 1 mu M p-IRS1 peptide(Jil Biochemical, 86703) preincubation for 5 to 10 minutes activates the enzyme, and then different concentrations of compound solution or DMSO are added as controls. After 30 minutes at room temperature, 100. Mu.M of substrate MDiFMUP (available from Invitrogen, D6567-5 mg) was added, and after 30 minutes at room temperature, 160. Mu.M of bpV (phen) (available from Sigma, SML0889-5 mg) was added to terminate the reaction. After the reaction, the plate was transferred to a spectromax spectrometer for plate reading, excitation wavelength was 350nm, emission wavelength was 450nm, and the catalytic rate of the enzyme was determined by monitoring the change in fluorescence signal accumulated at room temperature by DiFMUP, a reaction product. IC is then inferred by normalized fitting based on control ₅₀ Values, inhibitor dose-response curves were plotted and data are shown in table 4. The results show that the compound has a strong inhibition effect on the activity of SHP2 enzyme.

TABLE 4 Table 4

Industrial applicability

The present application provides a SHP2 inhibitor compound that can be used to inhibit SHP2 activity and/or treat, prevent or alleviate SHP2 mediated diseases in a subject. Thus, it can be made into corresponding medicines, which are suitable for industrial application.

Although the present application has been described in detail herein, the present application is not limited thereto, and modifications may be made by those skilled in the art in light of the present principles, and it is therefore intended that all such modifications as fall within the scope of the present application.

Claims

1. An inhibitor of SHP2 comprising a compound of formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug thereof:

wherein,

a is aryl or heteroaryl, preferably selected from phenyl, imidazopyridinyl, oxadiazolyl, oxazolyl and isoxazolyl;

b is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine, pyrazolopyrimidinone, and pyrazolopyrazine;

m and n are each independently 0, 1 or 2;

R ₃ selected from H, hydroxy, and halogen;

2. The SHP2 inhibitor of claim 1, wherein R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution; more preferably, R ₁ And R is ₁ ' together formWhen R is present ₆ When R is ₆ Selected from halogen and C1-6 alkoxy.

3. The SHP2 inhibitor of claim 1 or 2, wherein a is selected from phenyl, imidazo [4,5-b ]Pyridinyl, [1,2,4 ]]Oxadiazol-3-yl, and isoxazol-3-yl; more preferably, A is selected from phenyl,And n is 1 or 2.

4. The SHP2 inhibitor of claim 1 or 2, wherein B is selected fromAnd m is 2, ">And m is 1, and->And m is 0.

5. The SHP2 inhibitor of claim 1, wherein

R ₁ And R is ₁ ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxy, C1-3 hydroxyalkyl, C1-3 alkylamido, and oxo, or R ₁ And R is ₁ ' taken together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with 1R ₆ Substitution;

R ₂ and R is ₂ ' each is H, or linked together to form ethylene;

R ₃ selected from H, hydroxy, and fluoro;

R ₄ each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkylC1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4 ylethyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazolyl;

R ₅ each independently selected from the group consisting of C1-C2 alkyl, C1-C2 hydroxyalkyl, and C1-C2 alkoxycarbonyl;

R ₆ each independently selected from fluorine, chlorine, amino and C1-3 alkoxy.

6. The SHP2 inhibitor of claim 1 or 2, wherein R ₂ And R is ₂ ' each is H; r is R ₃ Is H; r is R ₆ Each independently selected from halogen and C1-6 alkoxy.

7. The SHP2 inhibitor of claim 1, comprising a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite, or prodrug thereof:

8. the SHP2 inhibitor of claim 7, wherein

A is selected from phenyl, and imidazopyridinyl, oxadiazolyl, oxazolyl, and isoxazolyl;

n is 1 or 2;

R ₃ is H;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl C1-6Alkyl, phenyl, and 5-or 6-membered heterocycloalkyl;

R ₅ is C1-C4 alkyl;

R ₆ selected from halogen and C1-6 alkoxy.

9. SHP2 inhibitor according to claim 7 or 8, wherein a is an imidazopyridinyl group, preferably imidazo [4,5-b ]]Pyridyl, more preferably selected from

10. The SHP2 inhibitor of claim 7 or 8, wherein R ₁ And R is ₁ ' together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with halogen or C1-6 alkoxy, more preferably with fluoro or methoxy.

11. The SHP2 inhibitor of claim 1 or 7, wherein the compound is selected from:

12. the SHP2 inhibitor of claim 1, comprising a compound of formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite, or prodrug thereof:

13. the SHP2 inhibitor of claim 12, wherein

A is selected from phenyl, imidazopyridinyl, oxadiazolyl, oxazolyl and isoxazolyl;

n is 1 or 2;

R ₃ selected from H, hydroxy, and halogen;

R ₄ each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5-or 6-membered heterocycloalkyl C1-6 alkyl, and optionally substituted with 1 to 3R ₆ Substituted phenyl, pyridyl, pyrimidinyl, or isoxazolyl;

R ₆ each independently selected from halogen and C1-6 alkoxy.

14. SHP2 inhibitor according to claim 12 or 13, wherein a is an imidazopyridinyl group, preferably imidazo [4,5-b ]]Pyridyl, more preferably

15. The SHP2 inhibitor of claim 12 or 13, wherein R ₁ And R is ₁ ' together form a benzospirocyclopentyl group wherein the pentyl group is substituted with an amino group and the phenyl group is optionally substituted with a C1-6 alkoxy group, more preferably with a methoxy group.

16. The SHP2 inhibitor of claim 1 or 12, wherein the compound is selected from:

17. the SHP2 inhibitor of claim 1, comprising a compound of formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite, or prodrug thereof:

18. the SHP2 inhibitor of claim 17, wherein

A is selected from the group consisting of imidazopyridinyl, oxadiazolyl, oxazolyl and isoxazolyl;

n is 1 or 2;

R ₂ and R is ₂ ' each is H;

R ₃ is H;

R ₅ selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;

19. SHP2 inhibitor according to claim 17 or 18, wherein a is an imidazopyridinyl group, preferably imidazo [4,5-b]Pyridyl, more preferably

20. The SHP2 inhibitor of claim 17 or 18, wherein R ₅ Is a C1-C4 hydroxyalkyl group, preferably hydroxymethyl.

21. The SHP2 inhibitor of claim 1 or 17, wherein the compound is selected from:

22. a pharmaceutical composition comprising an SHP2 inhibitor according to any one of claims 1-21, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.

23. Use of an SHP2 inhibitor according to any one of claims 1-21 in the manufacture of a medicament for inhibiting SHP2 activity.

24. Use of the SHP2 inhibitor of any one of claims 1-21, in the manufacture of a medicament for treating, preventing or alleviating a disease mediated by SHP 2.

25. The use of claim 24, wherein the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis, or ocular disease.

26. The use of claim 24 or 25, wherein the disease is a cancer selected from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.