CN117384162A

CN117384162A - Selective HER2 inhibitors

Info

Publication number: CN117384162A
Application number: CN202210541365.XA
Authority: CN
Inventors: 王能辉
Original assignee: Zhejiang Wenda Pharmaceutical Technology Co ltd
Current assignee: Zhejiang Wenda Pharmaceutical Technology Co ltd
Priority date: 2022-05-17
Filing date: 2022-05-17
Publication date: 2024-01-12
Also published as: WO2023221900A1

Abstract

The present invention provides selective HER2 inhibitors. Specifically, the invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof, wherein each group variable is defined as in the specification.

Description

Selective HER2 inhibitors

Technical Field

The invention belongs to the field of medicines, and particularly relates to a selective HER2 inhibitor.

Background

HER2 (also known as ErbB 2) and HER2 mutagen have become therapeutic targets for many cancers. HER2 small molecule kinase inhibitors, which have been marketed and under development, generally have inhibitory effects on other pathways (e.g., EGFR). Therefore, side effects such as rash, diarrhea, etc. are caused. HER2 inhibitors with brain penetration function have particular application to patients with brain metastases. The only marketed selective HER2 small molecule kinase inhibitor, tucatinib, is undergoing many combined clinical studies due to its activity. Furthermore, new ADCs for HER2, such as T-DM1 and T-DXd, although having good potency, inevitably produce drug resistance and have poor brain penetration function.

In view of the foregoing, there is a strong need in the art to develop more excellent, highly selective inhibitors of HER2 small molecule kinase that have no inhibitory effect on EGFR to meet clinical demands.

Disclosure of Invention

It is an object of the present invention to provide novel selective HER2 inhibitors. It is a further object of the invention to provide a method of using the inhibitor or to provide a use of the inhibitor.

In a first aspect of the invention there is provided a compound, or a pharmaceutically acceptable salt thereof, as shown in formula I,

wherein,

Q ¹ is-CONR' -, Q ² Is a 4-6 membered monocyclic heterocyclyl containing one ring nitrogen (N) atom; or, -Q ¹ -Q ² -represents a fused or spiro ring formed by two identical or different 4-6 membered monocyclic heterocyclic groups containing one ring nitrogen atom; and the 4-6 membered monocyclic heterocyclyl is optionally substituted with one or more (e.g., 1, 2 or 3) R' groups; wherein R' are each independently H or C _1-2 An alkyl group;

R ¹ selected from the group consisting of: H. substituted or unsubstituted C _1-4 Alkyl, substituted or unsubstituted C _2-4 Alkenyl, substituted or unsubstituted C _2-4 Alkynyl, C _1-4 Alkoxy, and halogen;

R ² selected from the group consisting of: H. substituted or unsubstituted C _1-4 Alkyl, and halogen;

R ³ selected from the group consisting of:

R ⁴ is that

R ⁵ Is H or substitutedOr unsubstituted C _1-4 An alkyl group;

R ⁶ selected from the group consisting of: H. substituted or unsubstituted C _1-4 Alkyl, -C _1-2 alkylene-N (R') ₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R' is H or C _1-4 An alkyl group;

unless otherwise specified, the substitution means that one or more (e.g., 1, 2, or 3) H atoms on the group are substituted with a substituent selected from the group consisting of: deuterium (D), halogen, C1-4 alkyl, C1-4 haloalkyl.

In another preferred embodiment, R' is H.

In another preferred embodiment, the 4-6 membered monocyclic heterocyclic group containing one ring N atom is carbon (C) atoms on the ring except for the one ring N atom.

In another preferred embodiment, the 4-6 membered monocyclic heterocyclic group containing one ring nitrogen atom is saturated or unsaturated (e.g., contains 1 double bond); preferably saturated.

In another preferred embodiment, the fused or spiro ring formed by two identical or different 4-6 membered monocyclic heteroalkyl groups containing one ring nitrogen atom is saturated or unsaturated (e.g., contains 1 or 2 double bonds); preferably saturated.

In another preferred embodiment, -Q ¹ -Q ² -to the rest of the molecule through an N atom;

in another preferred embodiment, -Q ² -Q ¹ -is

Wherein,

represents a single bond or a double bond (preferably +.>Is a single bond);

* Representative is located at Q ¹ A ligation site thereon;

W ¹ is- (CR' ₂ ) _n1 -，W ² Is- (CR' ₂ ) _n2 -; wherein n1=0, 1 or 2, n2=0, 1 or 2, and n1+n2 is not less than 1;

W ³ is- (CR' ₂ ) _n3 -，W ⁴ Is- (CR' ₂ ) _n4 -; wherein n3=0, 1 or 2, n4=0, 1 or 2, and n3+n4 is not less than 1;

r' are each independently H or C _1-2 Alkyl (preferably, R's are each H).

In another preferred embodiment, -Q ² -Q ¹ -is

In another preferred example, n1+n2=1 or 2, and n3+n4=1 or 2.

In another preferred example, n1+n2=1 or 2, and n3+n4=2.

In another preferred example, n1+n2=2, and n3+n4=1 or 2.

In another preferred embodiment, -Q ² -Q ¹ -selected from the group consisting of:

in another preferred embodiment, -Q ² -Q ¹ -is

Wherein,

* Representative is located at Q ¹ A ligation site thereon;

W ⁵ is- (CR' ₂ ) _n5 -，W ⁶ Is- (CR' ₂ ) _n6 -; wherein n5=0, 1, 2 or 3, n6=0, 1, 2 or 3 and 2.ltoreq.n5+n6.ltoreq.4;

W ⁷ is- (CR' ₂ ) _n7 -，W ⁸ Is- (CR' ₂ ) _n8 -; wherein n7=0, 1, 2 or 3, n8=0, 1, 2 or 3 and 2.ltoreq.n7+n8.ltoreq.4;

r' are each independently H or C _1-2 Alkyl (preferably, R's are each H).

In another preferred example, n5=n6=1 or 2.

In another preferred example, n5=n6=2, and n7=n8=2.

In another preferred example, n5=n6=1, and one of n7 and n8 is 0 and the other is 1.

In another preferred embodiment, -Q ² -Q ¹ -is

Wherein,

* Representative is located at Q ¹ A ligation site thereon;

W ⁹ is- (CR' ₂ ) _n9 -; wherein n9=1, 2 or 3;

r' are each independently H or C _1-2 Alkyl (preferably, R's are each H).

In a further preferred embodiment, when the subscript n1, n2, n3, n4, n5, n6, n7, n8, or n9 is 0, the subscript is selected from the group consisting of- (CR' ₂ ) _n1 -、-(CR' ₂ ) _n2 -、-(CR' ₂ ) _n3 -、-(CR' ₂ ) _n4 -、-(CR' ₂ ) _n5 -、-(CR' ₂ ) _n6 -、-(CR' ₂ ) _n7 -、-(CR' ₂ ) _n8 -, a part of or- (CR' ₂ ) _n9 -no (single bond).

in another preferred embodiment, the compounds are of formula Ia

Wherein,

represents a single bond or a double bond;

W ¹ is- (CR' ₂ ) _n1 -，W ² Is- (CR' ₂ ) _n2 -; wherein, subscript n1=0, 1 or 2, subscript n2=0, 1 or 2, and n1+n2 is not less than 1;

W ³ is- (CR' ₂ ) _n3 -，W ⁴ Is- (CR' ₂ ) _n4 -; wherein, subscript n3=0, 1 or 2, subscript n4=0, 1 or 2, and n3+n4 is not less than 1;

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as defined previously.

In another preferred embodiment, W ¹ 、W ² 、W ³ 、W ⁴ Subscripts n1, n2, n3, and n4 are as previously defined.

In another preferred embodiment, the compound is represented by formula Ib

Wherein,

W ⁵ is- (CR' ₂ ) _n5 -，W ⁶ Is- (CR' ₂ ) _n6 -; wherein, subscript n5=0, 1, 2, or 3, subscript n6=0, 1, 2, or 3, and 2.ltoreq.n5+n6.ltoreq.4;

W ⁷ is- (CR' ₂ ) _n7 -，W ⁸ Is- (CR' ₂ ) _n8 -; wherein, subscript n7=0, 1, 2, or 3, subscript n8=0, 1, 2, or 3, and 2.ltoreq.n7+n8.ltoreq.4;

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as previously defined.

In another preferred embodiment, W ⁵ 、W ⁶ 、W ⁷ 、W ⁸ Subscripts n5, subscripts n6, subscripts n7, and subscripts n8 are as previously defined.

In another preferred embodiment, the compound is of formula Ic

Wherein,

W ⁹ is- (CR' ₂ ) _n9 -; wherein subscript n9=1, 2, or 3;

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as previously defined.

In another preferred embodiment, W ⁹ Subscript n9 is as previously defined.

In another preferred embodiment, R ¹ Selected from the group consisting of: H. substituted or unsubstituted C _1-4 An alkyl group. In another preferred embodiment, R ¹ Is substituted or unsubstituted C _1-4 An alkyl group. In another preferred embodiment, R ¹ Is C _1-4 An alkyl group. In another preferred embodiment, R ¹ Selected from the group consisting of: methyl, ethyl. In another preferred embodiment, R ¹ Is methyl.

In another preferred embodiment, R ² Selected from the group consisting of: H. methyl, and ethyl. In another preferred embodiment, R ² H.

In another preferred embodiment, R ³ Is that

In another preferred embodiment, R ⁵ Is C _1-4 An alkyl group. In another preferred embodiment, R ⁵ Is methyl.

In another preferred embodiment, R ⁶ Selected from the group consisting of: H. -C _1-2 alkylene-N (R') ₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R' is C _1-4 Alkyl (preferably methyl).

In another preferred embodiment, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹ 、Q1、Q2、R'、R"、W ¹ 、W ² 、W ³ 、W ⁴ 、W ⁵ 、W ⁶ 、W ⁷ 、W ⁸ 、W ⁹ Subscripts n1, n2, n3, n4, n5, n6, n7, n8, and n9 are each independently a corresponding group in the compounds of tables a, B, and C.

In another preferred embodiment, the compound is selected from table a, table B and table C:

table A

Table B

Table C

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) The compound of claim 1, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

In a third aspect of the invention there is provided the use of a compound as described in the first aspect in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition mediated by HER2 or ameliorated by the inhibition of HER 2.

In another preferred embodiment, the compound treats or prevents the disease or condition by selectively inhibiting HER 2.

In another preferred embodiment, the disease or condition comprises: cancer.

In another preferred embodiment, the disease or condition comprises: brain cancer, breast cancer, gall bladder cancer, and bladder cancer. Cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, astrointestinal cancer, cholangiocarcinoma, renal cancer, liver cancer, pancreatic cancer, lung cancer or prostate cancer.

In a fourth aspect of the invention, there is provided a method of inhibiting HER2, the method comprising: contacting a subject with a compound according to the first aspect.

In another preferred embodiment, the subject is a cell.

In another preferred embodiment, the HER2 comprises wild-type HER2, mutant HER2 (e.g., HER2 YVMA), or a combination thereof.

In another preferred embodiment, the inhibition is selective inhibition of HER 2.

In another preferred embodiment, the method is non-therapeutic in vitro.

In a fifth aspect of the invention there is provided a method of treating or preventing a disease or condition mediated by HER2, or a disease or condition ameliorated by the inhibition of HER2, the method comprising the steps of:

Administering to a subject in need thereof a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect, thereby treating or preventing the disease or disorder.

In another preferred embodiment, the disease or condition comprises: cancer.

In another preferred embodiment, the subject is a mammal, preferably a human.

In another preferred embodiment, the method further comprises administering to a subject in need thereof a therapeutically effective amount of an additional agent.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

The inventors have conducted extensive and intensive studies. The compounds of formula I of the present application were found to have excellent HER2 inhibitory activity as well as selectivity. Based on this, the present inventors completed the present invention.

Terminology

As used herein, the term "halogen" refers to F, cl, br or I. Accordingly, "halo" means that a hydrogen atom in a group is replaced with F, cl, br or I.

Unless otherwise specified, the term "alkyl" by itself or as part of another substituent means a straight or branched hydrocarbon radical having the indicated number of carbon atoms (i.e., C _1-6 Representing 1-6 carbons). Alkyl (e.g. C _1-6 Alkyl) examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.

Unless otherwise specifiedThe term "cycloalkyl" refers to a compound having a specified number of ring atoms (e.g., C _3-6 Cycloalkyl groups having 3 to 6 ring atoms) and fully saturated hydrocarbon rings, cycloalkyl groups (e.g. C _3-6 Cycloalkyl) examples include cyclopropyl, cyclobutyl, cyclopentylcyclohexyl and the like. "cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, e.g., bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, and the like.

Unless otherwise specified, the term "alkenyl" refers to an unsaturated alkyl group having one or more (preferably 1) double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more (preferably 1) triple bonds. Typically, alkenyl groups have 1 to 4 carbon atoms, i.e. C _1-4 Alkenyl groups, alkynyl groups having 1-4 carbon atoms, i.e. C _1-4 Alkynyl groups. Examples of such unsaturated alkyl groups include: vinyl, 2-propenyl, ethynyl, 1-and 3-propynyl, 3-butynyl.

Unless otherwise specified, the term "alkoxy" is used in its conventional sense to refer to those alkyl groups of the indicated number of carbon atoms, e.g., C, attached to the remainder of the molecule via an oxygen atom _1-4 Alkoxy can be methoxy (-OCH) ₃ ) Ethoxy, and the like.

The term "alkylene", as used herein, by itself or as part of another substituent, refers to a divalent group derived from an alkane, e.g., -CH ₂ -。

Unless otherwise specified, the term "heterocyclyl" refers to cycloalkyl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. In this context, heterocyclyl preferably means a saturated or single ring heterocycle containing from 4 to 6 ring atoms (i.e. 4-6 membered). Preferably, in this context, the heterocyclyl contains only 1 aza atom, the remaining ring atoms being carbon atoms.

For the compounds provided herein, a bond from a substituent (typically an R group) to the center of the ring will be understood to refer to a bond attached to any available vertex of the ring.

As used herein, the terms "comprising," "including," or "comprising" mean that the various ingredients can be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "containing.

As used herein, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), commensurate with a reasonable benefit/risk ratio.

It is to be understood that the description of the name terms of each group, unless otherwise specified, covers the case where the number of carbon atoms/the number of ring atoms is specified, for example, to satisfy the number of carbon atoms, examples/instances of alkyl groups may also be C _1-6 Examples/instances of alkyl groups.

Unless otherwise indicated, all compounds present in the present invention are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). Among all the compounds of the invention, each chiral carbon atom may optionally be in the R configuration or in the S configuration, or in a mixture of R and S configurations.

As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S).

Certain compounds of the invention possess an asymmetric carbon atom (optical center) or double bond; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., isolated enantiomers) are all intended to be included within the scope of the present invention. When compounds provided herein have a defined stereochemistry (denoted R or S, or indicated with dashed or wedge-shaped bonds), those compounds will be understood by those skilled in the art to be substantially free of other isomers (e.g., at least 80%,90%,95%,98%,99% and up to 100% free of other isomers).

The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more of the isotopic atoms constituting such compounds. The unnatural proportion of an isotope can be defined as from the naturally found amount of the atom in question to 100% of the amount of that atom. For example, the compounds may incorporate radioactive isotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) Or non-radioactive isotopes, e.g.Deuterium ² H) Or C-13% ¹³ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite Such isotopic variants may provide additional uses beyond those described herein. For example, isotopic variants of the compounds of the present invention can have additional uses including, but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotherapeutic agents. In addition, isotopic variations of the compounds of the present invention can have altered pharmacokinetic and pharmacodynamic characteristics to facilitate increased safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Active ingredient

As used herein, the term "compound of the invention" or "compound of the invention" refers to a compound of formula I, formula Ia, ib or Ic herein. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I, formula Ia, ib or Ic.

Wherein the term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.

The term "solvate" refers to a complex of the compound of the invention coordinated to a solvent molecule to form a specific ratio. "hydrate" refers to a complex of the compound of the present invention coordinated to water.

In addition, the compounds of the present invention also include prodrugs of compounds of formula I, formula Ia, formula Ib or formula Ic. The term "prodrug" includes a class of compounds which may themselves be biologically active or inactive, and which upon administration by an appropriate method undergo a metabolic or chemical reaction in the human body to convert to a compound of formula I, formula Ia, ib or Ic, or a salt or solution of a compound of formula I, formula Ia, ib or Ic. The prodrugs include, but are not limited to, carboxylic acid esters, carbonic acid esters, phosphoric acid esters, nitric acid esters, sulfuric acid esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compound.

Preparation method

The process for preparing the compounds of the structures of formula I, formula Ia, ib or Ic according to the invention is described in detail herein, but these particular processes do not constitute any limitation on the invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.

Pharmaceutical compositions and methods of administration

Because the compound of the present invention has excellent selective inhibitory activity and antitumor activity against HER2, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and amelioration of diseases associated with or mediated by HER2 or for the treatment, prevention and amelioration of tumors. According to the prior art, the compounds of the invention are useful for the treatment of: brain cancer, breast cancer, gall bladder cancer, and bladder cancer. Cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, astrointestinal cancer, cholangiocarcinoma, renal cancer, liver cancer, pancreatic cancer, lung cancer or prostate cancer.

As used herein, the term "selective" refers to a higher activity or potency (e.g., inhibitory activity) for a given target (e.g., HER 2) than for other targets (e.g., EGFR).

The pharmaceutical compositions of the present invention comprise a safe and effective amount or range of therapeutically effective amounts of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 0.01 to 100mg of the compound of the invention per dose, more preferably 0.01 to 50mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. For example, the compounds of the present invention may be administered as sensitizers for antitumor drugs in combination with at least one additional antitumor drug. The additional antineoplastic agents may be targeted agents or chemotherapy and radiotherapy agents (e.g., carboplatin, paclitaxel, temozolomide, etc.), and proton therapy.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 0.01 to 100mg, preferably 0.01 to 50mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

The main advantages of the invention include:

1. The compounds of the present invention have excellent inhibitory activity while having excellent selectivity

2. The compounds of the present invention have excellent selectivity. Thus, the compounds of the present invention have lower toxicity and superior safety.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

A. Preparation example

EXAMPLE 1 Synthesis of Compound 1

/>

Step A

Compound 1a (2 g,14.80 mmol), compound 1b (2.53 g,16.28 mmol) and cesium carbonate (12.06 g,37.00 mmol) were added sequentially to dimethyl sulfoxide (50 mL) and stirred at 80℃for 6 hours. LCMS monitors the reaction, after completion of the reaction, diluted with water (200 mL), extracted with ethyl acetate (200 mL. Times.3), the organic phase washed with saturated aqueous sodium chloride (100 mL. Times.2), dried over anhydrous sodium sulfate and separated by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to afford compound 1c as an off-white solid (3.5 g, 87.50%). 1HNMR (400 MHz, CDCl 3): δppm 8.62 (d, J=7.2 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.17 (dd, J=8.8, 2.4Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.00 (dd, J=7.6, 2.4Hz, 1H), 2.36 (s, 3H). LCMS:271.2[ M+H ] +.

Step B

Compound 1c (3.5 g,14.80 mmol) and reduced iron powder (3.62 g,64.76 mmol) were successively added to ethanol (125 mL), and an aqueous ammonium chloride solution (3.46 g,64.76mmol dissolved in 25mL of water) was added thereto and stirred at 70℃for 4 hours. LCMS monitors the reaction, after completion of the reaction, the solvent was removed under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (200 mL. Times.3), dried over anhydrous sodium sulfate, and isolated by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 3/1, v/v) to afford compound 1d as a pale yellow solid (2 g, 64.27%). 1H NMR (400 MHz, CDCl 3): delta ppm 8.44 (d, J=7.6 Hz, 1H), 8.19 (s, 1H), 6.81-6.86 (m, 2H), 6.77 (d, J=2.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.4, 2.8Hz, 1H), 2.07 (s, 3H): LCMS:241.2[ M+H ] +.

Step B

Compound 1d (2 g,8.32 mmol), compound 1e (1.94 g,9.99 mmol), N, N-diisopropylethylamine (1.78 g,13.73 mmol) and PyBOP (5.72 g,9.99 mmol) were added sequentially to N, N-dimethylformamide (100 mL) and stirred at room temperature for 4 hours. LCMS monitored reaction, after completion of reaction, solvent was removed under reduced pressure, dissolved in water (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and isolated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/10, v/v) to afford compound 1f (2.5 g, 72.12%) as a pale brown solid. LCMS 417.0[ m+h ] +.

Step C

Compound 1f (2.5 g,6.00 mmol) was added to dichloromethane (50 mL), the ice water bath was cooled to 0deg.C, and m-chloroperoxybenzoic acid (1.81 g,8.40mmol, 80%) was added and stirred at room temperature for 4 hours. LCMS was monitored, and after completion of the reaction, the ice-water bath was cooled to 0deg.C, quenched by the addition of saturated aqueous sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL. Times.2), dried over anhydrous sodium sulfate, and separated by medium pressure flash chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to afford compound as a brown solid 1g (1 g, 38.52%). LCMS 432.9[ M+H ] +.

Step D

1g (150 mg,0.35 mmol) of compound, 1h (100 mg,0.50 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and isolated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to give yellow viscosified compound 1i (60 mg, 30.5%). LCMS 567[ m+h ] +.

Step E

Compound 1i (60 mg,0.076 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 1j (40 m) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 467.0[ m+h ] +.

Step F

/>

Compound 1j (40 mg, crude) and N, N-diisopropylethylamine (45 mg,0.35 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M in DCM,0.12mL) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (30-50%) ], to give compound 1 (4.5 mg, 8.1%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.09 (s, 1H), 8.77 (d, J=7.6 Hz, 1H), 8.55 (d, J=2 Hz, 1H), 8.34 (s, 1H), 7.94-7.86 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 7.11 (dd, J=7.6, 2.4Hz, 1H), 6.83-6.79 (m, 1H), 6.58-6.25 (m, 2H), 5.87-5.69 (m, 1H), 5.43-5.08 (m, 2H), 4.75-4.30 (m, 2H), 4.06-3.66 (m, 2H), 2.63-2.40 (m, 1H), 2.27 (s, 3H), 2.25-2.10 (m, 1H): LCM+2.521.2.M ] +.

EXAMPLE 2 Synthesis of Compound 2

Step A

Compound 1h (250 mg,0.6 mmol) and N, N-diisopropylethylamine (324 mg,2.51 mmol) were dissolved in dichloromethane (10 mL) and acryloyl chloride (170 mg,1.88 mmol) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 h. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2a as a yellow viscous compound (300 mg, 94.4%). The reaction mixture was used in the next reaction without purification. LCMS 253.1[ m+h ] +.

Step B

Compound 2a (300 mg,1.18 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave yellow viscous compound 2b (170 mg), crude. The reaction mixture was used in the next reaction without purification. LCMS 153.2[ m+h ] +.

Step C

Compound 2b (32 mg,0.21 mmol), compound 1g (60 mg,0.14 mmol) and N, N-diisopropylethylamine (54 mg,0.42 mmol) were added sequentially to 1, 4-dioxane (5 mL), and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (25-55%) ] to give compound 2 (8.5 mg, 11.75%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 8.99 (d, J=3.0 Hz, 1H), 8.72 (d, J=7.5 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.27 (s, 1H), 7.91-7.87 (m, 2H), 7.17 (d, J=8.6 Hz, 1H), 7.05 (dd, J=7.5, 2.4Hz, 1H), 6.77-6.56 (m, 2H), 6.34-6.30 (m, 1H), 5.85-5.73 (m, 1H), 5.36-5.24 (m, 1H), 4.93-4.86 (m, 1H), 4.53-4.46 (m, 1H), 4.17 (m, 1H), 4.00-3.62 (m, 2H), 2.62-2.52 (m, 2H), 6.34-6.30 (m, 1H), 5.85-5.73 (m, 1H), 4.53-4.86 (m, 1H), 4.53-4.46 (m, 1H).

EXAMPLE 3 Synthesis of Compound 3

Step A

1g (200 mg,0.46 mmol) of compound 3a (183 mg,0.92 mmol) and N, N-diisopropylethylamine (178 mg,1.39 mmol) were successively added to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and separated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to give compound 3b (150 mg, 56.5%) as a yellow viscous compound. LCMS 567.2[ m+h ] +.

Step B

/>

Compound 3b (150 mg,0.26 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 3c (90 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 467.2[ m+h ] +.

Step C

Compound 3c (90 mg, crop) and N, N-diisopropylethylamine (75 mg,0.58 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M in DCM,0.38mL) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (25-55%) ], to give compound 3 (24 mg, 16.9% in two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6): delta ppm 9.64-9.59 (m, 1H), 9.13 (s, 1H), 8.84 (d, J=7.6 Hz, 1H), 8.47 (d, J=4.4 Hz, 1H), 8.38 (s, 1H), 8.01-7.96 (m, 2H), 7.26-7.23 (m, 1H) & 7.03 (dd, J=7.2, 2.4Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.54-6.24 (m, 1H), 6.18-6.08 (m, 1H), 5.75-5.64 (m, 1H), 5.23-4.95 (m, 1H), 4.61-4.50 (m, 1H), 4.40 (t, J=8.4 Hz, 1H), 4.13-3.89 (m, 1H), 3.4.58 (m, 2S, 1H), 6.54-6.24 (m, 1H), 6.18-6.6.18 (m, 1H), 4.50 (m, 1H).

EXAMPLE 4 Synthesis of Compound 4

Step A

Compound 3a (100 mg,0.5 mmol) and N, N-diisopropylethylamine (319 mg,2.0 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (136 mg,1.5 mmol) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 ml×2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow viscous material 120mg, yield: 94.4%. The reaction mixture was used in the next reaction without purification. LCMS 275.2[ m+na ] +.

Step B

Compound 4a (120 mg,0.47 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature under nitrogen for 2 hours. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave yellow viscous compound 4b (70 mg), crude. The reaction mixture was used in the next reaction without purification. LCMS 153.1[ m+h ] +.

Step C

Compound 4b (70 mg,0.46 mmol), compound 1g (80 mg,0.18 mmol) and N, N-diisopropylethylamine (94 mg,0.92 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (25-55%) ] to give compound 4 (29 mg, 28.64%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.08 (d, J=4.4 Hz, 1H), 8.85 (d, J=7.2 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 7.92-7.73 (m, 2H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.88 (s, 1H), 6.79-6.62 (m, 1H), 6.32-6.26 (m, 1H), 5.83-5.71 (m, 1H), 5.25 (s, 4.67-4.63 (m, 2H), 4.34-4.32 (m, 1H), 4.00-3.90 (m, 1H), 3.65-3.61 (m, 1H), 3.43-3.32 (m, 2H), 2.32-6.26 (m, 1H), 5.83-5.71 (m, 1H), 4.34-4.32 (m, 1H).

EXAMPLE 5 Synthesis of Compound 5

Step A

/>

1g (150 mg,0.35 mmol) of compound 5a (118 mg,0.52 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) were successively added to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and separated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to give compound 5b (48 mg, 23.2%) as a yellow viscous compound. LCMS 595.1[ m+h ] +.

Step B

Compound 5b (45 mg,0.076 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 5c (40 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 495.1[ m+h ] +.

Step C

Compound 5c (35 mg, crop) and N, N-diisopropylethylamine (45 mg,0.35 mmol) were dissolved in dichloromethane (10 mL), and Compound 5 (0.5M in DCM,0.17mL) was added dropwise at 0deg.C under nitrogen, and stirred at room temperature for 1 hour. LCMS monitoring, after completion of the reaction, quench the reaction by adding methanol (1 mL), concentrate under reduced pressure, dilute the residue with ethyl acetate (30 mL), wash with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, HPLC separate [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (25-55%) ], give compound 5 (8.7 mg, 20.9%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): δppm 8.94 (s, 1H), 8.71 (d, J=7.5 Hz, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.03-7.79 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.04 (dd, J=7.5, 2.4Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.40-6.37 (m, 1H), 6.24 (dd, J=17.0, 1.9Hz, 1H), 5.73 (dd, J=10.3, 1.8Hz, 1H), 4.10 (s, 2H), 4.04-4.02 (m, 4H), 3.86 (s, 2H), 2.22 (s, 3H), 1.95-1.81 (m, 4H).

LCMS:549.1[M+H]+.

EXAMPLE 6 Synthesis of Compound 6

Step A

1g (150 mg, 0.349 mmol) of compound 6a (95 mg,0.420 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and separated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to give compound 6b (80 mg, 38.78%) as a yellow viscous compound. LCMS 595.3[ m+h ] +.

Step B

Compound 6b (80 mg,0.134 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at 0deg.C, nitrogen blanket, and stirred at room temperature for 2 hours. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 6c (50 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 495.1[ m+h ] +.

Step C

Compound 6c (50 mg, crop) and N, N-diisopropylethylamine (35 mg,0.346 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M in DCM,0.11mL) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (20-50%) ], to give compound 6 (8 mg, 14.42%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): δppm 8.84 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.82 (s, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.96 (dd, J=7.6, 2.4Hz, 1H), 6.71-6.67 (m, 2H), 6.10 (dd, J=16.8, 2Hz, 1H), 5.65 (dd, J=10.4, 1.6Hz, 1H), 3.97 (s, 4H), 3.64-3.54 (m, 4H), 2.14 (s, 3H), 1.86-1.78 (m, 4H): 549.3 M+H ] +.

EXAMPLE 7 Synthesis of Compound 7

Step A

1g (150 mg,0.35 mmol) of compound 7a (255 mg,0.52 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) were successively added to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and separated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to give compound 7b (55 mg, 27.8%) as a yellow viscous compound. LCMS 567.1[ m+h ] +.

Step B

Compound 7b (55 mg,0.097 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 7c (50 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 467.0[ m+h ] +.

Step C

Compound 7c (50 mg, crop) and N, N-diisopropylethylamine (45 mg,0.35 mmol) were dissolved in dichloromethane (10 mL), and Compound 5 (0.5M in DCM,0.21mL), nitrogen shielded, was added dropwise at 0deg.C and stirred at room temperature for 1 hour. LCMS was monitored, after completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (25-55%) ], to give compound 7 (13.0 mg, 25.8% in two steps) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.02 (s, 1H), 8.78 (d, J=7.5 Hz, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 7.94-7.82 (m, 2H), 7.24 (d, J=8.6 Hz, 1H), 7.11 (dd, J=7.5, 2.5Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.37-6.21 (m, 2H), 5.74 (dd, J=10.1, 2.1Hz, 1H), 4.55 (s, 2H), 4.49 (s, 4H), 4.29 (s, 2H), 2.26 (s, 3H). S521.0 M+H ] +.

EXAMPLE 8 Synthesis of Compound 8

Step A

Compound 8a (100 mg,0.5 mmol) and diisopropylethylamine (195 mg,1.5 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (91 mg,1.01 mmol) was added dropwise at 0deg.C, nitrogen protection, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 8b (100 mg, 78.7%) as a yellow viscous compound. The reaction mixture was used in the next reaction without purification. LCMS 253.1[ m+h ] +.

Step B

Compound 8b (100 mg,1.16 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 8c (100 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 153.2[ m+h ] +.

Step C

Compound 8c (110 mg, crop), 1g (80 mg,0.19 mmol) and N, N-diisopropylethylamine (120 mg,0.9 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% tfa) and MeCN as eluents (20-50%) ] to give compound 8 (11 mg, 11.1%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): δppm 9.04 (s, 1H), 8.79 (d, J=7.6 Hz, 1H), 8.60 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 7.89-7.83 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.13 (dd, J=7.6, 2.4Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.55-6.21 (m, 1H), 5.76-5.72 (m, 1H), 5.01-4.98 (m, 2H), 4.43 (d, J=10.4 Hz, 2H), 4.24-4.20 (m, 2H), 2.68-2.64 (m, 2H), 2.26-2.23 (m, 4H): 1 S+2.2M ] +.

EXAMPLE 9 Synthesis of Compound 9

Step A

Compound 8a (130 mg,0.65 mmol) and N, N-diisopropylethylamine (337 mg,2.6 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (177 mg,1.95 mmol) was added dropwise at 0deg.C, nitrogen-protected, and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 9a as a yellow viscous compound (110 mg, 66.5%). The reaction mixture was used in the next reaction without purification. LCMS 253.1[ m+h ] +.

Step B

Compound 9a (110 mg,0.41 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 9b (60 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 153.2[ m+h ] +.

Step C

Compound 9b (60 mg,0.39 mmol), compound 1g (80 mg,0.18 mmol) and N, N-diisopropylethylamine (72 mg,0.56 mmol) were added sequentially to 1, 4-dioxane (5 mL), and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (25-55%) ] to give compound 9 (16 mg, 16.1%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 8.79 (d, J=5.6 Hz, 1H), 8.73 (d, J=7.6 Hz, 1H), 8.53 (S, 1H), 8.37 (S, 1H), 7.86-7.74 (m, 2H), 7.18-7.13 (m, 1H), 7.08-7.06 (m, 1H), 6.75 (S, 1H), 6.41-6.28 (m, 1H), 6.22-6.13 (m, 1H), 5.69-5.65 (m, 1H), 5.05-4.94 (m, 2H), 4.46-4.42 (m, 1H), 4.16-4.13 (m, 3H), 2.70-2.66 (m, H), 2.18 (S, 3H). S:521.0[ M+H ] +.

EXAMPLE 10 Synthesis of Compound 10

Step A

Compound 10a (300 mg,1.41 mmol) and triethylamine (284 mg,2.81 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (191 mg,2.11 mmol) was added dropwise at 0deg.C under nitrogen and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10b as a yellow viscous compound (315 mg, 83.78%). The reaction mixture was used in the next reaction without purification. LCMS 267.2[ m+h ] +.

Step B

Compound 10b (310 mg,1.16 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, nitrogen blanketing, and stirring was performed at room temperature for 2 hours. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 10c (230 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.1[ m+h ] +.

Step C

Compound 10c (60 mg, crop), compound 1g (80 mg,0.19 mmol) and N, N-diisopropylethylamine (74 mg,0.57 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% tfa) and MeCN as eluents (20-50%) ] to give compound 10 (41.7 mg, 41.1%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): δppm 9.03 (d, J=0.8 Hz, 1H), 8.79 (d, J=7.5 Hz, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.39 (s, 1H), 7.95-7.81 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.13 (dd, J=7.5, 2.5Hz, 1H), 6.82 (s, 1H), 6.65-6.57 (m, 1H), 6.28 (d, J=16.8 Hz, 1H), 5.77-5.73 (m, 1H), 4.33-4.26 (m, 4H), 3.92 (s, 1H), 3.85-3.68 (m, 2H), 3.62 (t, J=7.6 Hz, 1H), 2.34 (t, J=6.57 (m, 1H), 6.33-4.26 (m, 1H), 6.34 (2S, 1H), 3.35 (2.18S, 1H).

EXAMPLE 11 Synthesis of Compound 11

Step A

Compound 11a (300 mg,1.41 mmol) and triethylamine (284 mg,2.81 mmol) were dissolved in dichloromethane (10 mL), and Compound 2 (191 mg,2.11 mmol) was added dropwise at 0deg.C under nitrogen protection and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11b as a yellow viscous compound (300 mg, 82.9%). The reaction mixture was used in the next reaction without purification. LCMS 289.1[ m+na ] +.

Step B

Compound 11b (300 mg,1.13 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 11c (260 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.1[ m+h ] +.

Step C

Compound 11c (50 mg, crop), 1g (60 mg,0.14 mmol) and N, N-diisopropylethylamine (90 mg,0.69 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% tfa) and MeCN as eluents (20-50%) ] to give compound 11 (30 mg, 40.4%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.06 (s, 1H), 8.79 (d, J=7.5 Hz, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 7.90-7.83 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.12 (dd, J=7.5, 2.4Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 6.40-6.23 (m, 2H), 5.74 (dd, J=10.2, 1.9Hz, 1H), 4.34 (s, 2H), 4.15-3.95 (m, 4H), 3.91-3.79 (m, 2H), 2.36 (t, J=6.7 Hz, 2H), 2.26 (s, 3H): 535.1 M+H ] +.

EXAMPLE 12 Synthesis of Compound 12

Step A

Compound 12a (100 mg,0.47 mmol) and N, N-diisopropylethylamine (145 mg,1.43 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M dichloromethane solution, 0.70 mL) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 12b (120 mg) as a yellow viscous compound, crude product. The reaction mixture was used in the next reaction without purification. LCMS 211[ M-56] +.

Step B

Compound 12b (120 mg, crude) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 12c (60 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.2[ m+h ] +.

Step C

Compound 12c (60 mg, crude), 1g (60 mg,0.14 mmol) and N, N-diisopropylethylamine (54 mg,0.42 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (25-55%) ] to give compound 12 (10.1 mg, 14.3%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.10 (s, 1H), 8.82 (d, J=7.6 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.93-7.88 (m, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.16 (dd, J=7.6, 2.4Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65 (dd, J=16.8, 10.4Hz, 1H), 6.30 (dd, J=16.8, 1.6Hz, 1H), 5.78 (dd, J=10.4, 2Hz, 1H), 3.98-4.16 (m, 3H), 3.85-3.93 (m, 1H), 3.75-3.85 (m, 2H), 3.65-3.73 (m, 1.8, 10.4Hz, 1H), 6.30 (dd, J=16.8, 1.4 Hz, 1H), 5.78 (ddS, 1.35S), 3.30 (2H).

EXAMPLE 13 Synthesis of Compound 13

Step A

Compound 13a (50 mg,0.24 mmol) and N, N-diisopropylethylamine (90 mg,0.70 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M in DCM,0.35mL) was added dropwise at 0deg.C, nitrogen protection, and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow viscous compound 13b (55 mg), crude product. The reaction mixture was used in the next reaction without purification. LCMS 267.1[ m+h ] +.

Step B

Compound 13b (55 mg, crude) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 13c (70 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.2[ m+h ] +.

Step C

Compound 13c (50 mg, crude), 1g (60 mg,0.14 mmol) and N, N-diisopropylethylamine (54 mg,0.42 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (20-70%) ] to give compound 13 (4.8 mg. Yield: 6.4%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.02 (s, 1H), 8.74 (d, J=7.6 Hz, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 7.89-7.97 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.79 (s, 1H), 6.68-6.62 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.68 (m, 1H), 3.99-3.81 (m, 4H), 3.72-3.61 (m, 2H), 3.22-3.13 (m, 1H), 2.31-2.25 (m, 1H), 2.25 (s, 3H), 2.04-1.98 (m, 1H), 1.33-1.28 (m, 2H). 535.2[ M+H ] +.

EXAMPLE 14 Synthesis of Compound 14

Step A

Compound 14a (100 mg,0.47 mmol) and N, N-diisopropylethylamine (243 mg,1.89 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (128 mg,1.41 mmol) was added dropwise at 0deg.C, nitrogen blanket, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 14b (110 mg, 87.7%) as a yellow viscous compound. The reaction mixture was used in the next reaction without purification. LCMS 289.1[ m+na ] +.

Step B

Compound 14b (110 mg,0.41 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 14c (70 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.1[ m+h ] +.

Step C

Compound 14c (70 mg,0.42 mmol), compound 1g (80 mg,0.18 mmol) and N, N-diisopropylethylamine (95 mg,0.74 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% fa) and MeCN as eluents (25-55%) ] to give compound 14 (20 mg, 19.8%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 8.96 (d, J=4.0 Hz, 1H), 8.69 (d, J=7.2 Hz, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 7.82-7.79 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.04-7.02 (m, 1H), 6.74 (s, 1H), 6.58-6.51 (m, 1H), 6.29-6.20 (m, 1H), 5.76-5.66 (m, 1H), 4.74-4.60 (m, 1H), 4.41-3.92 (m, 3H), 3.76-3.69 (m, 3H), 3.21-3.13 (m, 1H), 2.20-2.13 (m, 4H), 1.96-1.91 (m, 1H): 0.0.M.

EXAMPLE 15 Synthesis of Compound 15

Step A

Compound 15a (100 mg,0.47 mmol) and diisopropylethylamine (182 mg,1.41 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (85 mg,0.94 mmol) was added dropwise at 0deg.C, nitrogen protection, and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 15b (110 mg, 87.8%) as a yellow viscous compound. The reaction mixture was used in the next reaction without purification. LCMS 267.1[ m+h ] +.

Step B

Compound 15b (110 mg,0.41 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 15c (100 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 167.1[ m+h ] +.

Step C

Compound 15c (100 mg, crop), 1g (80 mg,0.19 mmol) and N, N-diisopropylethylamine (120 mg,0.9 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% tfa) and MeCN as eluents (20-50%) ] to give compound 15 (10.2 mg, 10.1%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.00 (s, 1H), 8.71 (d, J=7.6 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.92-7.88 (m, 2H), 7.16 (d, J=8.8 Hz, 1H), 7.04 (dd, J=7.6, 2.0Hz, 1H), 6.78-6.76 (m, 1H), 6.74-6.61 (m, 1H), 6.37-6.26 (m, 1H), 5.83-5.73 (m, 1H), 5.01-4.92 (m, 1H), 4.85-4.77 (m, 1H), 4.23 (s, 1H), 3.98-3.88 (m, 1H), 3.56-3.49 (m, 2H), 2.42-2.37 (m, 2H), 6.37-6.26 (m, 1H), 5.83-5.73 (m, 1H), 4.35 (m, 2.35S, 2.35).

EXAMPLE 16 Synthesis of Compound 16

Step A

Compound 16a (300 mg,1.32 mmol) and triethylamine (267 mg,2.64 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (178 mg,1.98 mmol) was added dropwise at 0deg.C under nitrogen and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 16b as a yellow viscous compound (300 mg, 80.8%). The reaction mixture was used in the next reaction without purification. LCMS 281.1[ m+h ] +.

Step B

Compound 16b (300 mg,1.07 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitoring and concentrating under reduced pressure after completion of the reaction gave compound 16c (230 mg) as a yellow viscous crude. The reaction mixture was used in the next reaction without purification. LCMS 181.1[ m+h ] +.

Step C

Compound 16c (50 mg, crop), 1g (60 mg,0.14 mmol) and N, N-diisopropylethylamine (54 mg,0.42 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 hours. LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure, and chromatographed using hplc [ (Gemini-C18 column,5 μsilica,21mm diameter,150mm length), water (0.1% tfa) and MeCN as eluents (20-50%) ] to give compound 16 (8.9 mg, 11.7%) as a yellow solid. 1H NMR (400 MHz, CD3 OD): delta ppm 9.06 (s, 1H), 8.78 (d, J=7.5 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.35 (s, 1H), 7.92-7.87 (m, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.12 (dd, J=7.5, 2.4Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.71-6.56 (m, 1H), 6.32-6.26 (m, 1H), 5.79-5.72 (m, 1H), 3.98-3.54 (m, 8H), 2.28 (s, 3H), 2.20-2.03 (m, 4H). LCMS:549.3[ M H ] +.

EXAMPLE 17 Synthesis of Compound 17

Step A

Compound 17a (235 mg,0.864 mmol) and triethylamine (210 mg,2.08 mmol) were dissolved in N, N-dimethylformamide (10 mL) and stirred at room temperature for 10 min. 1g (150 mg,0.347 mmol) of the compound was added thereto, and the mixture was stirred at 70℃for 6 hours under nitrogen. LCMS was monitored, after completion of the reaction, diluted with water (30 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium pressure flash chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to afford compound 17b (50 mg, 30.1%) as a pale yellow solid. LCMS 479.2[ m+h ] +.

Step B

Compound 17b (50 mg,0.105 mmol) and N, N-diisopropylethylamine (32 mg,0.319 mmol) were dissolved in dichloromethane (10 mL), and acryloyl chloride (0.5M in DCM,0.23mL) was added dropwise at 0deg.C, nitrogen protection, and stirred at room temperature for 1 hr. After completion of the reaction, the reaction was quenched by addition of methanol (1 mL), concentrated under reduced pressure, the residue diluted with ethyl acetate (30 mL), washed with water (20 mL. Times.2), saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC [ (Gemini-C18 column, 5. Mu. Silica,21mm diameter,150mm length), water (0.1% FA) and MeCN as eluents (25-55%) ], to give compound 17 (4 mg, 7.19%) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6): delta ppm 9.50 (s, 1H), 9.14 (s, 1H), 8.94 (d, J=7.6 Hz, 1H), 8.47 (s, 1H), 8.39 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.03 (dd, J=7.6, 2.4Hz, 1H), 6.81 (d, J=2 Hz, 1H), 6.56-6.68 (m, 1H), 6.23 (dd, J=16.8, 2Hz, 1H), 5.75 (dd, J=10.4, 2.4Hz, 1H), 4.58-4.40 (m, 6H), 4.28 (d, J=13.6 Hz, 2.4Hz, 1H), 3.21 S+2.533 (S, 3+2H): 3.0.8.M.533 (m, 1H).

EXAMPLE 18 Synthesis of Compound 18

Step A

Step B

Step C

Compound 1d (2 g,8.32 mmol), compound 1e (1.94 g,9.99 mmol), N, N-diisopropylethylamine (1.78 g,13.73 mmol) and PyBOP (5.72 g,9.99 mmol) were added sequentially to N, N-dimethylformamide (100 mL) and stirred at room temperature for 4 hours. LCMS monitored reaction, after completion of reaction, solvent was removed under reduced pressure, dissolved in water (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and isolated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/10, v/v) to afford compound 1f (2.5 g, 72.12%) as a pale brown solid.

LCMS:417.0[M+H]+.

Step D

Compound 18d (2.5 g,6.00 mmol) was added to dichloromethane (50 mL), the ice water bath was cooled to 0deg.C, and m-chloroperoxybenzoic acid (1.81 g,8.40mmol, 80%) was added and stirred at room temperature for 4 hours. LCMS was monitored, and after completion of the reaction, the ice-water bath was cooled to 0deg.C, quenched with saturated aqueous sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL. Times.2), dried over anhydrous sodium sulfate, and separated by medium pressure flash chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to afford compound 18e (1 g, 38.52%) as a brown solid product. LCMS 432.9[ M+H ] +.

Step E

Compound 18e (150 mg,0.35 mmol), compound 1h (100 mg,0.50 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) were added sequentially to 1, 4-dioxane (5 mL) and stirred at 70℃for 6 h. After completion of the reaction, the crude product was concentrated under reduced pressure and isolated by medium pressure flash chromatography (eluent: dichloromethane/ethyl acetate, 1/1to 1/10, v/v) to afford yellow viscosified compound 18f (60 mg, 30.5%). LCMS 567[ m+h ] +.

Step F

Step G

Examples 19-50 can be synthesized by referring to the methods of examples 1-18 and using the corresponding starting materials.

EXAMPLE 19 Synthesis of Compound 19

Step A

EXAMPLE 20 Synthesis of Compound 20

Step A

EXAMPLE 21 Synthesis of Compound 21

Step A

EXAMPLE 22 Synthesis of Compound 22

Step A

EXAMPLE 23 Synthesis of Compound 23

Step A

EXAMPLE 24 Synthesis of Compound 24

Step A

Compound 18g Compound 24a Compound 24

EXAMPLE 25 Synthesis of Compound 25

/>

EXAMPLE 26 Synthesis of Compound 26

EXAMPLE 27 Synthesis of Compound 27

Step A

EXAMPLE 28 Synthesis of Compound 28

EXAMPLE 29 Synthesis of Compound 29

EXAMPLE 30 Synthesis of Compound 30

/>

EXAMPLE 31 Synthesis of Compound 31

EXAMPLE 32 Synthesis of Compound 32

EXAMPLE 33 Synthesis of Compound 33

EXAMPLE 34 Synthesis of Compound 34

EXAMPLE 35 Synthesis of Compound 35

EXAMPLE 36 Synthesis of Compound 36

EXAMPLE 37 Synthesis of Compound 37

EXAMPLE 38 Synthesis of Compound 38

EXAMPLE 39 Synthesis of Compound 39

EXAMPLE 40 Synthesis of Compound 40

EXAMPLE 41 Synthesis of Compound 41

EXAMPLE 42 Synthesis of Compound 42

EXAMPLE 43 Synthesis of Compound 43

EXAMPLE 44 Synthesis of Compound 44

EXAMPLE 45 Synthesis of Compound 45

EXAMPLE 46 Synthesis of Compound 46

EXAMPLE 47 Synthesis of Compound 47

EXAMPLE 48 Synthesis of Compound 48

EXAMPLE 49 Synthesis of Compound 49

EXAMPLE 50 Synthesis of Compound 50

B. Test examples

1 purpose of experiment

The test adopts CellTiter-Glo (CTG) kit provided by Promega company, which is a method for detecting cell viability by a homogenization method, and the cell viability of the cultured cells is determined by quantifying ATP. The objective of this experiment was to evaluate the effect of test compounds on cell proliferation of BAF3-HER2 WT cell lines using CTG methods.

2 experiment material and instrument

2.1 Experimental reagent consumable

2.2 laboratory apparatus

3 Experimental method

3.1 cell culture

1) Cell lines: BAF3-HER2 WT

2) Complete culture medium RPMI 1640+10% foetal calf serum+1X penicillin streptomycin

3) Cell inoculation culture medium RPMI 1640+10% foetal calf serum+1X penicillin streptomycin

3.3Ba/F3-HER2 WT cell line proliferation assay

1) Ba/F3-HER2 WT cell lines were cultured in complete medium at 37℃under 5% CO 2.

2) The stock solutions of the reference compound and the stock solutions of the test compound were diluted to 1mM and then subjected to 3-fold serial dilutions, 10 doses, and two multiplex wells for use.

3) Serial dilutions of compounds were then transferred to 30nL to 384 well cell plates, 200g each, and centrifuged at room temperature for 3-5 seconds using Echo.

4) The cells were collected and resuspended in seeding medium and seeded in corresponding experimental wells of 384 well cell culture plates with 30 μl total of 600 cells per well

5) The cell culture plates were then incubated at 37℃for 72 hours.

6) Preparing CTG detection reagent working solution for later use.

7) After incubation is complete, the cell culture plate is equilibrated to room temperature, and then 30 μl CTG reagent is added to all experimental wells of the cell plate.

8) The cell culture plates were placed on a shaker for 3 minutes and then left at room temperature in the dark for 30 minutes.

9) Reading chemiluminescent signal values using Envision and collecting data

3.4 data analysis

1)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)

2)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)

3)CVMax＝(SDMax/MeanMax)*100％

4)CVMin＝(SDMin/MeanMin)*100％

5) Experimental window = signal value/background value

6) Negative control: 0.1% DMSO

7) Positive control 1,000nM lenatinib

8) Compound IC50 was calculated using GraphPad nonlinear fit formula:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

x is the log value of the compound concentration; percentage of inhibition Y

9)Inhibition(％)＝(1-(Cpd-MeanMin)/(MeanMax-MeanMin))×100％

100% inhibition 10=, 000nM lenatinib; 0% inhibition ratio 0.1% DMSO

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which is characterized in that the compound is shown as a formula I,

wherein,

Q ¹ is-CONR' -, Q ² Is a 4-6 membered monocyclic heterocyclic group containing one ring nitrogen atom; or, -Q ¹ -Q ² -represents a fused or spiro ring formed by two identical or different 4-6 membered monocyclic heterocyclic groups containing one ring nitrogen atom; and the 4-6 membered monocyclic heterocyclyl is optionally substituted with one or more R' groups; wherein R' are each independently H or C _1-2 An alkyl group;

R ³ selected from the group consisting of:

R ⁴ is that

R ⁵ Is H or substituted or unsubstituted C _1-4 An alkyl group;

2. The compound according to claim 1, wherein the compound is represented by formula Ia

Wherein,

represents a single bond or a double bond;

W ¹ is- (CR' ₂ ) _n1 -，W ² Is- (CR' ₂ ) _n2 -; wherein the subscript n1=0, 1Or 2, subscript n2=0, 1, or 2, and n1+n2++1;

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as defined in claim 1.

3. The compound according to claim 1, wherein the compound is represented by formula Ib

Wherein,

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as defined in claim 1.

4. The compound of claim 1, wherein said compound is of formula Ic

Wherein,

W ⁹ is- (CR' ₂ ) _n9 -; wherein subscript n9=1, 2, or 3;

R ¹ 、R ² 、R ³ 、R ⁴ and R' is as defined in claim 1.

5. The compound of claim 1, wherein R ¹ Is substituted or unsubstituted C _1-4 An alkyl group; and/or R ² Selected from the group consisting of: H. methyl, and ethyl.

6. The compound of claim 1, wherein said compound is selected from the group consisting of table a, table B and table C:

Table A

Table B

Table C

7. A pharmaceutical composition comprising: (i) The compound of claim 1, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

8. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition mediated by HER2, or a disease or condition ameliorated by the inhibition of HER 2.

9. The use of claim 8, wherein the disease or condition comprises: cancer.

10. The use of claim 8, wherein the disease or condition comprises: brain cancer, breast cancer, gall bladder cancer, and bladder cancer. Cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, astrointestinal cancer, cholangiocarcinoma, renal cancer, liver cancer, pancreatic cancer, lung cancer or prostate cancer.