CN110577524B

CN110577524B - Kinase selective inhibitor

Info

Publication number: CN110577524B
Application number: CN201810580435.6A
Authority: CN
Inventors: 潘峥婴; 石莉扬; 钟振鹏
Original assignee: Peking University Shenzhen Graduate School
Current assignee: Peking University Shenzhen Graduate School
Priority date: 2018-06-07
Filing date: 2018-06-07
Publication date: 2022-01-28
Anticipated expiration: 2038-06-07
Also published as: WO2019233438A1; CN110577524A

Abstract

The invention relates to a kinase selective inhibitor, a pharmaceutical composition containing the same and medical application thereof.

Description

Kinase selective inhibitor

Technical Field

Background

Fibroblast growth factor receptor 4(FGFR-4) is a protein encoded by the FGFR-4 gene in humans. Such proteins are members of the fibroblast growth factor receptor family, in which the amino acid sequences between the members are highly conserved throughout evolution. FGFR family members 1-4 have different ligand affinities and tissue distributions from each other. A full-length representative protein consists of an extracellular region consisting of three immunoglobulin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, initiating a downstream signaling cascade that ultimately affects mitosis and differentiation. The genomic organization of the FGFR-4 gene comprises 18 exons. Although alternative splicing has been observed, there is no evidence that half of the IgIII domain at the C-terminus of this protein differs between the other three forms (designated FGFR 1-3).

Disclosure of Invention

Inhibitors of FGFR-4 are described. The invention also describes pharmaceutical formulations comprising an FGFR-4 inhibitor.

Specifically, the invention provides the following technical scheme:

technical scheme 1. A compound represented by the formula (I), a salt thereof or a stereoisomer thereof

G₁And G₂Independently of one another, identical or different, from the group consisting of H, C (O) and S (O)₂；

L₁And L₂Independently of one another, identical or different, from the group optionally substituted by C_1-3Alkyl substituted C_2-3Alkenyl radical, C_0-3alkyl-C_2-3Alkenyl and C_1-3alkyl-NHC (O) -C_2-3An alkenyl group;

provided that when G is₁When it is H, L₁Is absent, and when G₂When it is H, L₂Is absent.

Wherein the content of the first and second substances,

ar is a 5-or 6-membered monocyclic aromatic ring,

for example: furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole,

preferably: benzene, pyridine;

R₁

selected from H, halogen (preferably-Cl), -OH, -C_1-4Alkyl radical, -C_1-4An alkyl-oxy group, a carboxyl group,

m is an integer of 0, 1, 2, 3, 4, 5;

W₁is CH, CR₁Or N;

W₂is CH, CR₁Or N;

W₃is CH, CR₁Or N;

W₄is CH, CR₁Or N;

W₅is CH, CR₁Or N;

W₆is CH, CR₁Or N;

W₇is CH, CR₁Or N;

l is selected from: a bond, -O-, -NH-, -S-, -CH₂-，-CH＝CH-，-CH≡CH-，-C(CH₃)H-，-C(CH₃)₂-，-C(CH₂-CH₂)-，-CClH-，-CCl₂-, -CO-, -SO-, and-SO₂-；

n is an integer of 0, 1, 2, 3, 4, 5;

R₂

R₃selected from H, -C_1-4An alkyl group.

Technical scheme 2. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,

wherein G is₂Is H, L₂Is absent.

Technical scheme 3. the compound of any one of the aforementioned technical schemes, a salt thereof or a stereoisomer thereof,

wherein W₁，W₂，W₃，W₄，W₅，W₆，W₇Are all CH.

Technical scheme 4. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,

wherein R is₃Is H.

Technical scheme 5. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,

wherein-N (G)₁L₁)(G₂L₂) is-NH-CO-C_2-3An alkenyl group.

Technical scheme 6. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,

wherein Ar is phenyl.

Technical scheme 7. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,

wherein L is

Technical scheme 8. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, Ar or Ar- (R)₁)_mIs that

Technical scheme 9. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, Ar or Ar- (R)₁)_mIs that

Scheme 10. the compound of any of the preceding schemes, salts or stereoisomers thereof, Ar or Ar- (R)₁)_mIs that

Scheme 11. the compound of any of the preceding schemes, salts or stereoisomers thereof, Ar or Ar- (R)₁)_mIs that

Technical scheme 12. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs H.

Technical scheme 13. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 14. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 15. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 16. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 17. the compound of any of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 18. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R₂Or (R)₂)_nIs that

Technical scheme 19. a compound, a salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:

technical solution 20. a pharmaceutical composition comprising a compound of any one of the preceding technical solutions, a salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

Technical scheme 21 use of a compound of any one of the preceding technical schemes, a salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of any one of the preceding technical schemes, in the manufacture of a medicament for treating a condition mediated by FGFR-4, a condition characterized by overexpression of FGFR-4, a condition characterized by amplification of FGFR4, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by overexpression of FGF 19.

Technical solution 22 the use of any one of the preceding technical solutions, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, or hyperlipidemia.

Drawings

FIG. 1 illustrates the results of a "time-dependent inhibition experiment".

Detailed Description

In one aspect, the present invention provides a compound of formula (I) as described above (including stable isotope substitutes thereof), salts thereof, or stereoisomers thereof, which is an FGFR-4 selective inhibitor.

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I (including stable isotopic substitutes thereof), or a pharmaceutically acceptable salt thereof, or a compound of formula II (including stable isotopic substitutes thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include inert solid fillers or excipients and sterile aqueous or organic solutions. The compound should be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage of the agent. Techniques for formulating and administering the compounds disclosed herein are well known to those skilled in the art and may be found, for example, in Remington: the Science and Practice of Pharmacy, Remington's pharmaceutical Science and Practice, 19 th edition, Mack publishing company, Easton, Pa (1995).

The invention provides the use of a compound of formula I (including stable isotopic surrogates thereof), or a pharmaceutically acceptable salt thereof, a compound of formula II (including stable isotopic surrogates thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of a condition mediated by FGFR-4, a condition characterized by FGFR-4 overexpression, a condition characterized by FGFR4 amplification, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by FGF19 overexpression; in particular the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.

As used herein, "alkyl" refers to a monovalent group of a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-6, 1-4, or 1-3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-methyl-1-pentyl, 2-dimethyl-1-pentyl, 3-dimethyl-1-butyl, and, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. In this context, an alkyl group is understood as a C1-6 alkyl group, if the upper and/or lower limit of the number of carbon atoms of the alkyl group is not specified. In this context, for example C_0-3C in alkyl₀Alkyl means a bond.

"alkenyl" as used herein refers to an aliphatic group containing at least one double bond.

"alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and characterized by having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent.

"amplification" as used herein means the production of additional copies of a gene or chromosome fragment in a cancer cell that may confer a growth or survival advantage.

As used herein, "aryl" or synonymous terms (e.g., aromatic ring) refer to 5-, 6-, and 7-membered monocyclic aromatic groups that may include 0 to 4 heteroatoms, e.g., furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring may be substituted at one or more ring positions with a substituent such as described above (e.g., halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclyl, hydroxyl, alkoxy, amino, nitro, thiol, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like).

As used herein, "-C- (CH2-CH2) -" refers to cyclopropylene.

Any substitutable ring atom may be substituted (e.g., with one or more substituents).

"covalent inhibitor" as used herein means an inhibitor that can form a covalent bond with a protein.

"FGFR-4" or "FGFR-4 protein" refers to any form of FGFR-4 protein, including wild-type and all variant forms (including without limitation mutant forms and splice variants). The FGFR-4 protein is the product of the FGFR-4 gene, and thus the FGFR-4 protein includes any protein encoded by any form of the FGFR-4 gene, including all aberrations, e.g., point mutations, insertions/deletions, translocation fusions, and focal amplifications.

As used herein, "inhibitor" refers to a compound that inhibits an enzyme such that a decrease in enzyme activity is observable, for example, in biochemical assays.

In certain embodiments, the inhibitor has an IC50 of less than about 1 μ Μ, less than about 500nM, less than about 250nM, less than about 100nM, less than about 50nM or less than about 10 nM.

FGFR-4 inhibitors refer to compounds that inhibit FGFR-4.

As used herein, "overexpression" means that the yield of gene product in a sample is significantly higher than that observed in a control sample population (e.g., normal tissue).

By "selective" is meant that a compound inhibits the activity of a target protein (e.g., FGFR-4) more effectively than it inhibits the activity of other proteins. In this case, the isoforms FGFR-1, FGFR-2, FGFR-3 and FGFR-4 are all considered to be different proteins.

In some embodiments, a compound can inhibit the activity of a target protein (e.g., FGFR-4) at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold or more than it inhibits the activity of a non-target protein.

Whether preceded by the term "optionally", "substituted" or not, refers herein to moieties in which a hydrogen on one or more carbons of the backbone is replaced by a substituent. It is understood that "substitution" or "substitution with … …" includes the implicit proviso that such substitution is according to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., that it does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidino, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be optionally substituted. For example, substituents for substituted alkyl groups may include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups in both substituted and unsubstituted forms, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like. Alkenyl and alkynyl groups can be similarly substituted to yield, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups. As used herein, the definition of each expression (e.g., alkyl, m, n, etc.) appearing more than once in any structure is intended to be independent of its definition elsewhere in the same structure.

"sulfonyl" as used herein refers to-SO 2-.

"sulfonamide" as used herein refers to-S (O) -N (R1) (R)₂) or-N (R1) -S (O) -R₂Wherein R1 and R₂Each independently is H or alkyl.

The compounds described herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with a radioactive isotope (such as for example tritium(s) (iii))³H) Or carbon-14 (¹⁴C) Is radiolabeled. All isotopic variations of the compounds disclosed herein (whether or not those areWhether radioactive) are intended to be within the scope of the present invention. For example, deuterated compounds or compounds containing¹³Compounds of C are intended to be encompassed within the scope of the present invention.

Certain compounds may exist in different tautomeric forms, and all possible tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the invention. The "enantiomeric excess" or "percent enantiomeric excess" of a composition can be calculated using the formula shown below. In the examples shown below, the compositions contain 90% of one enantiomer (e.g., the S-enantiomer) and 10% of the other enantiomer (i.e., the R-enantiomer).

ee＝(90-10)/100＝80％。

Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%. Some of the compositions described herein contain a compound (S-enantiomer) with an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In other words, the composition contains an enantiomeric excess of the S-enantiomer compared to the R-enantiomer.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations (for each asymmetric center), Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds described herein may be used as the free base or as a salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts, and the like. (see, e.g., Berge et al (1977) "Pharmaceutical Salts", J.pharm.Sci.66: 1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms.

In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Pharmaceutical composition

Although the compounds disclosed herein can be administered alone, the compounds are preferably administered as a pharmaceutical formulation, wherein the compounds are combined with one or more pharmaceutically acceptable excipients or carriers.

The compounds disclosed herein may be formulated for administration in any convenient manner for use in human or veterinary medicine.

In certain embodiments, the compounds included in the pharmaceutical formulation may be active themselves, or may be prodrugs capable of being converted to active compounds, for example, in a physiological environment.

In certain embodiments, the compounds provided herein include hydrates thereof.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases.

Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undecanoate.

Salts derived from suitable bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N- (alkyl)₄ ⁺And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds described herein. Water-or oil-soluble or dispersible products can be obtained by such quaternization.

Examples of pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) cyclodextrins, and (22) other non-toxic compatible materials used in pharmaceutical formulations, such as polymer-based compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant.

Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.

In addition to the active ingredients, 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, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

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 metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.

Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

Dosage forms of the compounds of the invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.

The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants which may be required.

When administered as a medicament to humans and animals, the compounds disclosed herein can be administered as such or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The formulation may be administered topically, orally, transdermally, rectally, vaginally, parenterally (parentally), intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

Indications of

FGFR-4 regulates proliferation, survival and α -fetoprotein secretion during hepatocellular carcinoma (HCC) progression; FGFR-4 inhibitors are therefore promising potential therapeutic agents for this unmet medical need (Ho et al, Journal of Hepatology, 2009, 50: 118-27).

HCC afflicts more than 550,000 people worldwide each year and is one of the worst 1-year survival rates among any type of cancer. The involvement of FGF19 (a Fibroblast Growth Factor (FGF) family member, which is composed of hormones) in the regulation of blood glucose, blood lipid and energy homeostasis shows additional evidence of a link between FGFR-4 and HCC. Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 transgenic mice. FGF19 activates FGFR-4, its major receptor in the liver, and FGFR-4 activation is believed to be the mechanism by which FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al, J Biol Chem (2010)285 (8): 5165-5170). FGF19 has also been identified by others as a driver in HCC (Sawey et al, Cancer Cell (2011) 19: 347-358). Accordingly, the compounds disclosed herein, which are potential and selective inhibitors of FGFR-4, are believed to be useful in the treatment of HCC and other liver cancers. Tumor genome screening has identified the activated fibroblast growth factor receptor 4(FGFR-4) Y367C mutation in the human breast cancer cell line MDA-MB-453. Thus, it has been shown that FGFR-4 may be the driver of tumor growth in breast cancer (Roidl et al, Oncogene (2010)29 (10): 1543-1552). Accordingly, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated breast cancer. Molecular changes (e.g., translocations) of genes upstream of FGFR-4 result in FGFR-4 activation/overexpression. For example, PAX3-FKHR translocation/gene fusion results in FGFR-4 overexpression. Thus, mechanistically induced overexpression of FGFR-4 is associated with Rhabdomyosarcoma (RMS) (Cao et al, Cancer Res (2010)70 (16): 6497-. Mutations in FGFR-4 itself (e.g., kinase domain mutations) can lead to protein overactivation; this mechanism has been associated with the RMS subfamily (Taylor et al, J Clin Invest (2009) 119: 3395-. Accordingly, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated RMS and other sarcomas. Other diseases are associated with changes in genes upstream of FGFR-4 or with mutations in FGFR-4 itself. For example, mutations in the kinase domain of FGFR-4 lead to overactivation, which is associated with lung adenocarcinoma (Ding et al, Nature (2008)455 (7216): 1069-. Amplification of FGFR-4 is associated with pathologies such as renal cell carcinoma (TCGA transient data). In addition, silencing FGFR4 and inhibiting ligand-receptor binding significantly slowed ovarian tumor growth, suggesting that inhibitors of FGFR4 may be useful in the treatment of ovarian cancer. (Zaid et al, Clin. cancer Res. (2013) 809). The pathogenic elevation of bile acid levels is associated with changes in FGF19 levels (Vergnes et al, Cell Metabolism (2013)17, 916-28). Thus, a reduced level of FGF19 may have a benefit in promoting bile acid synthesis and thus in the treatment of hyperlipidemia.

Dosage levels the actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, and which is non-toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound disclosed herein or an ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular compound employed, the age, sex, body weight, condition, general health and prior medical history of the patient to be treated, and like factors well known in the medical arts. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin administration of a compound of the invention for use in a pharmaceutical composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the invention will be that amount of the lowest dose of the compound which is effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Typically, the dose of a compound of the invention for a patient will be from about 0.0001mg to about 100mg per kilogram of body weight per day. For example, the dose may be between 10mg and 2000mg per day. Alternatively, the dose may be between 100mg and 1000mg per day, or between 200mg and 600mg per day. If desired, an effective daily dose of the active compound may be administered in one, two, three, four or more separately administered sub-doses at appropriate intervals throughout the day, optionally in unit dosage forms.

Combinations and targeted therapies the FGFR-4 inhibitors disclosed herein can be administered in combination with other cancer treatments. For example, the inhibitor may be administered in combination with surgical therapy, radiation or other therapeutic agents (such as antibodies), other selective kinase inhibitors, or chemotherapeutic agents. The inhibitor may also be administered in combination with RNAi therapy or antisense therapy. The FGFR-4 inhibitors described herein can be combined with one, two, or more other therapeutic agents. In the examples outlined below, it will be understood that "second therapeutic agent" also includes more than one therapeutic agent other than an FGFR-4 inhibitor. For example, the compounds disclosed herein may be combined with agents such as sorafenib. The FGFR-4 inhibitors described herein can be administered with one, two, or more other therapeutic agents. The FGFR-4 inhibitor and the second therapeutic agent described herein need not be administered in the same pharmaceutical composition and can be administered by different routes due to different physical and chemical properties. For example, the FGFR-4 inhibitor can be administered orally, while the second therapeutic agent is administered intravenously. The mode of administration and the determination of the rationality of the administration (if possible, in the same pharmaceutical composition) are well within the knowledge of the skilled clinician. Initial administration can be carried out according to established protocols known in the art, and the skilled clinician can then vary the dosage, mode of administration, and time of administration based on the observed effect. The FGFR-4 inhibitor and the second therapeutic agent can be administered simultaneously (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially (i.e., one after the other, with any time interval in between), depending on the nature of the proliferative disease, the condition of the patient, and the actual second therapeutic agent selected to be administered.

Additionally, the FGFR-4 inhibitors disclosed herein can be administered as part of an antibody-drug conjugate, wherein the FGFR-4 inhibitor is the "payload" portion of the conjugate.

Synthesis compounds of the invention (including salts and N-oxides thereof) may be prepared using known organic synthesis techniques and may be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below. For preparing the present inventionThe reaction of the compounds can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out (e.g., temperatures in the range of solvent freezing temperatures to solvent boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. The skilled person can select a solvent suitable for a particular reaction step depending on the particular reaction step. The preparation of the compounds of the invention may involve the protection and deprotection of different chemical groups. The skilled person can easily decide whether protection and deprotection is required and the choice of appropriate protecting groups. The chemical nature of the protecting Groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4 th edition, John Wiley&Sons: new Jersey, (2006), which is incorporated herein by reference in its entirety. The reaction may be monitored by any suitable method known in the art. For example, it can be determined by spectroscopic means, such as Nuclear Magnetic Resonance (NMR) spectroscopy (e.g.¹H or¹³C) Infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), Mass Spectrometry (MS)), or by chromatographic methods such as High Performance Liquid Chromatography (HPLC) or Thin Layer Chromatography (TLC).

The following examples are intended to be illustrative, and are not intended to be limiting in any way. The following schemes are intended to provide general guidance in connection with the preparation of the compounds of the present invention. It will be appreciated by those skilled in the art that modifications or optimisation of the preparation shown in the schemes may be made using common general knowledge of organic chemistry to prepare the compounds of the invention.

Synthetic examples

All reagents used herein were commercially available and were not purified, unless otherwise specified. The solvent was re-evaporated before use. The reaction was monitored on a thin layer silica gel plate (TLC, GF254, 60-F250, 0.2mm, Tintario silica gel thin layer chromatography). The flash column chromatography is carried out by using chemical silica gel (ZCX-II, 200-300 meshes) of the department of spectrometry. NMR was measured using a Bruker Advance 400 (1H: 400 MHz; 13C: 100MHz) or Bruker Advance 500 (1H: 500 MHz; 13C: 125MHz) nuclear magnetic resonance apparatus with TMS as an internal standard. High Resolution Mass Spectrometry (HRMS) was performed using an ABI Q-star Elite high resolution mass spectrometer; detection of end product purity the wavelength was determined to be 254 nm using a High Performance Liquid Chromatography (HPLC) Agilent 1260 series chromatograph (Agilent PN959990-902Eclipse Plus C18(250 mm. times.4.6 mm) column).

The abbreviations used in the following examples are explained by the conventional meanings in the field of organic synthesis, for example, the following abbreviations have the following meanings.

Conditions and reagents:

(a) 2-nitroaniline, Pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 ℃, and standing overnight;

(b) NIS, DMF, room temperature;

(c) (3, 5-Dimethoxyphenyl) boronic acid, Pd (dppf) Cl₂1, 4-dioxane: H2O is 3: 1, 100 ℃, microwave lh,

(d)H₂Pd/C, EtOAc, room temperature;

(e) acryloyl chloride, DIEA, THF, 0 deg.C, then room temperature

Conditions and reagents:

Pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 ℃ overnight

N- (2-Nitrophenyl) -1H-pyrrolo [2, 3-b]Pyridin-6-amine (I1): mixing 6-chloro-7-azaindole (0.50g, 3.3mmol), 2-nitroaniline (0.50g, 3.6mmol) and Pd₂(dba)₃(0.30g, 0.33mmol), X-Phos (0.31g, 0.66mmol), potassium carbonate (0.91g, 6.6mmol) in anhydrous 1, 4-dioxane (C)25mL) was purged with argon to remove oxygen. The reaction mixture was stirred at 110 ℃ overnight, cooled to room temperature, filtered, extracted with water and ethyl acetate (3X 60mL), the organic phase was collected, washed with saturated brine (2X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.49g of a yellow solid in 58% yield.¹H NMR (400MHz, chloroform-d) δ 10.24(s, 1H), 9.03(s, 1H), 8.61(dd, J ═ 8.8, 1.3Hz, 1H), 8.25(dd, J ═ 8.5, 1.7Hz, 1H), 7.91(d, J ═ 8.3Hz, 1H), 7.52(ddd, J ═ 8.7, 7.0, 1.6Hz, 1H), 7.11(dd, J ═ 3.6, 2.4, 1H), 6.91(ddd, J ═ 8.4, 7.0, 1.3Hz, 1H), 6.85(d, J ═ 8.3Hz, 1H), 6.47(dd, J ═ 3.6, 2.1, 1H).¹³C NMR(101MHz，CDCl₃)δ148.33，146.67，140.00，135.76，131.27，126.44，123.25，119.00，118.90，115.88，108.62，101.61.

Conditions and reagents: NIS, DMF, Room temperature

3-iodo-N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b]Pyridin-6-amine (I2): compound I1(0.39g, 1.6mmol) was dissolved in anhydrous DMF (4.0mL) and NIS (0.38g, 1.7mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at room temperature for 2 hours, it was diluted with water, extracted with ethyl acetate (3X 80mL), and the organic phase and the brine (2X 40mL) were collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.37g of a yellow solid with a yield of 61%.¹H NMR(400MHz，DMSO-d₆)δ11.80(s，1H)，9.81(s，1H)，8.32(d，J＝8.4Hz，1H)，8.07(dd，J＝8.5，1.6Hz，1H)，7.67-7.63(m，1H)，7.59(d，J＝8.4Hz，1H)，7.42(d，J＝2.5Hz，1H)，7.06(t，J＝7.5Hz，1H)，6.91(d，J＝8.4Hz，1H).¹³C NMR(101MHz，DMSO)δ150.34，146.22，137.82，137.34，135.52，130.95，128.30，126.21，121.71，120.91，117.51，108.35，55.14.

Conditions and reagents: pd (dppf) Cl₂1, 4-dioxane: H2O is 3: 1, 100 degree centigrade, microwave, 1H

3- (3, 5-Dimethoxyphenyl) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b]Pyridin-6-amine (I3): compound I2(0.15g, 0.39mmol), 3, 5-dimethoxyphenylboronic acid (0.11g, 0.59mmol), Pd (dppf) Cl₂(0.39g, 1.6mmol) and potassium carbonate (0.16g, 1.2mmol) were dissolved in a mixed solvent (4mL) of 1, 4-dioxane and water (3: 1), and argon gas was introduced to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ℃ for 1 hour, cooled to room temperature, filtered, and the filtrate was extracted with water and ethyl acetate (3 × 40mL), and the organic phase was collected, washed with saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 61mg of a yellow solid with a yield of 40%.¹H NMR(400MHz，DMSO-d₆)δ11.67(s，1H)，9.84(s，1H)，8.40(d，J＝8.6Hz，1H)，8.19(d，J＝8.5Hz，1H)，8.09(d，J＝8.4Hz，1H)，7.64(d，J＝10.6Hz，2H)，7.05(t，J＝7.8Hz，1H)，6.94(d，J＝8.4Hz，1H)，6.89-6.64(m，2H)，6.50-6.26(m，1H)，3.79(s，6H).¹³C NMR(101MHz，DMSO)δ161.34，149.29，147.33，138.27，137.60，136.79，135.63，130.62，126.27，122.24，121.32，120.52，115.43，113.00，107.97，104.67，98.32，55.69.

Conditions and reagents: h₂Pd/C, EtOAc, room temperature;

n1- (3- (3, 5-dimethoxyphenyl) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) benzene-1, 2-diamine (I4): compound I3(61mg, 0.16mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C, hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected and concentrated to give intermediate I4(36mg) as a white solid which was used in the next reaction without further purification.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

N- (2- ((3- (3, 5-dimethoxyphenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (1): compound I4(36mg, 0.10mmol) was dissolved in tetrahydrofuran (2.0mL), DIEA (33. mu.L, 0.20mmol) and acryloyl chloride (9.7. mu.L, 0.12mmol) were added sequentially in an ice-water bath, and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 25mg of a white solid with a yield of 61%.¹H NMR(400MHz，DMSO-d₆)δ11.46(d，J＝2.6Hz，1H)，9.81(s，1H)，8.12(s，1H)，8.06(d，J＝8.6Hz，1H)，7.88-7.77(m，1H)，7.63-7.55(m，1H)，7.50(d，J＝2.5Hz，1H)，7.15(td，J＝7.7，1.6Hz，1H)，7.02(td，J＝7.7，1.5Hz，1H)，6.76(d，J＝2.3Hz，2H)，6.69(d，J＝8.6Hz，1H)，6.47(dd，J＝17.0，10.1Hz，1H)，6.35(t，J＝2.2Hz，1H)，6.23(dd，J＝17.0，2.0Hz，1H)，5.72(dd，J＝10.1，2.0Hz，1H)，3.78(s，6H).¹³C NMR(101MHz，DMSO)δ164.14，161.30，152.47，147.99，137.98，135.08，132.51，130.31，129.72，127.14，125.81，125.39，122.74，122.65，120.46，115.38，110.92，105.41，104.55，98.08，55.66.HRMS(ESI)m/z C₂₄H₂₂N₄O₃[M+H]⁺414.1692; found 415.1767.

Conditions and reagents:

(a) 3-methoxybenzaldehyde, NaOH, DMSO, air, 100 ℃;

(b) SEM-Cl, NaH, DMF, 0 deg.C, then room temperature;

(c) 2-nitroaniline, Pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 deg.C,staying overnight;

(d)i)TFA/DCM，ii)K₂CO₃MeOH, room temperature;

(e) m-CPBA, DCM, room temperature;

(f)H₂Pd/C, EtOAc, room temperature;

(g) acryloyl chloride, DIEA, THF, 0 deg.C, then room temperature

Conditions and reagents: NaOH, DMSO, air, 100 deg.C

6-chloro-3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2, 3-b]Pyridine (I5): 6-chloro-7-azaindole (0.3g, 2.0mmol) was dissolved in DMSO (5.0mL), and sodium hydroxide (0.16g, 3.9mmol) and 3-methoxythiophenol (0.55g, 0.49mL, 3.9mmol) were added in that order. The reaction solution was heated to 100 ℃ and stirred under air atmosphere overnight, after the completion of TLC monitoring, water (50mL) was added for dilution, ethyl acetate (3X 50mL) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.52g of a white solid with a yield of 89%.¹H NMR(400MHz，DMSO)δ12.51(s，1H)，7.98(d，J＝2.5Hz，1H)，7.82(d，J＝8.2Hz，1H)，7.22-7.16(m，1H)，7.16-7.10(m，1H)，6.68(ddd，J＝8.2，2.3，1.0Hz，1H)，6.58(ddd，J＝2.5，1.9，1.0Hz，2H)，3.64(s，3H).¹³C NMR(101MHz，DMSO)δ160.18，148.21，144.68，140.11，134.40，130.53，130.47，120.53，118.37，117.07，111.84，111.24，99.91，55.54.

Conditions and reagents: SEM-Cl, NaH, DMF, 0 deg.C, then room temperature

6-chloro-3- ((3-methoxyphenyl) thio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b]Pyridine (I6): compound I5(0.10g, 0.35mmol) was dissolved in anhydrous DMF (2.0mL) and 6 was added with stirring at 0 deg.C0% sodium hydride (0.021g, 0.53 mmol). After the reaction mixture was stirred at 0 ℃ for 30min, SEM-Cl (0.087g, 0.093mL, 0.53mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC for completion, diluted with water (10mL), extracted with ethyl acetate (3X 10mL), the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.14g of a colorless oily liquid in 95% yield.¹H NMR(500MHz，CDCl₃)δ7.79(d，J＝8.2Hz，1H)，7.61(s，1H)，7.13(d，J＝8.2Hz，1H)，7.10(dd，J＝8.8，7.8Hz，1H)，6.68-6.62(m，3H)，5.67(s，2H)，3.70(s，3H)，3.62-3.57(m，2H)，0.97-0.91(m，2H)，-0.05(s，9H).¹³C NMR(101MHz，CDCl₃)δ160.06，147.64，146.11，139.44，134.03，130.61，129.81，120.59，118.65，117.71，112.13，110.88，102.66，73.13，66.85，55.24，17.82，-1.37.

Conditions and reagents: pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 ℃ overnight

3- ((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b]Pyridin-6-amine (I7): mixing compound I6(0.14g, 0.33mmol), 2-methyl-6-nitroaniline (0.051g, 0.37mmol), Pd₂(dba)₃(0.030g, 0.033mmol), X-Phos (0.032g, 0.067mmol), and potassium carbonate (0.0.093g, 0.67mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL), and argon was passed through to remove oxygen. The reaction mixture was stirred at 110 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellow solid (0.15g, 87% yield).

¹H NMR(400MHz，CDCl3)δ10.39(s，1H)，8.96(dd，J＝8.7，1.1Hz，1H)，8.26(dd，J＝8.6，1.6Hz，1H)，7.83-7.77(m，1H)，7.58(ddd，J＝8.6，7.1，1.5Hz，1H)，7.50(s，1H)，7.13-7.07(m，1H)，6.96(ddd，J＝8.4，7.1，1.3Hz，1H)，6.81(d，J＝8.4Hz，1H)，6.72-6.69(m，1H)，6.69-6.67(m，1H)，6.64(ddd，J＝8.2，2.4，0.7Hz，1H)，5.66(s，2H)，3.70(s，3H)，3.65-3.60(m，2H)，0.97-0.92(m，2H)，-0.08(s，9H).13C NMR(101MHz，CDCl3)δ160.04，149.67，146.91，139.97，139.34，135.61，134.56，132.15，130.51，129.75，126.44，119.53，119.42，118.55，117.05，111.99，110.72，109.11，102.55，73.24，66.71，55.25，17.82，-1.38.

Conditions and reagents: i) TFA/DCM; ii) K₂CO₃MeOH, room temperature;

3- ((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-amine (I8): compound I7(0.63g, 1.20mmol) was dissolved in dichloromethane (3.0mL) and trifluoroacetic acid (3.0mL) was added. The reaction mixture was stirred at room temperature for 5 hours, and the solid obtained after concentration was dissolved in methanol (3.0mL), and potassium carbonate was added to adjust the pH to 12, followed by stirring at room temperature overnight. After the completion of the TLC monitoring reaction, concentration was carried out, water (20mL) and ethyl acetate (3X 20mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 100mg of a yellow solid with a yield of 21%.¹H NMR(400MHz，DMSI-d₆)δ11.99(d，J＝2.6Hz，1H)，9.81(s，1H)，8.38(dd，J＝8.6，1.3Hz，1H)，8.08(dd，J＝8.4，1.6Hz，1H)，7.69(d，J＝8.4Hz，1H)，7.66-7.62(m，2H)，7.13(t，J＝8.0Hz，1H)，7.07(ddd，J＝8.4，7.1，1.3Hz，1H)，6.91(d，J＝8.5Hz，1H)，6.66(ddd，J＝8.3，2.5，1.0Hz，1H)，6.61-6.56(m，1H)，3.63(s，3H).¹³C NMR(101MHz，DMSO)δ160.16，150.27，147.21，140.78，137.86，137.28，135.54，131.04，130.43，129.68，126.22，121.72，120.90，118.23，116.35，111.71，110.94，108.48，99.51，55.53.

Conditions and reagents: h₂Pd/C, EtOAc, room temperature

N1- (3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) benzene-1, 2-diamine (I9): compound I8(100mg, 0.25mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C, hydrogen (1atm) and stirred overnight at room temperature, filtered, the filtrate collected and concentrated to give intermediate I9(69mg) as a white solid which was used in the next reaction without further purification.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

N- (2- ((3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (2): compound I9(69mg, 0.19mmol) was dissolved in tetrahydrofuran (2.0mL), DIEA (63. mu.L, 0.38mmol) and acryloyl chloride (18. mu.L, 0.23mmol) were added sequentially in an ice-water bath, and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellowish solid 23mg with a yield of 29%. 1H NMR (400MHz, DMSO-d6) δ 11.78(d, J ═ 2.6Hz, 1H), 9.74(s, 1H), 8.16(s, 1H), 7.81(dd, J ═ 8.1, 1.5Hz, 1H), 7.60(d, J ═ 7.9Hz, 1H), 7.55(d, J ═ 8.5Hz, 1H), 7.48(d, J ═ 2.4Hz, 1H), 7.19-7.07(m, 2H), 7.03(td, J ═ 7.6, 1.5Hz, 1H), 6.69-6.61(m, 2H), 6.60-6.53(m, 2H), 6.47 (J, J ═ 17.0, 10.2Hz, 1H), 6.22 (ddd, dd7.22, 2H), 6.38, 7.7.7, 3, 19-7.7.7.7.7.7.7.6, 3H), 365967.6, 7.6, 1.7.7.6, 1H, 6, 6.7.7.7.7.7.7, 6, 6.7.7.7.7.7, 6, 3, etc., HRMS (ESI) m/z C₂₃H₂₀N₄O₂S[M+H]⁺Meter (2)Calculation 416.1307; found 417.1382.

Conditions and reagents: m-CPBA, DCM, RT

3- ((3-methoxyphenyl) sulfinyl) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-amine (I10): compound I8(0.29g, 0.73mmol) was dissolved in dichloromethane (5.0mL) and m-CPBA (0.13g, 0.73mmol) was added. The reaction was stirred at room temperature for 2 h. After completion of the reaction was monitored by TLC, the reaction was quenched by addition of saturated sodium thiosulfate solution (10mL), extracted with dichloromethane (3X 30mL), and the organic phase was collected, washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 175mg of a yellow solid in 59% yield. Ms (esi): 409[ M + H]⁺.

Conditions and reagents: m-CPBA, DCM, RT

3- ((3-methoxyphenyl) sulfonyl) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b]Pyridin-6-amine (I11): compound I8(0.11g, 0.28mmol) was dissolved in dichloromethane (3.0mL) and m-CPBA (0.12g, 0.28mmol) was added. The reaction was stirred at room temperature for 2 h. After completion of the reaction was monitored by TLC, the reaction was quenched by addition of saturated sodium thiosulfate solution (10mL), extracted with dichloromethane (3X 30mL), and the organic phase was collected, washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 67mg of a yellow solid in 57% yield.¹H NMR(400MHz，DMSO-d₆)δ9.79(s，1H)，8.18(dd，J＝8.5，1.3Hz，1H)，8.09(d，J＝8.6Hz，1H)，8.07-8.01(m，2H)，7.64(ddd，J＝8.6，7.2，1.6Hz，1H)，7.55(dt，J＝7.8，1.3Hz，1H)，7.50(d，J＝8.0Hz，1H)，7.46(dt，J＝2.6，1.6Hz，1H)，7.18(ddd，J＝8.1，2.6，1.1Hz，1H)，7.12(ddd，J＝8.4，7.1，1.3Hz，1H)，7.01(d，J＝8.6Hz，1H)，3.81(s，3H).¹³C NMR(101MHz，DMSO)δ160.06，151.34，146.73，145.01，138.54，136.81，135.28，131.28，130.08，129.58，126.09，122.59，121.72，119.14，118.93，114.82，111.78，110.70，109.62，56.19.

N- (2- ((3- ((3-methoxyphenyl) sulfinyl) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) amino) phenyl) acrylamide (3): the synthesis method is the same as that of the compound 2.

1H NMR(400MHz，DMSO-d6)δ12.03(d，J＝2.9Hz，1H)，9.68(s，1H)，8.19(s，1H)，7.87(d，J＝2.8Hz，1H)，7.73(dd，J＝8.3，1.5Hz，1H)，7.66-7.58(m，1H)，7.45-7.37(m，2H)，7.23(dd，J＝2.6，1.5Hz，1H)，7.18-7.09(m，2H)，7.09-6.99(m，2H)，6.55(d，J＝8.7Hz，1H)，6.47(dd，J＝17.0，10.2Hz，1H)，6.22(dd，J＝17.0，2.0Hz，1H)，5.71(dd，J＝10.1，2.0Hz，1H)，3.78(s，3H).13C NMR(101MHz，DMSO)δ164.17，160.20，153.71，148.30，147.22，134.24，132.44，130.72，130.41，129.83，127.43，127.20，125.72，125.21，123.68，123.32，116.94，116.61，116.21，109.87，108.63，106.31，55.95.

N- (2- ((3- ((3-methoxyphenyl) sulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) amino) phenyl) acrylamide (4): the synthesis method is the same as that of the compound 2. White solid 16mg, yield 42%.

¹H NMR(400MHz，DMSO-d₆)δ12.37(d，J＝3.0Hz，1H)，9.69(s，1H)，8.31(s，1H)，7.97(d，J＝8.6Hz，1H)，7.92(d，J＝3.0Hz，1H)，7.75(dd，J＝8.1，1.5Hz，1H)，7.64(d，J＝8.0Hz，1H)，7.56-7.46(m，2H)，7.44(dd，J＝2.6，1.6Hz，1H)，7.22-7.13(m，2H)，7.07(td，J＝7.6，1.6Hz，1H)，6.78(d，J＝8.7Hz，1H)，6.49(dd，J＝17.0，10.2Hz，1H)，6.24(dd，J＝17.0，2.0Hz，1H)，5.72(dd，J＝10.2，2.0Hz，1H)，3.81(s，3H).¹³C NMR(101MHz，DMSO)δ164.17，160.01，154.10，147.54，145.21，134.07，132.42，131.22，130.56，129.62，128.14，127.20，125.73，125.21，123.81，123.51，118.99，118.85，114.64，111.70，108.91，107.50，56.18.HRMS(ESI)m/z C₂₃H₂₀N₄O₄S[M+H]⁺448.1205; found 449.1279.

Conditions and reagents:

(a) NIS, DMF, room temperature, 1 h;

(b)Boc₂o, DMAP, DCM, room temperature;

(c) 1-ethynyl-3, 5-dimethoxybenzene, CuI, Pd (PPh)₃)₂Cl₂，Et₃N, DCM at room temperature for 16 h;

(d) 2-nitroaniline, Pd (AcO)₂，Xant-phos，Cs₂CO₃1, 4-dioxane, 100 ℃, and staying overnight;

(e)SnCl₂EtOAc, reflux;

(f) acryloyl chloride, DIEA, THF, 0 deg.C, then room temperature

Conditions and reagents: NIS, DMF, RT, 1h

6-chloro-3-iodo-1H-pyrrolo [2, 3-b]Pyridine (I14): compound 7-azaindole (0.20g, 1.3mmol) was dissolved in anhydrous DMF (5.0mL) and NIS (0.32g, 1.4mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with water, extracted with ethyl acetate (3X 80mL), and the organic phase was collected, washed with brine (2X 40mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.31g of a yellow solid with a yield of 85%.¹H NMR(400MHz，DMSO)δ12.33(s，1H)，7.97-7.52(m，2H)，7.19(d，J＝8.2Hz，1H).¹³C NMR(101MHz，DMSO)δ147.23，144.70，131.80，131.76，121.64，116.80，55.24.

Conditions and reagents: boc₂O, DMAP, DCM, at room temperature

6-chloro-3-iodo-1H-pyrrolo [2, 3-b]Pyridine-1-carboxylic acid tert-butyl ester (I15): compound I14(0.31g, 1.1mmol) was dissolved in DCM and Boc was added sequentially₂O (0.36g, 0.38mL, 1.7mmol), DMAP (0.007g, 0.056mmol), stirring at room temperature for 2h, concentrating, extracting with water and ethyl acetate, collecting the organic phase, washing with brine (2 × 40mL), drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography to give a yellow solid 0.41g, 96% yield.¹H NMR(400MHz，CDCl₃)δ7.79(s，1H)，7.65(d，J＝8.2Hz，1H)，7.29(d，J＝8.2Hz，1H)，1.67(s，9H).¹³C NMR(101MHz，CDCl₃)δ147.95，146.69，145.93，132.08，131.11，124.07，119.82，85.40，61.25，28.12.

Conditions and reagents: CuI, Pd (PPh)₃)₂Cl₂，Et₃N, DCM, RT, 16h

6-chloro-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2, 3-b]Pyridine-1-carboxylic acid tert-butyl ester (I16): mixing compound I15(0.10g, 0.26mmol), 3, 5-dimethoxyphenylacetylene (0.047g, 0.29mmol), Pd (PPh)₃)₂Cl₂(0.018g，0.026mmol)、CuI(0.010g，0.052mmol)、Et₃N (0.031g, 43. mu.L, 0.32mmol) was dissolved in dry dichloromethane (3.0mL) and purged with argon to remove oxygen. Stirring the reaction solution at room temperature for 16h, cooling to room temperature, filtering, adding water (20mL) and dichloromethane (3X 20mL) into the filtrate for extraction, collecting the organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography0.074g of a yellow solid is obtained in 69% yield.¹H NMR (500MHz, chloroform-d) δ 8.00(d, J ═ 8.1Hz, 1H), 7.88(s, 1H), 7.31(d, J ═ 8.2Hz, 1H), 6.70(d, J ═ 2.3Hz, 2H), 6.49(t, J ═ 2.2Hz, 1H), 3.82(s, 6H), 1.69(s, 8H) ms (esi): 413[ M + H]⁺.

Conditions and reagents: pd (AcO)₂，Xant-phos，Cs₂CO₃1, 4-dioxane, 100 ℃ overnight

3- ((3, 5-Dimethoxyphenyl) ethynyl) -6- ((2-nitrophenyl) amino) -1H-pyrrolo [2, 3-b]Pyridine-1-carboxylic acid tert-butyl ester (I17): mixing compound I16(0.074g, 0.18mmol), 2-nitroaniline (0.027g, 0.20mmol), Pd (OAc)₂(0.004g, 0.018mmol), Xant-Phos (0.021g, 0.036mmol), and cesium carbonate (0.12g, 0.36mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.045g of a yellow solid in 48% yield.¹H NMR (400MHz, chloroform-d) δ 10.60(s, 1H), 9.32(dd, J ═ 8.8, 1.3Hz, 1H), 8.26(dd, J ═ 8.6, 1.6Hz, 1H), 7.99(d, J ═ 8.4Hz, 1H), 7.80(s, 1H), 7.66(ddd, J ═ 8.7, 7.1, 1.7Hz, 1H), 7.00-6.97(m, 1H), 6.94(d, J ═ 8.4Hz, 1H), 6.72(d, J ═ 2.3Hz, 2H), 6.49(t, J ═ 2.3Hz, 1H), 3.82(s, 6H), 1.69(s, 9H).¹³C NMR(101MHz，CDCl₃)δ160.70，150.82，147.58，145.50，139.17，136.33，134.49，130.76，127.94，126.33，124.40，119.82，119.64，117.84，110.29，109.46，101.96，101.11，92.76，84.74，80.32，55.55，28.30.

Conditions and reagents: SnCl₂EtOAc, reflux

N¹- (3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2, 3-b]Pyridin-6-yl) benzene-1, 2-diamine (I18): compound I17(0.045g, 0.087mmol) was dissolved in ethyl acetate and SnCl was added₂(0.084g, 0.44mmol), refluxing and stirring for 2h, cooling to room temperature, adding saturated sodium bicarbonate to dissolve in the quenching reaction, filtering, adding ethyl acetate into the filtrate for extraction, collecting the organic phase, washing with water, washing with saturated saline, and concentrating to obtain intermediate I9(37mg), which can be used in the next reaction without purification. Ms (esi): 385[ M + H ]]⁺.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

N- (2- ((3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (5): compound I18(37mg, 0.098mmol) was dissolved in tetrahydrofuran (2.0mL), and DIEA (33uL, 0.20mmol) and acryloyl chloride (9.5. mu.L, 0.12mmol) were added sequentially in an ice-water bath and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 10mg of a white solid with a yield of 23%.¹H NMR(500MHz，DMSO-d₆)δ11.68(d，J＝2.7Hz，1H)，9.76(s，1H)，8.19(s，1H)，7.88(d，J＝8.5Hz，1H)，7.84(d，J＝8.0Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.51(d，J＝2.4Hz，1H)，7.20-7.14(m，1H)，7.04(td，J＝7.6，1.5Hz，1H)，6.73(d，J＝8.5Hz，1H)，6.68(d，J＝2.3Hz，2H)，6.54-6.44(m，2H)，6.24(dd，J＝17.1，1.9Hz，1H)，5.73(dd，J＝10.2，2.0Hz，1H)，3.77(s，6H).MS(ESI)：439[M+H]⁺.

Conditions and reagents:

(a)TFA，Et₃SiH, CH3CN, room temperature, 2 h;

(b) NaH, SEM-Cl, 0 ℃ and then room temperature;

(c) 2-nitroaniline, Pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 ℃, and standing overnight;

(d)SnCl₂EtOAc, reflux;

(e) acryloyl chloride, DIEA, THF, 0 deg.C, then room temperature

Conditions and reagents: TFA, Et₃SiH, CH3CN, room temperature, 2h

6-chloro-3- (3, 5-dimethoxybenzyl) -1H-pyrrolo [2, 3-b]Pyridine (I19): compound I24b (0.50g, 1.5mmol) was dissolved in acetonitrile (20mL) and trifluoroacetic acid (0.67mL, 9.0mmol) and Et were added₃SiH (0.74mL, 6.0 mmol). After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50mL), extracted with ethyl acetate (3X 50mL), the organic phase was collected and washed with saturated brine (3X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.11g of a white solid with a yield of 24%. Ms (esi): 303[ M + H]⁺.

The remaining synthesis steps b-d for compound 6 are analogous to compound 5.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

N- (2- ((3- (3, 5-dimethoxybenzyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (6): white solid 8mg, yield 19%.¹H NMR(400MHz，DMSO-d₆)δ10.95(d，J＝2.3Hz，1H)，9.81(s，1H)，7.97(s，1H)，7.77(d，J＝8.0Hz，1H)，7.62(d，J＝8.4Hz，1H)，7.55(d，J＝7.9Hz，1H)，7.16-7.09(m，1H)，6.99(td，J＝7.6，1.5Hz，1H)，6.91(d，J＝2.3Hz，1H)，6.54(d，J＝8.5Hz，1H)，6.49-6.37(m，3H)，6.28(t，J＝2.3Hz，1H)，6.22(dd，J＝17.0，2.0Hz，1H)，5.71(dd，J＝10.1，2.0Hz，1H)，3.86(s，2H)，3.67(s，6H).¹³C NMR(101MHz，DMSO)δ164.12，160.88，152.22，147.57，144.52，135.37，132.49，129.55，127.13，125.82，125.38，122.48，122.42，119.97，113.49，113.03，107.13，104.18，97.91，55.55，32.08.HRMS(ESI)m/z C₂₅H₂₄N₄O₃[M+H]⁺428.4920; found 429.1924.

For I24-I29 and the product, R1 is 3-methoxy, 3, 5-dioxy, or 2, 6-dichloro-3, 5-dioxy; r₂H or CH3.

Conditions and reagents:

(a) ArCHO, KOH, MeOH, overnight;

(b) DDQ, H2O/1, 4-dioxane, room temperature, 2H;

(c) NaH, SEM-Cl, 0 ℃ and then room temperature;

(d) 2-nitroaniline or 2-methyl-6-nitroaniline, Pd₂(dba)₃，X-phos，K₂CO₃1, 4-dioxane, 110 ℃, and standing overnight;

(e) i) TFA, DCM, room temperature; ii) K₂CO₃MeOH, room temperature;

(f)H₂Pd/C, EtOAc, room temperature or SnCl₂EA, reflux;

(g) acryloyl chloride, DIEA, THF, 0 degrees celsius, then room temperature.

Conditions and reagents: KOH, MeOH, room temperature

(6-chloro-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) (3, 5-dimethoxyphenyl) methanol (124 b): 6-chloro-7-azaindole (2.0g, 13mmol) was dissolved in methanol (65mL), and potassium hydroxide (2.9g, 52mmol) and 3, 5-dimethoxybenzaldehyde (2.4g, 14mmol) were added in that order. The reaction solution was stirred overnight at room temperature, after TLC monitoring of the reaction, 4N hydrochloric acid was added to adjust the pH to 7, after concentration, ethyl acetate (3X 200mL) and water were added for extraction, the organic phase was collected and washed with saturated brine (3X 80mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 3.7g of a white solid with 89% yield.¹H NMR(500MHz，DMSO)δ11.66(s，1H)，7.89(d，J＝8.2Hz，1H)，7.30(d，J＝2.3Hz，1H)，7.04(d，J＝8.2Hz，1H)，6.61(d，J＝2.2Hz，2H)，6.34(t，J＝2.3Hz，1H)，5.84(d，J＝4.5Hz，1H)，5.75(d，J＝4.5Hz，1H)，3.69(s，6H).¹³C NMR(126MHz，DMSO)δ160.69，148.22，148.00，143.35，131.32，123.94，119.27，117.25，115.17，104.81，98.84，69.11，55.54.

Conditions and reagents: DDQ, 1, 4-dioxane/H2O, Room temperature, 2H

(6-chloro-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I25 b): compound I24b (0.65g, 2.0mmol) was dissolved in 1, 4-dioxane (20mL) and DDQ (0.74g, 3.3mmol) and water (0.80mL) were added sequentially. After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50mL), extracted with ethyl acetate (3X 50mL), the organic phase was collected and washed with saturated brine (3X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.51g of a white solid with a yield of 81%.¹H NMR(400MHz，DMSO)δ12.82(s，1H)，8.52(d，J＝8.2Hz，1H)，8.22(d，J＝2.9Hz，1H)，7.37(d，J＝8.2Hz，1H)，6.91(d，J＝2.3Hz，2H)，6.74(t，J＝2.3Hz，1H)，3.81(s，6H).¹³C NMR(101MHz，DMSO)δ189.81，160.89，148.52，145.24，141.84，136.83，133.35，118.68，118.15，114.25，106.81，104.11，55.99.

Conditions and reagents: NaH, SEM-Cl, 0 deg.C, then room temperature

(6-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I26 b): compound I25b (0.38g, 1.2mmol) was dissolved in anhydrous DMF (5.0mL) and 60% sodium hydride (0.073g, 1.8mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at 0 ℃ for 30min, SEM-Cl (0.31g, 0.32mL, 1.8mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction was monitored by TLC, it was diluted with water (50mL), extracted with ethyl acetate (3X 50mL), and the organic phase was collected and washed with saturated brine (3X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.35g of a colorless oily liquid in 78% yield.¹H NMR(400MHz，CDCl₃)δ8.65-8.53(m，1H)，7.87(s，1H)，7.33-7.27(m，1H)，6.94(d，J＝2.3Hz，2H)，6.65(t，J＝2.3Hz，1H)，5.66(s，2H)，3.83(s，6H)，3.64-3.55(m，2H)，0.98-0.87(m，2H)，-0.06(s，9H).¹³C NMR(101MHz，CDCl₃)δ190.26，160.88，147.71，146.80，141.39，135.92，133.67，119.42，118.13，115.34，106.77，103.86，73.53，67.28，55.68，17.82，-1.41.

(3, 5-Dimethoxyphenyl) (6- ((2-methyl-6-nitrophenyl) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methanone (I27 d): compound I26b (0.18g, 0.41mmol), 2-methyl-6-nitroaniline (0.069g, 0.45mmol), Pd₂(dba)₃(0.038g，0.041mmol), X-Phos (0.039g, 0.082mmol), potassium carbonate (0.11g, 0.82mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction was stirred at 110 ℃ for 6h, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellow solid 0.16g, 69% yield.¹H NMR(400MHz，CDCl₃)δ8.46(dd，J＝8.5，4.3Hz，1H)，8.03(s，1H)，7.92(dd，J＝8.3，1.1Hz，1H)，7.65(s，1H)，7.50(d，J＝7.0Hz，1H)，7.22-7.16(m，1H)，6.95(d，J＝2.3Hz，2H)，6.66-6.60(m，2H)，5.46(s，2H)，3.84(s，6H)，3.51-3.45(m，2H)，2.26(s，3H)，0.87-0.81(m，2H)，-0.07--0.11(m，9H).¹³C NMR(101MHz，CDCl₃)δ190.54，160.75，152.07，147.44，144.29，141.87，136.52，136.17，134.10，133.96，133.24，123.87，123.40，115.71，113.41，107.30，106.72，103.67，73.32，66.87，55.65，19.58，17.83，-1.42.

Conditions and reagents: i) TFA, DCM, room temperature; ii) K₂CO₃MeOH, room temperature

(3, 5-Dimethoxyphenyl) (6- ((2-methyl-6-nitrophenyl) amino) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methanone (I28 d): compound I27d (0.12g, 0.21mmol) was dissolved in dichloromethane (2.0mL) and trifluoroacetic acid (2.0mL) was added. The reaction mixture was stirred at room temperature for 5 hours, and the solid obtained after concentration was dissolved in methanol (2.0mL), and potassium carbonate was added to adjust the pH to 12, followed by stirring at room temperature overnight. After the completion of the reaction monitored by TLC, the reaction mixture was concentrated, extracted with water (20mL) and ethyl acetate (3X 20mL), and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 39mg of a yellow solid in 43% yield.¹H NMR(400MHz，CDCl₃)δ10.60(s，1H)，8.54(d，J＝8.5Hz，1H)，8.24(s，1H)，7.82(dd，J＝8.3，1.0Hz，1H)，7.41(d，J＝7.1Hz，1H)，7.11(d，J＝2.9Hz，1H)，7.10-7.04(m，1H)，6.91(d，J＝2.3Hz，2H)，6.71(d，J＝8.5Hz，1H)，6.69-6.66(m，1H)，3.86(s，6H)，2.24(s，3H).¹³C NMR(101MHz，CDCl₃)δ190.64，160.80，151.87，147.41，144.07，141.84，136.72，136.48，133.92，133.81，131.68，124.14，123.61，115.81，113.47，107.77，106.67，103.53，55.68，19.76.

Conditions and reagents: h2, Pd/C, EtOAc, room temperature

(6- ((2-amino-6-methylphenyl) amino) -1H-pyrrolo [2, 3-b ] pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I29 d): compound I28d (39mg, 0.090mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C under hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected, and concentrated to give intermediate I29d (29mg) as a white solid, which was used in the next reaction without further purification.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -3-methylphenyl) acrylamide (10): compound I29d (29mg, 0.072mmol) was dissolved in tetrahydrofuran (2.0mL) and reacted in ice water bath with DIEA (7.0. mu.L, 0.087mmol) and acryloyl chloride (24. mu.L, 0.14mmol) added sequentially for 30min at room temperature. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a white solid 16mg, yield 49%.¹H NMR(400MHz，DMSO-d₆)δ12.07(d，J＝2.8Hz，1H)，9.45(s，1H)，8.20(d，J＝8.5Hz，1H)，7.89(s，1H)，7.77(d，J＝8.0Hz，1H)，7.62(d，J＝2.7Hz，1H)，7.15(t，J＝7.8Hz，1H)，7.11-7.00(m，1H)，6.83(d，J＝2.3Hz，2H)，6.69(t，J＝2.3Hz，1H)，6.56-6.40(m，2H)，6.17(dd，J＝17.0，2.0Hz，1H)，5.65(dd，J＝10.2，2.0Hz，1H)，3.78(s，6H)，2.14(s，3H).¹³C NMR(101MHz，DMSO)δ189.71，163.92，160.76，155.45，148.77，142.52，137.24，135.88，132.53，132.08，131.63，127.24，127.08，126.20，121.20，114.83，110.98，106.69，105.73，103.59，55.94，19.02.HRMS(ESI)m/z C₂₆H₂₄N₄O₄[M+H]⁺456.1798; found 457.1868.

The synthesis of compounds 7, 8, 9, 11, 21 and 23 was similar to compound 10.

N- (2- ((3- (3-methoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (7):¹H NMR(400MHz，DMSO-d₆)δ12.16(d，J＝3.0Hz，1H)，9.74(s，1H)，8.37-8.17(m，2H)，7.82(d，J＝8.1Hz，1H)，7.68(d，J＝3.0Hz，1H)，7.61(d，J＝7.9Hz，1H)，7.47-7.39(m，1H)，7.34(dt，J＝7.6，1.2Hz，1H)，7.25(dd，J＝2.7，1.5Hz，1H)，7.15(ddd，J＝8.2，2.7，1.1Hz，2H)，7.05(td，J＝7.7，1.5Hz，1H)，6.79(d，J＝8.6Hz，1H)，6.48(dd，J＝17.0，10.2Hz，1H)，6.23(dd，J＝17.0，2.0Hz，1H)，5.72(dd，J＝10.1，2.0Hz，1H)，3.81(s，3H).¹³C NMR(101MHz，DMSO)δ189.93，164.20，159.67，153.80，148.21，141.79，134.58，132.64，132.47，132.19，130.08，127.19，125.81，125.37，123.18，123.09，121.27，117.68，114.98，113.73，111.74，107.25，55.79.HRMS(ESI)m/z C₂₄H₂₀N₄O₃[M+H]⁺412.1535; found 413.1609.

N-(2- ((3- (3, 5-Dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (8):¹h NMR (400MHz, chloroform-d) δ 12.32(s, 1H), 8.51(s, 1H), 8.40(d, J ═ 8.5Hz, 1H), 7.64(d, J ═ 8.1Hz, 1H), 7.45(s, 1H), 7.13(d, J ═ 8.0Hz, 1H), 7.11-7.01(m, 1H), 6.89(d, J ═ 2.3Hz, 2H), 6.84(td, J ═ 7.7, 1.4Hz, 1H), 6.68(t, J ═ 2.3Hz, 1H), 6.63(d, J ═ 8.5Hz, 1H), 6.54(d, J ═ 2.7Hz, 1H), 6.36(dd, 17.0, J ═ 1.6, 1.5H), 6.7 (dd, 1H, 9.85H), 9.5H, 9, 9.5H, 1H), 6.7 (dd, 1H), 6.7H, 1H, 6.6.7 (dd, 17, 17.0, 1H, 6.6.5H), 6.5H, 1H, 9, 1H, 6.85 (dd, 1H).¹³C NMR(101MHz，CDCl₃)δ190.28，164.79，160.48，152.72，147.69，142.11，134.91，133.72，132.70，130.38，129.58，128.65，127.15，124.78，124.07，123.30，115.28，112.97，107.73，107.28，103.26，60.50，55.89，31.67，22.74，21.15，14.28，14.21.HRMS(ESI)m/z C₂₅H₂₂N₄O₄[M+H]⁺442.1641; found 443.1717.

N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (9):¹H NMR(400MHz，DMSO-d₆)δ12.26(s，1H)，9.73(s，1H)，8.27(s，1H)，7.81(d，J＝8.1Hz，1H)，7.62(d，J＝8.0Hz，1H)，7.48(s，1H)，7.15(td，J＝7.7，1.6Hz，1H)，7.05(td，J＝7.6，1.5Hz，1H)，6.99(s，1H)，6.79(d，J＝8.6Hz，1H)，6.49(dd，J＝17.0，10.2Hz，1H)，6.24(dd，J＝17.0，2.0Hz，1H)，5.72(dd，J＝10.1，2.0Hz，1H)，3.95(s，6H).¹³C NMR(101MHz，DMSO)δ185.46，164.20，155.03，154.06，148.54，140.20，134.43，132.45，130.31，127.22，125.79，125.31，123.45，123.28，115.42，110.49，110.15，107.51，99.02，57.34.HRMS(ESI)m/z C₂₅H₂₀Cl₂N₄O₄[M+H]⁺510.0862; found 511.0934.

N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -3-methylphenyl) acrylamide (11):¹H NMR(400MHz，DMSO-d₆)δ12.18(s，1H)，9.43(s，1H)，8.14(s，1H)，7.93(s，1H)，7.79(d，J＝8.0Hz，1H)，7.38(s，1H)，7.17(t，J＝7.8Hz，1H)，7.12-7.07(m，1H)，6.98(s，1H)，6.62-6.36(m，2H)，6.18(dd，J＝17.0，2.0Hz，1H)，5.66(dd，J＝10.2，2.0Hz，1H)，3.95(s，6H)，2.15(s，3H).¹³C NMR(101MHz，DMSO)δ185.37，163.94，155.65，155.00，149.08，140.25，137.36，135.98，132.51，131.45，127.26，127.04，126.30，121.19，115.38，110.14，109.73，106.01，98.97，57.32，18.98.

n- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -3-methylphenyl) propanamide (21): ms (esi): 459[ M + H ]]⁺.

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (23):¹H NMR(400MHz，DMSO-d₆)δ9.70(s，1H)，8.35(s，1H)，8.28(d，J＝8.5Hz，1H)，7.91(d，J＝11.6Hz，2H)，7.60(d，J＝8.0Hz，1H)，7.18(t，J＝7.8Hz，1H)，7.05(t，J＝7.7Hz，1H)，6.87(s，2H)，6.81(d，J＝8.5Hz，1H)，6.72(s，1H)，6.49(dd，J＝17.1，10.1Hz，1H)，6.25(d，J＝16.9Hz，1H)，5.73(d，J＝10.3Hz，1H)，3.81(s，6H)，3.74(s，3H).

for I32, I34-I36, products 12-18, R ═ 4-methylpiperazine, 4-morpholine, 4-acetylpiperazine, 4- (1-methyl-1H-pyrazol-3-yl); for products 16-18, when R ═ 4-morpholine, Ar ═ 2-chloro-3, 5-dimethoxyphenyl or 2, 6-dichloro-3, 5-dimethoxyphenyl, when R ═ 4- (1-methyl-1H-pyrazol-3-yl), Ar ═ 2, 6-dichloro-3, 5-dimethoxyphenyl

Conditions and reagents:

(a)Boc₂o, THF, reflux, overnight;

(b) amine, Pd₂(dba)₃，Xant-Phos，Cs₂CO₃1, 4-dioxane, 100 ℃, and staying overnight;

(c) TFA/DCM, room temperature;

(d)Pd(dppf)Cl₂，K₂CO₃1, 4-dioxane/H2O (v: v ═ 3: 1), 100 ℃ microwave, 2H;

(e)Boc₂o, DMAP, DCM, room temperature;

(f)Pd(OAc)2，Xant-phos，Cs₂CO₃1, 4-dioxane, 110 ℃, and standing overnight;

(g)H₂Pd/C, EA, room temperature;

(h) acryloyl chloride, DIEA, THF, 0 ℃, then room temperature;

(i) TFA, DCM, room temperature;

(j)SO₂Cl₂DCM, 0 ℃.

Conditions and reagents: boc₂O, THF, refluxing, overnight

Tert-butyl (4-bromo-2-nitrophenyl) carbamate (I30): 4-bromo-2-nitroaniline (1.6g, 3.8mmol), Boc₂O (0.91g, 0.96mL, 4.2mmol) was dissolved in THF, stirred at refluxStirring overnight, cooling to room temperature, concentrating, and purifying by column chromatography to give 0.98g of white solid in 81% yield.¹H NMR(400MHz，CDCl₃)δ9.57(s，1H)，8.52-8.42(m，1H)，8.28(d，J＝2.4Hz，1H)，7.65(dd，J＝9.2，2.4Hz，1H)，1.52(s，9H).¹³C NMR(101MHz，CDCl₃)δ151.95，138.54，136.17，135.17，128.27，122.21，113.74，82.31，28.22.

Conditions and reagents: pd₂(dba)₃，Xant-Phos，Cs₂CO₃1, 4-dioxane, 100 ℃ overnight

Tert-butyl (4-morpholino-2-nitrophenyl) carbamate (I31 b): compound I30(0.50g, 1.6mmol), morpholine (0.21g, 0.21mL, 2.36mmol), Pd₂(dba)₃(0.15g, 0.16mmol), Xant-Phos (0.18g, 0.32mmol), cesium carbonate (1.0g, 3.2mmol) were dissolved in anhydrous 1, 4-dioxane (16.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (50mL) and ethyl acetate (3X 50mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.44g of a yellow solid with 86% yield.¹H NMR(400MHz，DMSO-d₆)δ9.18(s，1H)，7.40(d，J＝9.0Hz，1H)，7.36(d，J＝2.9Hz，1H)，7.28(dd，J＝9.0，2.9Hz，1H)，3.79-3.66(m，4H)，3.21-3.09(m，4H)，1.41(s，9H).¹³C NMR(101MHz，DMSO)δ153.45，148.28，143.34，126.59，123.99，121.07，110.28，80.34，66.38，48.58，28.49.

Conditions and reagents: TFA/DCM, room temperature

4-morpholino-2-nitroaniline (I32 b): compound I31b (0.44g) was dissolved in DCM (3mL), trifluoroacetic acid (3mL) was added, stirring at room temperature for 1h, concentration was performed, saturated aqueous sodium bicarbonate solution and ethyl acetate were added for extraction, the organic phase was collected, washed with water and saturated brine in this order, and the resulting yellow solid was concentrated to 0.30g and used in the next reaction without purification.

Conditions and reagents: pd (dpPf) Cl₂，K₂CO₃1, 4-dioxane/H2O (v: v ═ 3: 1), 100 ℃, microwave, 2H

4- (1-methyl-1H-pyrazol-3-yl) -2-nitroaniline (I32 d): 4-bromo-2-nitroaniline (0.30g, 1.4mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.43g, 2.1mmol), Pd (dppf) Cl₂(0.23g, 0.28mmol) and potassium carbonate (0.57g, 4.1mmol) were dissolved in a mixed solvent (12mL) of 1, 4-dioxane and water (3: 1), and argon gas was introduced to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ℃ for 2 hours, cooled to room temperature, filtered, and the filtrate was extracted with water and ethyl acetate (3 × 40mL), and the organic phase was collected, washed with saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.24g of a yellow solid, with a yield of 79%.¹H NMR(400MHz，DMSO-d₆)δ8.09(d，J＝0.9Hz，1H)，8.07(d，J＝2.2Hz，1H)，7.79(d，J＝0.8Hz，1H)，7.64(dd，J＝8.8，2.2Hz，1H)，7.41(s，2H)，7.03(d，J＝8.8Hz，1H)，3.83(s，3H).¹³C NMR(101MHz，DMSO)δ145.19，136.07，134.08，130.81，127.82，121.10，121.00，120.55，120.40，39.16.

Conditions and reagents: boc₂O, DMAP, DCM, at room temperature

6-chloro-3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b]Pyridine-1-carboxylic acid tert-butyl ester (I33): compound I25b (5.0g, 16mmol) was dissolved in DCM (80mL) and Boc was added sequentially₂O (5.2g, 5.5mL, 24mmol), DMAP (0.097g, 0.8mmol), stirring at room temperature for 2h, concentrating, extracting with water and ethyl acetate, collecting the organic phase, washing with brine (2 × 40mL), drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography to give a yellow solid 4.1g, 62% yield.¹H NMR(400MHz，CDCl₃)δ8.54(d，J＝8.3Hz，1H)，8.16(s，1H)，7.35(d，J＝8.3Hz，1H)，6.95(d，J＝2.3Hz，2H)，6.67(t，J＝2.3Hz，1H)，3.84(s，6H)，1.68(s，9H).¹³C NMR(101MHz，CDCl₃)δ190.17，160.95，148.03，147.35，146.80，140.49，133.83，133.57，120.80，119.98，116.72，106.75，104.64，86.29，55.70，28.05.

Conditions and reagents: pd (OAc)2, Xant-phos, Cs₂CO₃1, 4-dioxane, 100 ℃ overnight

3- (3, 5-Dimethoxybenzoyl) -6- ((4-morpholino-2-nitrophenyl) amino) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (I34 b): mixing compound I33(0.17g, 0.41mmol), 32b (0.088g, 0.40mmol), Pd (OAc)₂(0.009g, 0.040mmol), Xant-Phos (0.047g, 0.080mmol), and cesium carbonate (0.27g, 0.80mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.15g of a yellow solid with 62% yield.¹H NMR(400MHz，DMSI-d₆)δ9.58(s，1H)，8.32(d，J＝8.6Hz，1H)，8.13(d，J＝9.2Hz，1H)，7.90(s，1H)，7.48(d，J＝2.9Hz，1H)，7.39(dd，J＝9.2，3.0Hz，1H)，7.02(d，J＝8.7Hz，1H)，6.95(d，J＝2.3Hz，2H)，6.79(t，J＝2.3Hz，1H)，3.82(s，6H)，3.79-3.73(m，4H)，3.18-3.11(m，4H)，1.49(s，9H).¹³C NMR(101MHz，DMSO)δ190.11，161.01，153.22，146.61，146.19，141.12，140.40，128.41，125.24，123.30，116.81，113.82，110.49，110.15，106.93，85.49，66.47，56.10，49.06，27.98.

Conditions and reagents: h₂Pd/C, EA, room temperature

Tert-butyl 6- ((2-amino-4-morpholinophenyl) amino) -3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b ] pyridine-1-carboxylate (I35 b): compound I34b (0.15g, 0.25mmol) was dissolved in ethyl acetate (5mL), reduced with 10% Pd/C and hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected and concentrated to give intermediate I35b (0.1g) as a white solid which was used in the next reaction without further purification.

Conditions and reagents: DIEA, THF, 0 deg.C, then room temperature

6- ((2-acrylamido-4-morpholinophenyl) amino) -3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (I36 b): compound I35b (0.1g, 0.18mmol) was dissolved in tetrahydrofuran (2.0mL), and DIEA (60. mu.L, 0.36mmol) and acryloyl chloride (18. mu.L, 0.22mmol) were added sequentially under ice-water bath conditions and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 70mg of a white solid with a yield of 62%. Ms (esi): 628[ M + H]⁺.

Conditions and reagents: TFA/DCM, room temperature

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5-morpholinophenyl) acrylamide (13):compound I36b (70mg, 0.11mmol) was dissolved in DCM (1.0mL), trifluoroacetic acid (1.0mL) was added, stirred at room temperature for 1h, concentrated, extracted with saturated aqueous sodium bicarbonate and ethyl acetate, the organic phase was collected, washed successively with water, saturated brine, the white solid obtained was concentrated (63mg), a portion of the product was purified by column chromatography for activity test, and the remainder was used in the next reaction without purification.¹H NMR (400MHz, chloroform-d) δ 12.20(s, 1H), 8.50(s, 1H), 8.40(d, J ═ 8.5Hz, 1H), 7.55(d, J ═ 8.9Hz, 1H), 7.14(s, 1H), 6.94(d, J ═ 2.3Hz, 2H), 6.77(s, 1H), 6.73-6.66(m, 2H), 6.56(d, J ═ 8.5Hz, 1H), 6.50-6.43(m, 1H), 6.41(d, J ═ 1.5Hz, 1H), 6.30(dd, J ═ 16.9, 10.1Hz, 1H), 5.76(dd, J ═ 10.0, 1.5, 1H), 3.88(s, 6H), 3.70 (t, 4.4H), 4.70 (t, 4H), 4.4H, 4H).¹³C NMR(101MHz，CDCl₃)δ189.85，164.63，160.61，153.72，148.92，147.67，142.21，133.72，132.10，131.56，130.60，128.91，128.59，125.62，115.23，115.02，112.46，110.76，107.57，107.17，103.38，66.69，56.01，49.25.

The synthesis of compounds 12, 14, 15 and 20 was similar to compound 13.

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide (12): a white solid.¹H NMR(400MHz，DMSO-d₆)δ12.08(s，1H)，9.65(s，1H)，8.21(d，J＝8.6Hz，1H)，7.98(s，1H)，7.68(d，J＝2.4Hz，1H)，7.44(d，J＝8.8Hz，1H)，7.38-7.34(m，1H)，6.86(d，J＝2.3Hz，2H)，6.81(dd，J＝8.9，2.8Hz，1H)，6.71(t，J＝2.3Hz，1H)，6.63(d，J＝8.6Hz，1H)，6.47(dd，J＝17.0，10.2Hz，1H)，6.22(dd，J＝17.0，2.0Hz，1H)，5.71(dd，J＝10.1，2.0Hz，1H)，3.80(s，6H)，3.18-3.07(m，4H)，2.57(s，4H).¹³C NMR(101MHz，DMSO)δ189.74，164.00，160.79，155.02，148.54，147.98，142.54，132.54，132.32，132.06，127.22，125.88，125.75，114.92，113.42，111.61，111.15，106.69，106.27，103.58，55.95，54.92，48.84，45.87.MS(ESI)：541[M+H]⁺.

N- (5- (4-acetylpiperazin-1-yl) -2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (14): a white solid.¹H NMR (400MHz, chloroform-d) δ 12.11(s, 1H), 8.64(s, 1H), 8.40(d, J ═ 8.5Hz, 1H), 7.52(d, J ═ 8.8Hz, 1H), 7.16(s, 1H), 6.96-6.87(m, 3H), 6.73-6.64(m, 2H), 6.64-6.52(m, 2H), 6.41(dd, J ═ 16.9, 1.5Hz, 1H), 6.29(dd, J ═ 16.9, 10.1Hz, 1H), 5.74(dd, J ═ 9.9, 1.5Hz, 1H), 3.87(s, 6H), 3.55(t, J ═ 5.2, 2H), 3.40(t, J ═ 2.5, 1.5Hz, 1H), 3.06 (t, J ═ 2H), 3.6H), 3.55(t, J ═ 5.2H, 2H, 3.06 (t, J ═ 2H), 2H, 3.6H).¹³C NMR(101MHz，CDCl₃)δ189.84，169.08，164.62，160.64，153.79，148.40，147.76，142.16，133.64，131.96，131.76，130.72，128.49，126.62，125.52，115.61，115.29，112.46，111.84，107.47，107.09，103.26，55.97，49.62，49.25，46.06，41.23，21.32，14.26.

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (1-methyl-1H-pyrazol-3-yl) phenyl) acrylamide (15): a white solid. Ms (esi): 523[ M + H]⁺.

N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (4-methylpiperazine-1-yl) phenyl) propionamide (20): a white solid. Ms (esi): 543[ M + H ]]⁺.

Conditions and reagents: SO (SO)₂Cl₂DCM, 0 deg.C

N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5-morpholinophenyl) acrylamide (17): compound 13(50mg, 0.095mmol) was dissolved in anhydrous dichloromethane (2.0mL), sulfonyl chloride (32mg, 19. mu.L, 0.24mmol) was added dropwise at 0 deg.C, stirring was carried out at 0 deg.C for 0.5h, a saturated aqueous sodium bicarbonate solution (10mL) and dichloromethane (10mL) were added for extraction, the organic phase was collected, washed with water and saturated brine in this order, and separation and purification by concentrated column chromatography gave 11mg of a white solid with a yield of 19%. Ms (esi): 596[ M + H]⁺.

The synthesis of compounds 16, 18, 22, 19 was similar to compound 17.

N- (2- ((3- (2-chloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5-morpholinophenyl) acrylamide (16): a white solid.¹H NMR(400MHz，DMSO-d₆)δ12.12(s，1H)，9.61(s，1H)，8.08(s，1H)，7.98(s，1H)，7.44(d，J＝8.9Hz，1H)，7.36(d，J＝3.1Hz，2H)，6.85-6.77(m，3H)，6.65-6.57(m，2H)，6.46(dd，J＝16.9，10.2Hz，1H)，6.21(dd，J＝16.9，2.0Hz，1H)，5.70(d，J＝11.1Hz，1H)，3.88(s，3H)，3.78(s，3H)，3.74(t，J＝4.8Hz，4H)，3.06(t，J＝4.8Hz，4H).MS(ESI)：562[M+H]⁺.

N- (2- ((3- (2, 6-dichloro-3, 5-di)Methoxybenzoyl) -1H-pyrrolo [2, 3-b]Pyridin-6-yl) amino) -5- (1-methyl-1H-pyrazol-3-yl) phenyl) acrylamide (18):¹H NMR(400MHz，DMSO-d₆)δ12.25(s，1H)，9.75(s，1H)，8.24(s，1H)，8.07(s，1H)，7.79(d，J＝3.3Hz，3H)，7.48(s，1H)，7.36(dd，J＝8.4，2.1Hz，1H)，7.00(s，1H)，6.79(d，J＝8.6Hz，1H)，6.51(dd，J＝17.0，10.2Hz，1H)，6.26(dd，J＝17.0，2.0Hz，1H)，5.75(dd，J＝10.1，2.0Hz，1H)，3.96(s，6H)，3.86(s，3H).

n- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide (22): ms (esi): 609[ M + H ] +.

N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b ] pyridin-6-yl) amino) -3-methyl-5- (4-methylpiperazin-1-yl) phenyl) acrylamide (19): ms (esi): 623[ M + H ] +.

Biological activity assay

(I) Kinase Activity detection assay

Experimental materials: PE Envision microplate reader; a 384 well whiteboard (OptiPlate TM-384); FGFR4 kinase (08-136, Cama), Cisbio HTRF kit (Cisbio Assays 62TK0PEB)

The experimental method comprises the following steps: according to

The KinEaseTM assay standard method. An enzymatic reaction step: adding a concentration gradient inhibitor (30 mu M to 0.1nM, 12 concentration gradients diluted by 3.3 times, 4 mu L), FGFR4 kinase (2 ng/well, 2 mu L), a 1: 1 mixed solution (4 mu L) of a substrate (1 mu M) and ATP (120 mu M) into a 384-well plate in sequence, shaking and centrifuging, and incubating at 25 DEGAnd (4) 45 min. A detection step: adding Eu mixed in advance 1: 1³⁺The reaction was stopped by chelating the antibody (5. mu.L) and streptavidin-XL665 (0.125. mu.M, 5. mu.L), and the plate was read on a PE Envision microplate reader after standing at room temperature for 1 h. The IC was calculated by fitting a curve to GraphPad Prism 5.0 using the concentration as the abscissa and the signal value at 615nm/665nm as the ordinate₅₀The value is obtained.

Note: "+" denotes IC₅₀> 1000nM, "+ + +" indicates IC₅₀100-1000 nM, "+ + + + +" indicates IC₅₀10-100 nM, "+ ++" denotes IC₅₀< 10nM, "ND" means IC has not been detected yet₅₀The value is obtained.

(II) cell proliferation inhibition experiment

Experimental materials: HUH-7 cells (Mediterranean cell bank), MDA-MB-453 cells (Mediterranean cell bank), DMEM medium (11995065, Gibco), Leibovitz's L-15 medium (11415064, Gibco), and detection reagents (G7570, Promega).

The experimental method comprises the following steps: after trypsinization of adherent cells, treatment was stopped by addition of complete medium containing serum, cells were collected, centrifuged (1000 × rpm), cells were dispersed in suspension in fresh complete medium for cell counting, and cells were diluted to 5 × 10⁴one/mL. In a 96-well black plate, 100. mu.L of the above cell dilution suspension or cell-free medium was added to each well, and the mixture was incubated overnight at 37 ℃. AddingThe cells were incubated at 37 ℃ for 72h with different concentrations of inhibitor (50. mu.L) or DMSO (50. mu.L) diluted in culture medium. And (3) standing the 96-well plate for balancing at room temperature for 0.5h, adding a detection reagent (40 mu L), fully and uniformly mixing, standing for 1h, reading the plate on an enzyme-linked immunosorbent assay (ELISA) reader, and calculating the growth inhibition rate by taking the DMSO (dimethylsulfoxide) hole signal value as a positive control. Cellular EC were calculated by fitting a graph Pad Prism 5.0 plot of inhibition versus logarithm of inhibitor concentration₅₀The value is obtained.

The compounds 1-22 of the present invention have excellent cell proliferation inhibiting effect, and some of the compounds have the following results in cell lines HuH-7 and MDA-MB-453.

Note: "+" denotes IC₅₀> 1000nM, "+ + +" indicates IC₅₀100-1000 nM, "+ + + + +" indicates IC₅₀＜100nM。

(III) time-dependent inhibition experiment

Staurosporine (Staurosporine, a non-covalent inhibitor, 250nM), compound 11(40nM) and a kinase buffer (positive control) were incubated with FGFR4 kinase for various times (0, 1min, 2min, 4min, 8min, 16min, 30min, 45min) before the enzymatic reaction was initiated by adding ATP (120 μ M) and substrate (1 μ M) in a 1: 1 mixture (4 μ L). After shaking and centrifugation, incubation was carried out for 45min at 25 ℃. Adding Eu mixed in advance 1: 1³⁺The reaction was stopped by chelating antibody (5. mu.L) and streptavidin-XL665 (0.125. mu.M, 5. mu.L). The ratio of each time point to the positive control signal was used to calculate the inhibition ((1-signal)_sample/signal_control) X 100%) were fitted with GraphPad Prism 5.0 to plot inhibition versus time to obtain a time-dependent inhibition curve. The intensity of inhibitory activity of compound 11 on FGFR4 increased with increasing co-incubation time of compound 11 with FGFR4 kinase; but the inhibition intensity of the non-covalent inhibitor Staurosporine on FGFR4 did not change with the co-incubation time.

Claims

1. A compound represented by the formula (I) or a salt thereof

L₁And L₂Independently of one another, identical or different, from the group optionally substituted by C_1-3Alkyl substituted C_2-3Alkenyl radical, C_0-3alkylene-C_2-3Alkenyl and C_1-3alkylene-NHC (O) -C_2-3An alkenyl group;

provided that when G is₁When it is H, L₁Is absent, and when G₂When it is H, L₂Is absent;

wherein the content of the first and second substances,

ar is a 5-or 6-membered monocyclic aromatic ring,

R₁selected from H, halogen, -OH, -C_1-4Alkyl radical, -C_1-4An alkyl-oxy group, a carboxyl group,

m is an integer of 0, 1, 2, 3, 4, 5;

W₁is CH;

W₂is CH;

W₃is CH;

W₄is CH;

W₅is CH;

W₆is CH;

W₇is CH;

n is an integer of 0, 1, 2, 3, 4, 5;

R₂selected from H, halogen, -OH, -C_1-4Alkyl radical, -C_1-4An alkyl-oxy group, a carboxyl group,

R₃selected from H, -C_1-4An alkyl group;

provided that C is_0-3alkylene-C_2-3Alkenyl radicals not including C₀alkylene-C_2-3An alkenyl group.

2. The compound of claim 1 or a salt thereof, wherein G is₂Is H, L₂Is absent.

3. The compound of claim 1, or a salt thereof, wherein R₁is-Cl.

4. The compound of claim 1, or a salt thereof, wherein R₂is-Cl.

5. The compound of claim 1, or a salt thereof, wherein R₃Is H.

6. The compound of claim 1, wherein-N (G) is₁L₁)(G₂L₂) is-NH-CO-C_2-3An alkenyl group.

7. The compound of claim 1, or a salt thereof, wherein Ar is furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole.

8. The compound of claim 1, or a salt thereof, wherein Ar is benzene or pyridine.

9. The compound of claim 1, or a salt thereof, wherein Ar is phenyl.

10. A compound or a salt thereof, wherein the compound is selected from the group consisting of compounds 1-23,

wherein compounds 1-19 and 21 have the following general formula,

wherein the groups L, Ar, R in the compounds 1 to 19 and 21₁And R₂Has the following meanings:

11. a pharmaceutical composition comprising a compound of any one of claims 1-10, or a salt thereof, and a pharmaceutically acceptable carrier.

12. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a condition mediated by FGFR-4.

13. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a condition characterized by FGFR-4 overexpression.

14. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a condition characterized by FGFR4 amplification.

15. Use of a compound of any one of claims 1-10, or a salt thereof, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for treating a condition mediated by FGF 19.

16. Use of a compound of any one of claims 1-10, or a salt thereof, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for treating a condition characterized by expanded FGF 19.

17. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a condition characterized by overexpression of FGF 19.

18. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of hepatocellular carcinoma.

19. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of breast cancer.

20. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of ovarian cancer.

21. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of lung cancer.

22. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of liver cancer.

23. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a sarcoma.

24. Use of a compound or salt thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the treatment of hyperlipidemia.