CN111205227A

CN111205227A - 3-vinyl indazole derivative and preparation method and application thereof

Info

Publication number: CN111205227A
Application number: CN201811400823.8A
Authority: CN
Inventors: 叶庭洪; 魏于全; 刘志昊; 魏玮; 余洛汀
Original assignee: Sichuan University
Current assignee: Shanghai Phaarmaceuticals Holding Co ltd; Sichuan University
Priority date: 2018-11-22
Filing date: 2018-11-22
Publication date: 2020-05-29

Abstract

The invention relates to a 3-vinyl indazole derivative, a preparation method and application thereof, belonging to the field of chemical medicine. The invention provides a compound shown as a formula I, an optical isomer thereof, and a pharmaceutically acceptable salt of the compound or the optical isomer thereof. Biological experiments prove that the 3-vinyl indazole derivatives provided by the invention have a remarkable inhibitory effect on the activity of FGFR kinase, can effectively inhibit the proliferation of various cancer cells such as breast cancer, lung cancer, gastric cancer and the like, and have a broad-spectrum anticancer effect; in addition, the pharmaceutical composition also shows obvious inhibition effect on the proliferation of fibroblasts, has the effect equivalent to that of the currently clinically used medicament Nintedanib for treating pulmonary fibrosis, and has obvious anti-fibrosis curative effect. The invention provides a new choice for the development and application of anti-cancer and anti-fibrosis drugs.

Description

3-vinyl indazole derivative and preparation method and application thereof

Technical Field

The invention relates to a 3-vinyl indazole derivative, a preparation method and application thereof, belonging to the field of chemical medicine.

Background

The main methods for treating cancer are: traditional therapies such as surgery, radiotherapy and chemotherapy, targeted therapies including immunotherapy such as PD1/PD-L1 and CAR-T therapy, small molecule targeted drugs, monoclonal antibodies and antibody conjugated drugs, and the like. The traditional cancer treatment method has limited effect, is easy to relapse, transfer or have toxic and side effects, and has great influence on the life quality of patients. The molecular targeted drug has certain specificity, wherein the small molecular targeted drug is always an important treatment mode for treating diseases including cancer and the like.

Receptor Tyrosine Kinases (RTKs) are Receptor proteins located on cell membranes and can conduct extracellular signals into cells as a class of targets of molecular targeted drugs. Most oncogenic RTKs are poorly active or expressed in normal tissues, but are over-activated or up-regulated in cancer cells. Receptor tyrosine kinases play an important role in regulating and controlling tumor angiogenesis, tumor cell survival, proliferation, differentiation, migration and the like.

Fibroblast Growth Factor Receptors (FGFRs) are receptor tyrosine kinases located on cell membranes, can be combined with a ligand FGF to generate dimerization and autophosphorylation to be activated, and further activate four signal pathways of PI3K-AKT, RAS-RAF-MAPK, JAK-STAT and PLC gamma. FGFR plays an important role in normal physiological processes such as embryonic development, tissue repair, maintenance of homeostasis and the like. The abnormality of FGF/FGFR is closely related to cancer, skeletal diseases and the like. FGFR amplification, mutation and chromosome translocation cause the FGF/FGFR signal path to be abnormal, and promote the generation, development, metastasis and drug resistance of tumors. In each stage of tumor formation, development, metastasis, recurrence and the like, the FGFR signal pathway plays a certain role in regulation and control, and influences the progression and prognosis of cancer. Over-activation and over-expression of FGFR activate downstream signal pathways or autocrine-paracrine signals to generate a bypass compensation effect, so that the tumor is resistant to radiotherapy, chemotherapy, targeted therapy and other therapies. Therefore, targeting FGFR is one of the important strategies for treating cancer.

In addition to being closely related to cancer, FGFR has been reported to have a close relationship with pulmonary fibrosis in recent years, in IPF, proliferation of fibroblasts and increase of matrix deposition lead to lung injury and deterioration of lung function, in acute lung injury and pulmonary fibrosis patients, alveolar lavage fluid and tissues have found high levels of FGF2, FGF 2-expressing mast cells accumulate in extracellular matrix deposition regions of IPF and smooth muscle cells/myofibroblast-like cell proliferation regions, FGF2 has an important role in fibrosis formation, and is directly involved in cell proliferation and fibroplasia after bleomycin-induced mouse lung injury, and after angiogenesis in IPF is increased probably by FGF2/FGFR2 in an FGFR signaling pathway, FGF1/FGFR is expressed in a diseased site of IPF patients in a large amount, suggesting that after abnormal 493FGF 2/FGFR signaling occurs in IPF patients, the pulmonary fibrosis can be induced by promoting migration of fibroblasts and adding MAPK signaling to cause pulmonary fibrosis to occur in the course of pulmonary fibrosis, FGF- β -mediating SMA 4-mediated fibrosis, and FGFR is also reported to be released in mouse fibroblast activation, and FGFR 5 is also capable of inhibiting proliferation of liver fibrosis by SMF 2/FGFR-mediated by fibroblast proliferation and fibroblast activation in SMF signaling.

Disclosure of Invention

The invention aims to provide a 3-vinyl indazole derivative, and a preparation method and application thereof.

The invention provides a compound shown as a formula I, an optical isomer thereof, a compound or a pharmaceutically acceptable salt of the optical isomer thereof:

wherein ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted six-membered and five-membered aryl;

R₁、R₂、R₃independently selected from H, halogen, substituted or unsubstituted alkyl;

the ring B is selected from substituted or unsubstituted 5-to 8-membered aryl.

Further, when ring a is a substituted phenyl group, it contains at least one substituent selected from the group consisting of: halogen, unsubstituted alkyl, halogen substituted alkyl, unsubstituted alkoxy, halogen substituted alkoxy, hydroxy.

Preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: halogen, unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogen substituted C1-C6 alkoxy and hydroxyl.

Preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: halogen, unsubstituted C1-C2 alkyl, halogen substituted C1-C2 alkyl, unsubstituted C1-C2 alkoxy, halogen substituted C1-C2 alkoxy and hydroxyl.

Preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, hydroxy.

Further preferably, the substituted phenyl is selected from:

preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: fluorine, chlorine, methoxy.

Further preferably, the substituted phenyl is selected from:

further, when the ring A is a substituted or unsubstituted six-membered and five-membered aryl group, the six-membered and five-membered aryl group contains 0 to 2 heteroatoms.

Preferably, the six-membered aryl group is phenyl.

In the six-membered and five-membered aryl group, the five-membered aryl group contains at least one heteroatom nitrogen.

Preferably, the five-membered aryl group is selected from a substituted or unsubstituted imidazolyl, oxazolyl or pyrrolyl.

Preferably, the five-membered aryl group is selected from

Wherein R is₄～R₉Independently selected from H, substituted or unsubstituted alkyl.

Preferably, R₄～R₉Independently selected from H, unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl.

Preferably, R₄～R₉Independently selected from H, methyl or ethyl.

Preferably, R₅Selected from H, methyl or ethyl, R₄、R₆、R₇、R₈、R₉Are all made ofH。

Further preferably, the six-membered and five-membered aryl group is selected from:

further, R₁、R₂、R₃Independently selected from H, halogen, unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl.

Preferably, R₁、R₂、R₃Independently selected from H, halogen or unsubstituted C1-C3 alkyl.

Preferably, R₁、R₂、R₃Independently selected from H, fluoro, chloro or methyl.

Further preferably, R₂Selected from H, fluoro, chloro or methyl, R₁、R₃Are all H.

Further preferably, R₂Selected from H or methyl, R₁、R₃Are all H.

Further, the ring B is selected from substituted or unsubstituted 5-to 6-membered aryl.

Preferably, the aryl group contains 0 to 2 heteroatoms.

Preferably, the heteroatom is nitrogen.

Preferably, the aryl group is selected from phenyl, pyridyl, pyrimidinyl or pyrazolyl.

Further, when ring B is a substituted 6-membered aryl group, it contains at least one substituent selected from the group consisting of: halogen, unsubstituted alkyl, halogen-substituted alkyl, unsubstituted alkoxy, halogen-substituted alkoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 6, R₁₁、R₁₂Independently selected from substituted or unsubstituted alkyl, or, R₁₁And R₁₂Joined to form an alicyclic ring.

Preferably, when ring B is a substituted 6-membered aryl group, it contains at least one group selected fromA substituent of group (d): halogen, unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted C1-C6 alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 6, R₁₁、R₁₂Independently selected from substituted or unsubstituted C1-C6 alkyl, or, R₁₁And R₁₂Joined to form a 6-membered alicyclic ring.

Preferably, when ring B is a substituted 6-membered aryl group, it contains at least one substituent selected from the group consisting of: halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted C1-C6 alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 3, R₁₁、R₁₂Independently selected from substituted or unsubstituted C1-C6 alkyl, or, R₁₁And R₁₂Joined to form a 6-membered alicyclic ring, the 6-membered alicyclic ring containing 2 heteroatoms.

Preferably, when ring B is a substituted 6-membered aryl group, it contains only one substituent selected from the group consisting of: -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl, and X is selected from- (CH)₂)_n-or-C (═ O), n is an integer from 0 to 3, R₁₁、R₁₂Independently selected from unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl, or R₁₁And R₁₂Are linked to form a 6-membered alicyclic ring, the 6-membered alicyclic ring containing 2 heteroatoms, the heteroatoms being nitrogen or oxygen.

Further preferably, R₁₀Is unsubstituted C1-C6 alkyl.

Further preferably, R₁₀Is methyl.

Further preferably, n is 0 or 1.

Further preferably, R₁₁、R₁₂Is independently selected from the group consisting of not takingSubstituted C1-C6 alkyl, or, R₁₁And R₁₂Linked to form a substituted or unsubstituted morpholinyl, piperazinyl.

Further preferably, R₁₁、R₁₂Are all methyl.

Further preferably, said substituted morpholinyl, piperazinyl contains at least one substituent selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl.

Further preferably, said substituted morpholinyl, piperazinyl contains at least one substituent selected from the group consisting of: methyl, tert-butoxycarbonyl.

Further preferably, R₁₁And R₁₂Are connected to form

Wherein R is₁₃、R₁₅Independently selected from H or methyl, R₁₄Selected from H, methyl or tert-butyloxycarbonyl.

Further preferably, when ring B is a substituted 6-membered aryl group, it is selected from:

further, when ring B is an unsubstituted 6-membered aryl group, it is selected from

Further, ring B is substituted pyrazolyl containing at least one substituent selected from the group consisting of: unsubstituted alkyl, halogen substituted alkyl, hydroxy substituted alkyl.

Preferably, the substituted pyrazolyl contains at least one substituent selected from the group consisting of: unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, and hydroxyl substituted C1-C6 alkyl.

Preferably, the substituted pyrazolyl contains only one substituent which is a hydroxy-substituted C1-C6 alkyl group.

Preference is given toThe substituted pyrazolyl group contains only one substituent group which is

Further preferably, ring B is

Further, ring B is selected from:

further, the compound is selected from:

the invention provides a preparation method of the compound, the optical isomer thereof, the compound or the pharmaceutically acceptable salt of the optical isomer thereof, which comprises the following steps:

a. coupling compound 1 with compound 2 under the action of a palladium catalyst to obtain an intermediate I:

wherein Y is halogen, R₁₆、R₁₇Independently selected from H, substituted or unsubstituted alkyl, or, R₁₆And R₁₇Are connected to form an alicyclic ring;

b. reacting the intermediate I with acid anhydride and nitrite in the presence of alkali to obtain an intermediate II:

the nitrite is

R₁₈Selected from substituted or unsubstituted alkyl, R₂₁Selected from substituted or unsubstituted alkyl;

c. removing acyl from the intermediate II to obtain an intermediate III:

d. halogenating the intermediate III to obtain an intermediate IV:

e. coupling the intermediate IV and the compound 3 under the action of a palladium catalyst to obtain:

wherein R is₁₉、R₂₀Independently selected from H, substituted or unsubstituted alkyl, or, R₁₉And R₂₀Are connected with each otherAn alicyclic ring is formed.

Preferably, Y is bromine.

Preferably, R₁₆、R₁₇Independently selected from H or unsubstituted C1-C6 alkyl, or, R₁₆And R₁₇Are linked to form a 5-membered alicyclic ring.

Further preferably, compound 2 is

Preferably, R₁₈Is unsubstituted C1-C6 alkyl.

Further preferably, R₁₈Is isoamyl.

Preferably, R₂₁Is unsubstituted C1-C6 alkyl.

Further preferably, R₂₁Is methyl.

Preferably, R₁₉、R₂₀Independently selected from H or unsubstituted C1-C6 alkyl, or, R₁₉And R₂₀Are linked to form a 5-membered alicyclic ring.

Further preferably, compound 3 is

Further, the preparation method meets at least one of the following conditions:

the palladium catalyst in the step a is one or more than two of palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and tris (dibenzylidene indeneacetone) dipalladium;

step a, adding alkali into a reaction system, wherein the alkali is one or more than two of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate and cesium carbonate;

compound 1 in step a: compound 2: alkali: the molar ratio of the palladium catalyst is 1: (1.1-1.5): (2.0-3.0): (0.003-0.010);

the reaction solvent in the step a is one or more than two of dioxane, water, toluene, DMF, n-butanol, isopropanol and sec-butanol;

preferably, the reaction solvent of step a is 1, 4-dioxane: the volume ratio of water is (4-8): 1, a mixed solvent;

the reaction temperature of the step a is 90-110 ℃;

the reaction time of the step a is 5-10 h;

step a at N₂Reacting under protection;

step b, dissolving the intermediate I in a reaction solvent, adding alkali and acid anhydride, fully stirring, and adding nitrite for reaction to obtain an intermediate II;

the alkali in the step b is potassium acetate;

intermediate I in step b: alkali: acid anhydride: the molar ratio of the nitrous acid ester is 1: (1.1-1.5): (1.8-2.5): (3-5);

the reaction solvent in the step b is toluene;

adding nitrite into the step b, and performing reflux reaction for 4-8 hours;

c, reacting under an acidic condition;

preferably, hydrochloric acid is added into the reaction system in the step c;

preferably, step c adds 6N HCl to the reaction system;

the reaction solvent in the step c is an alcohol solvent;

preferably, the reaction solvent of step c is methanol;

c, performing reflux reaction for 1-2 h;

when Z is iodine, step d is to dissolve intermediate III in the reaction solvent, add base and add I₂Dissolving the intermediate in a reaction solvent, and dropwise adding the mixture into the reaction solution to react to obtain an intermediate IV;

preferably, the alkali is one or more than two of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;

intermediate iii in step d: i is₂: the molar ratio of the alkali is 1: (1.5-2.0): 2.0;

the reaction solvent in the step d is DMF;

the reaction temperature of the step d is 25-80 ℃;

the reaction time of the step d is 2-10 hours;

the palladium catalyst in the step e is one or more than two of palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and tris (dibenzylidene indene acetone) dipalladium;

step e, adding alkali into the reaction system, wherein the alkali is one or more than two of DIEA, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate and cesium carbonate;

intermediate iv in step e: compound 3: alkali: the molar ratio of the palladium catalyst is 1: (1.1-1.5): (2.0-3.0): (0.003-0.010);

the reaction solvent in the step e is one or more than two of dioxane, water, toluene, DMF, n-butanol, isopropanol and sec-butanol;

preferably, the reaction solvent of step e is 1, 4-dioxane: the volume ratio of water is (4-8): 1, a mixed solvent;

the reaction temperature of the step e is 90-110 ℃;

the reaction time of the step e is 5-10 hours;

step e in N₂And (4) reacting under protection.

The invention provides application of the compound, the optical isomer of the compound, or the pharmaceutically acceptable salt of the compound or the optical isomer of the compound in preparing FGFR kinase inhibitor medicaments.

Preferably, the medicament is an FGFR1, FGFR2 and/or FGFR3 kinase inhibitor.

The invention provides application of the compound, the optical isomer of the compound, and the pharmaceutically acceptable salt of the compound or the optical isomer of the compound in preparing a medicament for treating and/or preventing cancer.

Preferably, the cancer is breast cancer, lung cancer or gastric cancer.

Further preferably, the lung cancer is non-small cell lung cancer.

The invention provides application of the compound, the optical isomer of the compound, and the pharmaceutically acceptable salt of the compound or the optical isomer of the compound in preparing a medicament for treating and/or preventing organ fibrosis.

Preferably, the organ fibrosis is pulmonary fibrosis or liver fibrosis.

The invention provides a pharmaceutical composition, which is a preparation prepared by taking the compound, the optical isomer thereof, the compound or the pharmaceutically acceptable salt of the optical isomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients; preferably, the formulation is an oral formulation or an injectable formulation.

Definition of terms:

the compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

The term "alkyl" is a radical of a straight or branched chain saturated hydrocarbon group. C₁～C₆Examples of alkyl groups include, but are not limited to, methyl (C)₁) Ethyl (C)₂) N-propyl (C)₃) Isopropyl (C)₃) N-butyl (C)₄) Tert-butyl (C)₄) Sec-butyl (C)₄) Isobutyl (C)₄) N-pentyl group (C)₅) 3-pentyl radical (C)₅) Pentyl group (C)₅) Neopentyl (C)₅) 3-methyl-2-butyl (C)₅) Tert-amyl (C)₅) And n-hexyl (C)₆)。

The term "alkoxy" refers to the group-OR, wherein R is alkyl as defined above. C₁～C₆Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy.

The term "aryl" refers to a group of a 4n +2 aromatic ring system with or without heteroatoms in the aromatic ring system, wherein the heteroatoms are selected from nitrogen, oxygen and/or sulfur.

The term "alicyclic" refers to a saturated or partially unsaturated cyclic hydrocarbon group.

The term "alkoxycarbonyl" refers to the group R-O-C (O) -, wherein R is alkyl as defined above, preferably R is C₁～C₆Alkyl (i.e., C1-C6 alkoxycarbonyl as described herein). Examples thereofIncluding but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and t-butoxycarbonyl.

The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.

The term "pharmaceutically acceptable salts" refers to acid and/or base salts of the compounds of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by appropriately (e.g., equivalent) mixing the above compound with a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

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

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

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

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

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

The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.

The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.

The invention provides a 3-vinyl indazole derivative with a novel structure. Biological experiments prove that the compound provided by the invention has a remarkable inhibiting effect on the activity of FGFR kinase, can effectively inhibit the proliferation of various cancer cells such as breast cancer, lung cancer, gastric cancer and the like, and has a broad-spectrum anticancer effect; in addition, the pharmaceutical composition also shows obvious inhibition effect on the proliferation of fibroblasts, has the effect equivalent to that of the currently clinically used medicament Nintedanib for treating pulmonary fibrosis, and has obvious anti-fibrosis curative effect. The invention provides a new choice for the development and application of anti-cancer and anti-fibrosis drugs.

Drawings

FIG. 1 is a graph of pulmonary structural changes-HE (hematoxylin-eosin staining) of bleomycin-induced pulmonary fibrosis inhibited by compounds 4-20(C) of the present invention;

FIG. 2 is a graph of the collagen deposition change-Masson (Madin staining) of bleomycin-induced pulmonary fibrosis inhibited by compounds 4-20(C) of the present invention;

FIG. 3 is a graph of pulmonary structural changes-HE of compounds 4-22(A) of the present invention inhibiting bleomycin-induced pulmonary fibrosis;

FIG. 4 is a graph of the collagen deposition changes-Masson's profile of bleomycin-induced pulmonary fibrosis inhibited by compounds 4-22(A) of the present invention.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

EXAMPLE 1 preparation of the Compounds of the invention

Taking compound 1-1(1.86g,10mmol), compound 2-1(3.17g,12mmol), Pd (dppf) Cl₂(5 mmol%), Potassium carbonate (2.76g,20mmol) were added to 50mL of a mixed solvent of 1, 4-dioxane and water (volume ratio 4:1), and N was added₂After the displacement, the reaction was carried out at 100 ℃ for 6 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction solution was evaporated under reduced pressure, the residue was dissolved in a mixed solvent of dichloromethane and methanol, filtered through celite, and the filtrate was concentrated and subjected to column chromatography (PE: EA ═ 2:1) to give intermediate i-1 (pale yellow solid, 73%), MS m/z (esi): 244.1[ M + H]⁺。

Intermediate I-1 (1.21g,5mmol) was dissolved in toluene 30mL, potassium acetate (0.59g,6mmol) and acetic anhydride (0.94mL,10mmol) were added, stirred at room temperature for 1h, isoamyl nitrite (2mL,15mmol) was added, and the reaction was monitored by TLC after refluxing for 5 h. After the reaction is completed, the solvent is concentrated under reduced pressure, the residue is added with water and extracted by EA after being stirred, an organic phase is dried by anhydrous sodium sulfate and then concentrated, and column chromatography is carried out (PE: EA is 4:1) to obtain an intermediate II-1 (pale yellow solid, 57%), MS m/z (ESI): 297.2[ M + H]⁺。

Intermediate II-1 (1.48g,5mmol) was dissolved in 50mL of methanol, 6N HCl (20mL) was added, refluxed for 1h and monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure, the residue was adjusted to pH 8 with an aqueous solution of sodium hydrogencarbonate, and the precipitated solid was filtered and dried to obtain intermediate III-1 (light brown solid, 69%), MS m/z (ESI): 255.1[ M + H]⁺。

Intermediate III-1 (1.27g,5mmol) was dissolved in DMF 10mL, potassium carbonate (1.38g,10mmol) was added, and I was added with stirring at room temperature₂(1.9g,7.5mmol), reaction at 65 ℃ for 8h followed by TLC monitoring. After the reaction is finished, quenching the reaction by using saturated aqueous solution of sodium hydrosulfite, pouring the reaction liquid into water, precipitating white solid, filtering the solid and drying to obtain an intermediate IV-1 (pale yellow solid, 92%), MS m/z (ESI): 381.0[ M + H]⁺。

4-bromo-N, N-dimethylbenzylamine (642mg,3mmol), vinylboronic acid pinacol ester (612. mu.L, 3.6mmol) and DIEA (884. mu.L, 5.4mmol) were added to dry toluene 20mL, N₂After the displacement, the reaction was carried out at 95 ℃ for 6 hours and monitored by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in a mixed solvent of dichloromethane and methanol, filtered through celite, and the filtrate was concentrated and subjected to thin layer chromatography (DCM: MeOH ═ 15:1) to obtain compound 3-1 (pale yellow solid, 77%), MS m/z (esi): 288.2[ M + H]⁺。

Collecting intermediate IV-1 (190mg,0.5mmol), compound 3-1(172mg,0.6mmol), Pd (dppf) Cl₂(5 mmol%), Potassium carbonate (138mg,1mmol) and N in 15mL of a mixed solvent of 1, 4-dioxane and water (volume ratio 4:1)₂After the displacement, the reaction was carried out at 100 ℃ for 8 hours. Monitoring the reaction by TLC, and evaporating the reaction solution under reduced pressure after the reaction is completedThe residue was dissolved in a mixed solvent of dichloromethane and methanol, filtered through celite, and the filtrate was concentrated and then subjected to thin layer chromatography (DCM: MeOH ═ 10:1) to give compound 4-1 (pale yellow solid, 17%).¹H NMR(400MHz,DMSO-d₆)δ13.20(s,1H),8.23(d,J＝8.4Hz,1H),7.77–7.72(m,1H),7.67(d,J＝8.0Hz,2H),7.57–7.47(m,3H),7.32(d,J＝8.0Hz,2H),6.87(d,J＝2.3Hz,2H),6.55(t,J＝2.2Hz,1H),3.84(s,6H),3.40(s,2H),2.16(s,6H).

Using a similar procedure the following compounds were obtained:

compound 4-2

¹H NMR(400MHz,DMSO-d₆)δ13.08(s,1H),8.19(d,J＝8.5Hz,1H),7.72(s,1H),7.57(d,J＝8.5Hz,2H),7.51–7.39(m,2H),7.34(d,J＝16.7Hz,1H),6.96(d,J＝8.5Hz,2H),6.86(d,J＝2.2Hz,2H),6.54(t,J＝2.2Hz,1H),3.84(s,6H),3.20(t,J＝5.0Hz,4H),2.49–2.41(m,4H),2.24(s,3H).

Compound 4-3

¹H NMR(400MHz,DMSO-d₆)δ13.35(s,1H),8.28(d,J＝8.5Hz,1H),7.99(d,J＝8.1Hz,2H),7.88(d,J＝8.2Hz,2H),7.75(d,J＝17.2Hz,2H),7.62(d,J＝16.7Hz,1H),7.53(dd,J＝8.5,1.5Hz,1H),6.88(d,J＝2.2Hz,2H),6.56(d,J＝2.3Hz,1H),3.87(s,3H),3.85(s,6H).

Compound 4-4

¹H NMR(400MHz,DMSO-d₆)δ13.28(s,1H),8.26(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,2H),7.75(s,1H),7.66(d,J＝16.8Hz,1H),7.57(d,J＝16.7Hz,1H),7.52(dd,J＝8.5,1.5Hz,1H),7.45(d,J＝8.2Hz,2H),6.87(d,J＝2.2Hz,2H),6.55(t,J＝2.2Hz,1H),3.84(s,6H),3.40(s,8H),1.42(s,9H).

Compounds 4 to 6

1H NMR(400MHz,DMSO-d₆)δ13.33(s,1H),8.28(d,J＝8.5Hz,1H),7.86–7.76(m,3H),7.67(d,J＝16.7Hz,1H),7.62–7.51(m,2H),7.45(d,J＝7.9Hz,2H),7.23–7.13(m,2H),6.91–6.83(m,1H),4.08(s,4H),3.87(s,6H),3.09(s,2H),1.41(s,9H),1.10(d,J＝19.9Hz,6H).

Compounds 4 to 8

1H NMR(400MHz,DMSO-d₆)δ13.10(s,1H),8.15(d,J＝8.5Hz,1H),8.01(s,1H),7.84(s,1H),7.76(s,1H),7.49(d,J＝8.5Hz,1H),7.38(d,J＝16.7Hz,1H),7.28–7.11(m,3H),6.86(dt,J＝10.9,2.3Hz,1H),4.93(s,1H),4.16(t,J＝5.6Hz,2H),3.87(s,6H),3.77(q,J＝5.5Hz,2H).

Compounds 4 to 9

¹H NMR(400MHz,DMSO-d₆)δ13.40(s,1H),8.28(d,J＝8.5Hz,1H),7.82(d,J＝8.1Hz,3H),7.65(t,J＝17.6Hz,2H),7.58–7.51(m,1H),7.47(d,J＝7.9Hz,2H),7.24–7.11(m,2H),6.87(d,J＝10.9Hz,1H),3.87(s,6H),3.63(s,4H),3.00(s,4H)2.20(s,3H).

EXAMPLE 2 preparation of Compounds of the invention

Compound 4-4(50mg) was added to 10ml of HCl/1, 4-dioxane solution, stirred at room temperature for 5h, the solvent was concentrated, and the residue was dissolved in methanol and subjected to thin layer chromatography (DCM: MeOH ═ 8:1) to give compound 4-5 (light brown solid, 52%).¹H NMR(400MHz,DMSO-d₆)δ9.58(s,2H),8.26(d,J＝8.5Hz,1H),7.83(d,J＝7.9Hz,2H),7.77(s,1H),7.68(d,J＝16.7Hz,1H),7.58(d,J＝16.7Hz,1H),7.51(dd,J＝7.9,4.4Hz,3H),6.87(d,J＝2.2Hz,2H),6.55(t,J＝2.2Hz,1H),3.84(s,6H),3.78–3.63(m,4H),3.16(s,4H).

Using a similar procedure the following compounds can be obtained:

compounds 4 to 7

1H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.28(d,J＝8.5Hz,1H),7.84–7.78(m,3H),7.66(d,J＝16.8Hz,1H),7.61–7.51(m,2H),7.40(d,J＝8.0Hz,2H),7.23–7.13(m,2H),6.87(dt,J＝10.9,2.3Hz,1H),3.87(s,6H),3.63–3.35(m,3H),2.69(d,J＝8.5Hz,3H),1.10–0.80(m,7H).

The compounds in table 1 below were prepared in a similar manner to the compounds described above.

TABLE 1 Mass Spectrometry data for a portion of the compounds of the invention

The beneficial effects of the invention are proved by biological experiments.

First, experimental instrument and material

The main biological laboratory instruments and equipment are described below. Superclean bench BHC-1000 IIA/B3: sujing anti biotechnology; thermostatic water bath box polytscience 9505: polyscience, Inc.; sterilizing pot MLS-3780: SANYO corporation; oven: binder corporation; ultrapure water meter Milli-Q Integral 10: millipore Corp; microplate reader multiscan mk3, cell incubator, low speed centrifuge Sorvall ST 1: thermofoisher company; centrifuge 5415C ultracentrifuge: eppendorf, Germany; NUAIRE NU-425-: nuaire, USA; BCD-215YD type general refrigerator: haier corporation, China; SANYO (-80 ℃) ultra-low temperature refrigerator: the japan ocean electrical group; rock 51702 table: cole Parmer, USA; 96-well cell culture plates: costa Corning corporation; ordinary optical microscopes: olympus corporation; a liquid transferring gun: thermo corporation; a pH meter: coring Corning Corp; an autoclave: SANYO Inc.

Cell lines used in the experiments were purchased from ATCC, USA. Various requirements for cell culture were purchased from GibcoBRL, including DMEM medium, RPMI 1640 medium, Fetal Bovine Serum (FBS) and pancreatin. Tetramethyltetrazolium blue (MTT), dimethyl sulfoxide (DMSO) was purchased from Sigma, USA.

Second, Experimental methods

1. Kinase assay

Compounds were diluted with DMSO to 50-fold the final desired highest inhibitor concentration in the reaction. 100 μ L of compound dilutions were transferred to 96-well plates. Two blank wells of the same 96-well plate were loaded with 100. mu.L DMSO. The 96-well plate served as the source plate. 10 μ L of compound was transferred from the source plate to a 96-well plate as an intermediate plate. To each well of the intermediate plate 90. mu.L 1x kinase buffer was added. The compounds in the middle plate were mixed for 10 minutes on a shaker. Transfer 5. mu.L of each well of the 96-well intermediate plate to a 384-well plate, and set the sub-well. The kinase was added to 1x kinase base buffer. FAM-labeled peptide and ATP were added to 1x kinase base buffer. Assay plates already contained 5 μ L of compound 10% DMSO solution. To each well of a 384 well assay plate was added 10 μ L of an L2.5x enzyme solution. Incubate at room temperature for 10 minutes. To each well of a 384 well assay plate was added 10 μ L of a 2.5x peptide solution. After incubation at 28 ℃ for a specified time, 25. mu.L of stop buffer was added to stop the reaction. Collecting data on the Caliper, and converting the data into IC₅₀。

2. Cell culture

The tumor cells of the frozen preserved seeds are taken out from the liquid nitrogen, quickly placed in a thermostatic water bath at 37 ℃ for rewarming and thawing, and washed 1 time by using the culture medium under the aseptic condition. Then inoculating the whole culture medium into a culture flask at 37 ℃ and 5% CO₂Culturing in an incubator, and replacing fresh cell culture solution the next day. Passage of suspension-grown cells: after the cells are cultured for 2-3 days, taking out the culture flask from the incubator, collecting cell suspension in a centrifuge tube, centrifuging at 1500rpm/min for 3min, pouring out supernatant, resuspending cell precipitates by using complete culture medium, uniformly blowing, and then distributing to 3-5 bottles for culture. Generally, carrying out passage for 1 time in 3-4 days; passage of adherent growing cells: the cells grow to about 80% of the bottom of the flask by adhering to the wall, taking out the flask from the incubator, sucking out the culture medium, washing for 1 time by 0.25% pancreatin, adding 0.25% pancreatin digestive juice for digestion, observing cell contraction and rounding, adding complete culture medium to stop digestion, blowing to make the cells disperse and fall off, collecting cell suspension, 15%Centrifuging at 00rpm/min for 3min, pouring out supernatant, resuspending cell sediment by using complete culture medium, blowing uniformly, and then culturing by distributing to 3-5 bottles. Passage is generally carried out for 1 time in 3-4 days.

3. Cell proliferation inhibition assay (MTT method)

Collecting cells (4T1 mouse-derived breast cancer cell line; MDA-MB-231 human-derived breast cancer cell line; A549 human-derived non-small cell lung cancer cell line; SUN-16 human poorly differentiated gastric cancer cell; NIH3T3 mouse fibroblast; human lung fibroblast HPF (Catalog #3300)) at logarithmic growth phase at 2.5 × 10 per well³～1×10⁴The number of cells was seeded in 96-well plates at 37 ℃ with 5% CO₂Was cultured overnight for 24 hours in a cell culture chamber, and the test drugs were diluted with DMEM medium and added to 96-well plates in 8-gradient each containing 3 duplicate wells. Adding 100 μ L of culture medium solution of the compound into each well according to gradient (final concentration is 1000, 333, 127, 42.3, 14.1, 4.7, 1.56, 0.53nM respectively), and setting 3 multiple wells for each concentration; adding 100 microliter of blank culture medium containing 1 thousandth of DMSO into each hole of the negative control group, and repeating 6 holes; blank control group only 100. mu.L of medium was added to each well. The plates were placed at 37 ℃ in 5% CO₂Culturing in a cell culture incubator for 72 hours. After the drug-treated group, the stealth control group, and the blank group were incubated for 2 to 4 hours with 20. mu.L of MTT solution (5mg/mL) per well, after formazan was formed, the incubation was terminated, and after the supernatant was decanted, 150. mu.L of DMSO (50. mu.L of 20% SDS solution was directly added to suspension cells) per well was shaken on a shaker for 15 to 20 minutes. The absorbance (OD) of the cells per well was measured at a wavelength of 570nm using a microplate reader₅₇₀) And taking the average value to record the result. Cell proliferation inhibition rate (control group OD)₅₇₀Experimental group OD₅₇₀) /(control OD)₅₇₀Blank OD₅₇₀) X 100%. Finally, half maximal inhibitory concentrations were fitted using Graphpad Prism software.

4. Experiment for inhibiting pulmonary fibrosis in animal body

1. Animal model and drug delivery

Male C57BL/6 mice (7-9 weeks old, 18-22g body weight) were purchased from Huafukang (Beijing, China). Mice were housed and maintained in the facility under SPF conditions. On day 0 of the experiment, the mice were anesthetized with 10% chloral hydrate and then given a single intratracheal instillation of bleomycin sulfate in saline (3mg/kg body weight) while injecting an equal volume of saline into the rats of the control group. The following day, the mice were randomly divided into groups of 6 mice, each group was intraperitoneally injected with compounds 4-20(C), 4-22(a) of the present invention daily, and positive controls were Nintedanib (BIBF 1120) (20mg/Kg, solvent ratio DMS0: PED400: physiological saline 0.5:3.5:6) and an equal volume of solvent as controls. 28 days after dosing, mice were sacrificed.

HE and Masson staining

Mice were sacrificed on day 28 of the experiment. Lung tissue samples were placed in 4% (m/v) PBS-buffered paraformaldehyde solution, three days later, a portion of the tissue was flushed with water for 2h, then dehydrated with gradient ethanol and embedded in paraffin. The tissues wrapped in paraffin were cut into serial sections (3 μm) and stained with hematoxylin and eosin or Masson trichrome to assess histopathological changes and the extent of accumulated collagen fibers.

Third, in vitro experiment results

1. Table 2 below lists FGFR1 kinase inhibition by some of the compounds synthesized by the present invention. Letter A stands for IC₅₀50nM or less, and the letter B represents IC₅₀50nM to 100nM, letter C represents IC₅₀100nM to 500nM, letter D stands for IC₅₀Is more than 500 nM.

Table 2 IC of partial compounds of the invention inhibiting FGFR1 kinase₅₀Value of

2. Table 3 below lists the inhibition of SNU16 cell proliferation by some of the compounds synthesized according to the invention over 72 hours. Letter A stands for IC₅₀50nM or less, and the letter B represents IC₅₀50nM to 100nM, letter C represents IC₅₀100nM to 500nM, letter D stands for IC₅₀Is more than 500 nM.

TABLE 3 IC inhibition of SUN16 cell proliferation by partial compounds of the invention₅₀Value of

3. Table 4 below illustrates the inhibition of proliferation of a portion of tumor cells at 72 hours by a portion of the compounds synthesized in accordance with the present invention.

TABLE 4 inhibition of tumor cell proliferation IC of some of the compounds of the invention₅₀Value of

4. Table 5 below illustrates the inhibition of proliferation of NIH-3T3 cells and human lung fibroblasts 72h after the action of some of the synthetic compounds of the present invention.

TABLE 5 IC inhibition of NIH-3T3 cell and human lung fibroblast proliferation by a portion of the compounds of the invention₅₀Value of

NT means not tested.

Fourth, animal in vivo experimental results

The experimental results are shown in FIGS. 1 to 4. Figure 1, HE staining results show: in a sham operation group, the lung tissue structure of the mouse is complete and clear, the alveolar wall is not thickened, and inflammatory cells are not invaded; in the solvent control group, the pulmonary alveolar structure of the mouse is damaged, the pulmonary alveolar space is widened, a large amount of inflammatory cell infiltration and fibroblast proliferation are realized, and the fibrosis state is obvious; c is a 4-20 compound treatment group, compared with a solvent control group, the condition is obviously improved, the range of pathological changes is obviously reduced, and the lung parenchyma structure is not obviously damaged.

FIG. 2, the results of the Mahalanobis staining show: in the sham operation group, the lung tissue structure of the mouse is normal, and the alveolar wall is not thickened; the solvent control group, alveolus, pulmonary septum and terminal bronchus and other periphery have hyperplasia collagen fiber, and show fibrosis state; c is 4-20 compound treatment group, compared with solvent control group, the condition is obviously improved, the total content of collagen is reduced, and the fibrosis degree is reduced.

Fig. 3, HE staining results show: in the sham operation group, the lung tissue structure of the mouse is complete and clear, the alveolar wall is not thickened, inflammatory cells are not invaded, and fibroblast proliferation is not caused; in the solvent control group, the pulmonary alveolar structure of the mouse is damaged, the pulmonary alveolar space is widened, a large amount of inflammatory cell infiltration and fibroblast proliferation are caused, and an obvious fibrosis state is presented; the BIBF1120 positive control group has complete and clear lung tissue structure of mice, and is obviously improved compared with a solvent group; a is a 4-22 compound treatment group, compared with a solvent control group, the condition is obviously improved, the pathological change degree is obviously reduced, and the lung parenchyma structure is not obviously damaged.

FIG. 4, the results of Mahalanobis staining show: in the sham operation group, the lung tissue structure of the mouse is normal, and the alveolar wall is not thickened; no collagen deposition; the solvent control group, alveolus, pulmonary septum and terminal bronchus and other periphery have hyperplasia collagen fiber, and show fibrosis state; the BIBF1120 positive control group has complete lung tissue structure of mice, and compared with a solvent group, the collagen deposition phenomenon is obviously reduced and is obviously improved; a is 4-22 compound treatment group, compared with solvent control group, the condition is obviously improved, the total content of collagen is reduced, collagen hyperplasia is reduced, and the fibrosis degree is improved.

The experimental results show that the compounds 4-20(C) and 4-22(A) have the effect of resisting pulmonary fibrosis.

Claims

1. A compound represented by formula I, an optical isomer thereof, a compound or a pharmaceutically acceptable salt of the optical isomer thereof:

the ring B is selected from substituted or unsubstituted 5-to 8-membered aryl.

2. The compound of claim 1, wherein:

when ring a is a substituted phenyl group, it contains at least one substituent selected from the group consisting of: halogen, unsubstituted alkyl, halogen substituted alkyl, unsubstituted alkoxy, halogen substituted alkoxy, hydroxy;

preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: halogen, unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogen substituted C1-C6 alkoxy and hydroxyl;

preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: halogen, unsubstituted C1-C2 alkyl, halogen substituted C1-C2 alkyl, unsubstituted C1-C2 alkoxy, halogen substituted C1-C2 alkoxy and hydroxyl;

preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, hydroxy;

further preferably, the substituted phenyl is selected from:

preferably, the substituted phenyl group contains at least one substituent selected from the group consisting of: fluorine, chlorine, methoxy;

further preferably, the substituted phenyl is selected from:

3. a compound according to claim 1 or 2, characterized in that:

when the ring A is a substituted or unsubstituted six-membered and five-membered aryl group, the six-membered and five-membered aryl group contains 0-2 heteroatoms;

preferably, the six-membered aryl group is phenyl;

in the six-membered and five-membered aryl group, the five-membered aryl group contains at least one heteroatom nitrogen;

preferably, the five-membered aryl group is selected from a substituted or unsubstituted imidazolyl, oxazolyl or pyrrolyl;

preferably, the five-membered aryl group is selected from

Wherein R is₄～R₉Independently selected from H, substituted or unsubstituted alkyl;

preferably, R₄～R₉Independently selected from H, unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl;

preferably, R₄～R₉Independently selected from H, methyl or ethyl;

preferably, R₅Selected from H, methyl or ethyl, R₄、R₆、R₇、R₈、R₉Are all H;

4. a compound according to any one of claims 1 to 3, characterized in that:

R₁、R₂、R₃independently selected from H, halogen, unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl;

preferably, R₁、R₂、R₃Independently selected from H, halogen or unsubstituted C1-C3 alkyl;

preferably, R₁、R₂、R₃Independently selected from H, fluoro, chloro or methyl;

further preferably, R₂Selected from H, fluoro, chloro or methyl, R₁、R₃Are all H;

further preferably, R₂Selected from H or methyl, R₁、R₃Are all H.

5. The compound according to any one of claims 1 to 4, wherein:

the ring B is selected from substituted or unsubstituted 5-6 membered aryl;

preferably, the aryl group contains 0 to 2 heteroatoms;

preferably, the heteroatom is nitrogen;

6. The compound of claim 5, wherein:

when ring B is a substituted 6-membered aryl group, it contains at least one substituent selected from the group consisting of: halogen, unsubstituted alkyl, halogen-substituted alkyl, unsubstituted alkoxy, halogen-substituted alkoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 6, R₁₁、R₁₂Independently selected from substituted or unsubstituted alkyl, or, R₁₁And R₁₂Are connected to form an alicyclic ring;

preferably, when ring B is a substituted 6-membered aryl group, it contains at least one substituent selected from the group consisting of: halogen, unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted C1-C6 alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 6, R₁₁、R₁₂Independent selectionFrom substituted or unsubstituted C1-C6 alkyl, or, R₁₁And R₁₂Are linked to form a 6-membered alicyclic ring;

preferably, when ring B is a substituted 6-membered aryl group, it contains at least one substituent selected from the group consisting of: halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from substituted or unsubstituted C1-C6 alkyl, X is selected from- (CH)₂)_n-, -C (═ O) -or-SO₂N is an integer of 0 to 3, R₁₁、R₁₂Independently selected from substituted or unsubstituted C1-C6 alkyl, or, R₁₁And R₁₂Are linked to form a 6-membered alicyclic ring, said 6-membered alicyclic ring containing 2 heteroatoms;

preferably, when ring B is a substituted 6-membered aryl group, it contains only one substituent selected from the group consisting of: -C (═ O) OR₁₀、-X-NR₁₁R₁₂Wherein R is₁₀Selected from unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl, and X is selected from- (CH)₂)_n-or-C (═ O), n is an integer from 0 to 3, R₁₁、R₁₂Independently selected from unsubstituted C1-C6 alkyl or halogen substituted C1-C6 alkyl, or R₁₁And R₁₂Are connected to form a 6-membered alicyclic ring, wherein the 6-membered alicyclic ring contains 2 heteroatoms, and the heteroatoms are nitrogen or oxygen;

further preferably, R₁₀Is unsubstituted C1-C6 alkyl;

further preferably, R₁₀Is methyl;

further preferably, n is 0 or 1;

further preferably, R₁₁、R₁₂Independently selected from unsubstituted C1-C6 alkyl, or, R₁₁And R₁₂Linked to form a substituted or unsubstituted morpholinyl, piperazinyl;

further preferably, R₁₁、R₁₂Are both methyl;

further preferably, said substituted morpholinyl, piperazinyl contains at least one substituent selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl;

further preferably, said substituted morpholinyl, piperazinyl contains at least one substituent selected from the group consisting of: methyl, tert-butoxycarbonyl;

further preferably, R₁₁And R₁₂Are connected to form

Wherein R is₁₃、R₁₅Independently selected from H or methyl, R₁₄Selected from H, methyl or tert-butyloxycarbonyl;

7. the compound of claim 5, wherein: when ring B is an unsubstituted 6-membered aryl group, is selected from

8. The compound of claim 5, wherein:

ring B is substituted pyrazolyl containing at least one substituent selected from the group consisting of: unsubstituted alkyl, halogen substituted alkyl, hydroxy substituted alkyl;

preferably, the substituted pyrazolyl contains at least one substituent selected from the group consisting of: unsubstituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, hydroxyl substituted C1-C6 alkyl;

preferably, the substituted pyrazolyl contains only one substituent which is a hydroxy-substituted C1-C6 alkyl group;

preferably, the substituted pyrazolyl contains only one substituent which is

Further preferably, ring B is

9. The compound according to any one of claims 1, 5 to 8, wherein: ring B is selected from:

10. a compound according to any one of claims 1 to 9, characterized in that: the compound is selected from:

11. a process for producing a compound, an optical isomer thereof, a pharmaceutically acceptable salt of the compound or the optical isomer thereof according to any one of claims 1 to 10, characterized in that: the method comprises the following steps:

preferably, Y is bromo;

preferably, R₁₆、R₁₇Independently selected from H or unsubstituted C1-C6 alkyl, or, R₁₆And R₁₇Are linked to form a 5-membered alicyclic ring;

further preferably, compound 2 is

the nitrite is

preferably, R₁₈Is unsubstituted C1-C6 alkyl;

further preferably, R₁₈Is isoamyl;

preferably, R₂₁Is unsubstitutedC1-C6 alkyl;

further preferably, R₂₁Is methyl;

c. removing acyl from the intermediate II to obtain an intermediate III:

d. halogenating the intermediate III to obtain an intermediate IV:

preferably, Z is iodine;

wherein R is₁₉、R₂₀Independently selected from H, substituted or unsubstituted alkyl, or, R₁₉And R₂₀Are connected to form an alicyclic ring;

preferably, R₁₉、R₂₀Independently selected from H or unsubstituted C1-C6 alkyl, or, R₁₉And R₂₀Are linked to form a 5-membered alicyclic ring;

further preferably, compound 3 is

12. The method of claim 11, wherein: at least one of the following is satisfied:

the reaction temperature of the step a is 90-110 ℃;

the reaction time of the step a is 5-10 h;

step a at N₂Reacting under protection;

the alkali in the step b is potassium acetate;

the reaction solvent in the step b is toluene;

adding nitrite into the step b, and performing reflux reaction for 4-8 hours;

c, reacting under an acidic condition;

preferably, hydrochloric acid is added into the reaction system in the step c;

preferably, step c adds 6n hcl to the reaction system;

the reaction solvent in the step c is an alcohol solvent;

preferably, the reaction solvent of step c is methanol;

c, performing reflux reaction for 1-2 h;

the reaction solvent in the step d is DMF;

the reaction temperature of the step d is 25-80 ℃;

the reaction time of the step d is 2-10 hours;

the reaction temperature of the step e is 90-110 ℃;

the reaction time of the step e is 5-10 hours;

step e in N₂And (4) reacting under protection.

13. Use of the compound, the optical isomer thereof, the compound or the pharmaceutically acceptable salt of the optical isomer thereof according to any one of claims 1 to 10 for preparing FGFR kinase inhibitor drugs; preferably, the medicament is an FGFR1, FGFR2 and/or FGFR3 kinase inhibitor.

14. Use of a compound, an optical isomer thereof, a pharmaceutically acceptable salt of the compound or the optical isomer thereof according to any one of claims 1 to 10 for the preparation of a medicament for the treatment and/or prevention of cancer; preferably, the cancer is breast cancer, lung cancer or stomach cancer; further preferably, the lung cancer is non-small cell lung cancer.

15. Use of a compound, an optical isomer thereof, a pharmaceutically acceptable salt of the compound or the optical isomer thereof according to any one of claims 1 to 10 for the preparation of a medicament for treating and/or preventing organ fibrosis; preferably, the organ fibrosis is pulmonary fibrosis or liver fibrosis.

16. A pharmaceutical composition characterized by: the compound, the optical isomer thereof, the compound or the pharmaceutically acceptable salt of the optical isomer thereof as claimed in any one of claims 1 to 10 is used as an active ingredient, and pharmaceutically acceptable auxiliary materials or auxiliary ingredients are added to prepare the preparation; preferably, the formulation is an oral formulation or an injectable formulation.