HK40034445B - Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof - Google Patents

Description

Cyclopyrazolone formamide compound and preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a fused pyrazolone formamide compound, a preparation method thereof, a medicinal composition containing the compound and an application of the fused pyrazolone formamide compound as an AXL inhibitor, especially a medicament for treating tumors.

Background

Malignant tumors have become one of the major diseases that seriously threaten human health. The 2014 world cancer report indicates that the global cancer burden is rapidly increasing, and the Chinese new cancer cases are higher in the first place of the world, wherein the number of new cases in 2012 is about 306 ten thousand and causes about 220 ten thousand deaths, and the new cases account for about 20% of the global total amount and about 25% of the deaths respectively. At present, tumors exceed cardiovascular diseases, gradually rise to be the leading cause of death, cause great physiological and psychological pains to patients, and bring great economic burden to families and countries of patients. Although many anti-tumor drugs are currently marketed, malignant tumors still have serious diseases which are difficult to overcome up to now, and particularly, the problems of drug resistance and the like occur.

Compared with the traditional cytotoxic chemotherapeutic drugs, the micromolecular tyrosine kinase-targeted antitumor drug has become a hotspot of antitumor drug research at present due to the characteristics of excellent specificity and effectiveness, better patient tolerance, relatively fewer toxic and side effects and the like. Receptor Tyrosine Kinases (RTKs) are a class of cell surface transmembrane protein receptors with endogenous RTK activity whose structure includes an extracellular ligand binding domain, a transmembrane domain, and an intracellular kinase domain that regulate normal cellular processes, including survival, growth, differentiation, adhesion, and motility, by transducing signals from the extracellular environment to the cytoplasm and nucleus. At present, 58 receptor tyrosine kinases have been found, and can be divided into 20 subfamilies according to the homology of the amino acid sequences of the kinase domains and the similarity of the extracellular structures. Among them, AXL receptor is one of the receptor tyrosine kinase subfamily members, which was first found in human chronic myelogenous leukemia, and together with Tyro3 (Etk 2 or Tif) and Mer (aka Nyk, eyk or Tyro 12) constitutes receptor tyrosine kinase subfamily (TAM family). AXL, through its binding to its ligand Gas6, leads to kinase superfamily activation, playing an important role in regulating and controlling inflammatory immune response, maintaining the steady state of phagocytosis of the body, regulating the differentiation and maturation of NK cells, and the like. At present, the high expression of AXL is found in various solid tumors, including lung cancer, breast cancer, liver cancer, pancreatic cancer, prostatic cancer and the like, and is closely related to tumor recurrence and poor prognosis. AXL is abnormally expressed and activated to antagonize tumor cell apoptosis, promote tumor cell invasion and metastasis, promote tumor angiogenesis and promote tumor development. Of particular concern, recent studies have shown that high expression of AXL may mediate acquired resistance to EGFR, and clinical studies indicate that high expression of AXL is present in up to 20% of EGFR-resistant patients; preclinical studies have shown that combinations of AXL inhibitors can effectively overcome EGFR inhibitor resistance. In addition, the abnormal activation of AXL overexpression is also closely related to the drug resistance of other targeted inhibitors and chemotherapeutic drugs, and the fact that AXL may have wide application space of combined drugs is suggested. Unlike other kinases, AXL is highly expressed in macrophages, dendritic cells in the tumor microenvironment, and can synergistically promote tumor progression through interaction with tumor cells and other stromal cells. Therefore, in recent years, the development of targeted AXL inhibitors has become the frontier and hotspot of research on antitumor drugs.

Currently, there are up to 32 AXL inhibitors in development, with 25 small molecule inhibitors. The compound BGB324 developed by BergenBio is the only Axl kinase inhibitor reported to have high selectivity at present, but actually has strong inhibition on the family members Mer and Tyro-3, ABL, insR, EGFR, HER-2 and PDGFR beta. The preclinical research results show that the BGB324 has better pharmacological and toxicological properties, and can prevent breast cancer metastasis and prolong the survival period in two metastatic breast cancer mouse models; AXL signaling, which is capable of regulating metastasis of breast cancer and the like at multiple levels in tumor cells and tumor stromal cells, has been currently in clinical II studies. Although other clinical studies or compounds on the market have strong inhibitory effect on AXL, such as Cabozantinib, BMS777607, ninetinib and the like, the compounds are small molecule receptor tyrosine kinase inhibitors targeting other targets, have low selectivity on AXL, and belong to non-selective kinase inhibitors of multiple targets.

In view of the above, there is a lack in the art of a class of small molecule inhibitors that selectively target AXL kinase.

Disclosure of Invention

The invention aims to provide a class of small molecule inhibitors which selectively target AXL kinase.

The invention provides a cyclo-pyrazolone formamide compound with a structure shown in the following general formula I, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof:

wherein:

n is an integer of 0 to 2, preferably 0 or 1;

x, Y and Z are CH or N;

R ¹ and R ² Each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl radical, C ₂ -C ₆ Alkenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, and-O [ (CH) ₂ ) _q O] _r R ³ (ii) a Wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkoxycarbonyl group, C ₃ -C ₈ Cycloalkyl, halogen substituted C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, sulfonyl, C ₆ -C ₁₀ Aryl, and 3-12 membered heterocyclyl;

R ³ selected from hydrogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, and hydroxymethyl;

q is 1,2, 3 or 4;

r is 0, 1,2, 3 or 4;

or two R ¹ And the adjacent carbon atoms thereof together form a group selected from the group consisting of: a benzene ring, a 5-8 membered heteroaromatic ring;

or two R ² And the adjacent carbon atoms thereof together form a group selected from the group consisting of: a phenyl ring, a 5-8 membered heteroaromatic ring;

the ring is selected from the group consisting of: substituted or unsubstituted 7-20 membered polycyclic heterocycle, substituted or unsubstituted 7-20 membered polycyclic aromatic ring, substituted or unsubstituted 7-20 membered polycyclic aromatic heterocycle, wherein, said substitution means that the hydrogen atom on the group is substituted by 1,2, 3 or 4 substituents selected from the group consisting of: deuterium (D), tritium (T), halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, substituted or unsubstituted C ₃ -C ₈ Epoxyalkyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkylaminoalkyl, cyano, nitro, amino (preferably C) ₁ -C ₆ Amino), hydroxy, hydroxymethyl, carboxy, C ₆ -C ₁₀ Aryl radical, C ₆ -C ₁₀ An aryloxy group, a substituted or unsubstituted 3-12 membered heterocyclyl group, a substituted or unsubstituted 3-12 membered heterocyclyloxy group, and a substituted or unsubstituted 3-12 membered heterocyclylamino group; wherein, the aromatic heterocycle (base) and the heterocycle (base) respectively and independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; or two adjacent substituents together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S;

s is selected from the group consisting of: 0.1, 2,3 or 4;

ar is selected from the group consisting of: substituted or unsubstituted C ₆ -C ₁₂ Aryl, substituted or unsubstituted 5-12 membered heteroaryl;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkoxycarbonyl, halogen-substituted C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy.

In another preferred embodiment, in the present invention, the halogen is F, cl, br or I.

In another preferred embodiment, R ¹ And R ² Each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, cyano, hydroxy, carboxy; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkoxycarbonyl, cyano, amino, hydroxy, hydroxymethyl, carboxy; or two R ¹ And the adjacent carbon atoms thereof together form a group selected from the group consisting of: a benzene ring, a 5-8 membered heteroaromatic ring;

in another preferred embodiment, wherein,the ring is selected from the group consisting of:

wherein R is ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² Each of 1 to 4 substituents selected from the group consisting of: H. d, T halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, substituted or unsubstituted C ₃ -C ₈ Epoxyalkyl, substituted or unsubstituted C ₃ -C ₈ Cycloaminoalkyl, cyano, nitro, amino (preferably C) ₁ -C ₆ Amino), hydroxy, hydroxymethyl, carboxy, substituted or unsubstituted C ₆ -C ₁₀ Aryl, substituted or unsubstituted C ₆ -C ₁₀ Aryloxy, substituted or unsubstituted C ₆ -C ₁₀ Arylamine, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted 3-12 membered heterocyclyloxy, and substituted or unsubstituted 3-12 membered heterocyclylamino; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

In another preferred embodiment, R is ¹ And R ² Each independently is 1 to 3 substituents selected from the group consisting of: hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, cyano, hydroxy; or two R ¹ The carbon atoms adjacent thereto and the atoms to which they are attached may together form a group selected from: a benzene ring, a 5-to 8-membered heteroaromatic ring.

In another preferred embodiment, R is ¹ Each independently is 1 to 3 substituents selected from the group consisting of: fluoro, chloro, bromo, iodo, methoxy, trifluoromethyl, or two R ¹ With it as well asThe adjacent carbon atoms together form a benzene ring.

In another preferred embodiment, R is ² Each independently is 1 to 3 fluorines.

In another preferred embodiment, theThe ring is selected from the group consisting of:

in another preferred embodiment, R ⁴ 、R ⁵ Each of 1 to 4 substituents selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted 3-12 membered heterocyclyloxy, and substituted or unsubstituted 3-12 membered heterocyclylamino; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

In another preferred embodiment, ar is substituted or unsubstituted C ₆ -C ₁₂ And (4) an aryl group.

In another preferred embodiment, the cyclo-pyrazolone formamide compound is a compound DC621001-DC621108 shown in the embodiment.

In a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, said process comprising the steps of:

reacting a compound of formula 1-8 with a compound of formula 2-4 in an inert solvent to provide a compound of formula I.

In another preferred embodiment, the compounds of formulae 1-8 are prepared by the following process:

(b1) Reacting a compound of formula 1-5 in an inert solvent to obtain a compound of formula 1-6;

(b2) Reacting a compound of formula 1-6 in an inert solvent to obtain a compound of formula 1-7;

(b3) The compounds of formulae 1-7 are reacted in an inert solvent to give compounds of formulae 1-8.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I as described in the first aspect of the invention, or one or more of a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixtures thereof, optionally together with a pharmaceutically acceptable carrier, excipient, adjuvant and/or diluent.

In a fourth aspect of the invention, there is provided a kinase inhibitor, said inhibitor comprising: an inhibiting effective amount of one or more of a compound of formula I as described in the first aspect of the invention, or a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixtures thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant and/or diluent; and the kinase is selected from the group consisting of: AXL, c-Met, or a combination thereof.

In a fifth aspect of the invention, there is provided the use of a compound of formula I as described in the first aspect of the invention for one or more aspects selected from the group consisting of: (i) Treating or preventing a disease associated with kinase activity or expression; (ii) Inhibiting the activity of the kinase, or reducing the expression level of the kinase; (iii) Preparing a pharmaceutical composition for treating or preventing a disease associated with kinase activity; (iv) preparation of a kinase inhibitor;

wherein the kinase is selected from the group consisting of: AXL, c-Met, or a combination thereof.

In another preferred embodiment, the disease is a tumor, preferably a tumor selected from the group consisting of: lung cancer, gastric cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, prostate cancer, thyroid cancer, esophageal cancer, head and neck cancer, melanoma, glioma, acute myelogenous leukemia, and the like.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows the zymogram selectivity of compound DC 621044.

Detailed Description

The inventor designs and prepares a fused ring pyrazolone formamide compound with a novel structure through long-term and intensive research. The compounds can selectively inhibit kinases such as AXL, c-Met, and the like. Based on the above findings, the inventors have completed the present invention.

The invention aims to provide a fused pyrazolone formamide compound shown in a general formula I, and pharmaceutically acceptable salts, racemes, R-isomers, S-isomers or mixtures thereof.

The invention also aims to provide a preparation method of the cyclo-pyrazolone formamide compound shown in the general formula I.

Still another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the fused pyrazolone carboxamides represented by the above general formula I, pharmaceutically acceptable salts thereof, racemates, R-isomers, S-isomers and mixtures thereof.

Still another object of the present invention is to provide an AXL inhibitor comprising one or more selected from the group consisting of the fused pyrazolone carboxamides represented by the above general formula I, pharmaceutically acceptable salts thereof, racemates, R-isomers, S-isomers and mixtures thereof.

The invention also aims to provide the cyclo-pyrazolone formamide compound shown in the general formula I, and pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof for treating malignant tumor diseases.

Term(s) for

In the present invention, unless otherwise specified, the terms used have the ordinary meaning known to those skilled in the art.

In the present invention, the term "C ₁ -C ₆ Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.

In the present invention, the term "C ₁ -C ₆ Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

In the present invention, the term "C ₂ -C ₆ The alkenyl group "means a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, but is not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

In the present invention, the term "C ₂ -C ₆ Alkynyl "refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

In bookIn the present invention, the term "C ₃ -C ₈ Cycloalkyl "refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like. Other "cycloalkyl" terms have similar meanings.

In the present invention, the term "C ₆ -C ₁₀ Aryl "refers to an aromatic ring group having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring. The term "C ₆ -C ₁₂ Aryl "has a similar meaning.

Cyclopyrazolone carboxamides

The invention provides a cyclo-pyrazolone formamide compound with a structure shown in the following general formula I, and a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof:

in a more preferred embodiment of the invention, the compounds of formula I of the invention are preferably the following specific compounds:

the invention provides a medicinal salt of a compound shown in a general formula I, and particularly relates to a conventional medicinal salt formed by reacting the compound shown in the general formula I with an inorganic acid or an organic acid. For example, conventional pharmaceutically acceptable salts may be prepared by reacting a compound of formula I with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or sodium, potassium, calcium, aluminum or ammonium salts of compounds of formula I with inorganic bases; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound in the general formula I and organic base.

In another aspect, the present invention provides a method for preparing a compound represented by formula I, which is performed according to scheme 1, scheme 2 or scheme 3 below.

Scheme 1:

wherein R is ¹ 、R ² X, Y, Z and n are as defined above for formula I.

Step a: dissolving 1-1 (1 equiv) in appropriate amount of DCM, and adding 10% Na ₂ CO ₃ Aqueous solution (2 equiv), then 1-2 (1.1 equiv) was added dropwise with stirring at 0 ℃. The reaction was allowed to warm to room temperature and stirred overnight;

step b: dissolving 1-3 (1 equiv) in appropriate amount of DCM, and adding anhydrous Na ₂ CO ₃ (2 equiv), then stirring and dropwise adding 1-4 (2 equiv), and stirring and reacting at room temperature overnight;

step c: dissolving 1-5 (1 equiv) in a proper amount of DMF, then slowly adding NaH (3 equiv) under stirring at 0 ℃, reacting and moving to room temperature, and stirring for 5 hours;

step d: dissolving 1-6 (1 equiv) in proper amount of DBU (4 equiv), heating to 50 ℃, stirring and heating for 5h;

step e: dissolving 1-7 (1 equiv) in an appropriate amount of EtOH, and adding 2N KOH aqueous solution (3 equiv); reflux was stirred for 2h and then acidified.

Step f: dissolving 2-1 (1 equiv) in appropriate amount of DMF, adding 2-2 (1.2 equiv), K ₂ CO ₃ (2.5 equiv); then heating to 100 ℃, stirring and heating until the reaction is finished; the alkali can be potassium carbonate or potassium tert-butoxide, the temperature is 80-130 deg.C, and the time is 12-36h;

step g: dissolving 2-3 (1 equiv) in a proper amount of EtOH/H ₂ Adding iron powder (5 equiv) and NH into O (1: 1) ₄ Cl (5 equiv) and then stirred at reflux for 2h.

Step h: 1-8 (1 equiv), 2-3 (1.05 equiv) were dissolved in an appropriate amount of DCM, HATU (1.5 equiv), DIPEA (2 equiv) were added, and then stirred at room temperature overnight.

Scheme 2:

wherein R is ¹ 、R ² X, Y, Z and n are as defined above for formula I.

Step f: dissolving 3-1 (1 equiv) in a proper amount of DMF, stirring at 0 ℃ and slowly adding NaH (3 equiv), stirring for half an hour, then adding 3-2 (1.1 equiv), then moving to room temperature, and stirring until the reaction is finished;

steps a-e, g-h: the specific operation is the same as in scheme 1 above.

Scheme 3:

wherein R is ¹ 、R ² X, Y, Z and n are as defined above for formula I.

Step f: dissolving 4-1 (1 equiv) in an appropriate amount of PhCl, adding 4-2 (1.1 equiv), and stirring and refluxing at 140 ℃ overnight;

steps a-e, g-h: the specific operation is the same as in scheme 1 above.

Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I) above, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners, and the like.

The pharmaceutical composition provided by the invention preferably contains 1-99% by weight of active ingredients, the preferred proportion is that the compound of the general formula I is taken as the active ingredient and accounts for 65-99 wt% of the total weight, and the rest is pharmaceutically acceptable carriers, diluents or solutions or salt solutions.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the formulation thereof usually contains 0.05-400mg of the compound of the formula I, preferably 1-300 mg of the compound of the formula I.

The compounds and pharmaceutical compositions of the present invention may be administered to mammals in the clinical setting, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably oral. Most preferably, the daily dose is 0.01-400mg/kg body weight, and is administered once or in portions of 0.01-200mg/kg body weight. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.

The invention also provides an AXL kinase inhibitor, which comprises one or more compounds selected from the compounds shown in the general formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents.

The compounds and compositions of the invention are useful for the treatment and prevention of malignancies associated with the AXL kinase pathway.

Therefore, the invention also provides a compound shown in the general formula I, and pharmaceutically acceptable salts, racemes, R-isomers, S-isomers or mixtures thereof for preparing a medicament for treating malignant tumors related to the AXL kinase pathway.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.

Example 1N- (4- ((6,7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621001)

1.1 Synthesis of 5-chloro-N' -phenyl valeryl hydrazide

10g of phenylhydrazine and 10% of Na are added into a 500mL eggplant-shaped bottle ₂ CO ₃ After stirring the aqueous solution (180 mL) and 200mL of DCM at 0 ℃ for 10min, 5-chlorovaleryl chloride (11.85 mL) was added dropwise, and after the addition was complete, the mixture was stirred at that temperature for 10min, then allowed to warm to room temperature and stirred overnight. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the organic layer was separated, the aqueous layer was extracted with 100mL of DCM 3 times, the organic layers were combined, and the organic layer was washed with saturated brine, anhydrous Na ₂ SO ₄ Drying, suction filtering, spin drying the filtrate to obtain 16g of reddish brown oily liquid. LRMS (EI) m/z:227 (M + H) ⁺ (without purification, can be directly put into the next step)

1.2 Synthesis of ethyl 3- (2- (5-chlorovaleryl) -1-phenylhydrazino) -3-oxopropanoate

1lg 5-chloro-N' -phenylpentanohydrazide was dissolved in 250mL of DCM, and 15.0g of anhydrous Na was added ₂ CO ₃ A solution of 60mL ethyl chloroformylacetate (19.0 mL) in DCM was added dropwise with stirring at room temperature, and after the addition was completed, the mixture was stirred at room temperature overnight. By thin sheetsThe reaction was monitored by layer chromatography (TLC). After the reaction, the reaction solution was filtered with celite, the solid was washed with appropriate amount of water and DCM, the organic layer was separated from the filtrate, the aqueous layer was extracted with 100mL of DCM 3 times, the organic layers were combined, and the organic layer was washed with saturated brine successively and anhydrous Na ₂ SO ₄ Drying, suction filtering and spin drying the filtrate to obtain 17g of yellow oily liquid. LRMS (EI) m/z:341 (M + H) ⁺ (without purification, can be directly put into the next step)

1.3 Synthesis of ethyl 3-oxo-3- ((2-oxopiperidin-1-yl) (phenyl) amino) propionate

17g of ethyl 3- (2- (5-chlorovaleryl) -1-phenylhydrazino) -3-oxopropanoate was dissolved in 250mL of DMF and stirred at 0 ℃ for 10min, then 6.0g of NaH was added slowly and after the addition was complete, the mixture was stirred at this temperature for 10min and then allowed to warm to room temperature for 5h. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, saturated NaH is used for the reaction liquid ₂ PO ₄ Adjusting pH to 7, filtering, diluting the filtrate with large amount of water, extracting with 100mL EA for 3 times, combining the organic layers, washing the organic layer with saturated brine, and extracting with anhydrous Na ₂ SO ₄ Drying, suction filtering and spin drying the filtrate to obtain 14g of yellow oily liquid. LRMS (EI) m/z:305 (M + H) ⁺ (without purification, can be directly put into the next step)

1.4 Synthesis of ethyl 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxylate

14g of ethyl 3-oxo-3- ((2-oxopiperidin-1-yl) (phenyl) amino) propionate was dissolved in 35mL DBU, which was then warmed to 50 ℃ and heated with stirring for 5h. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, saturated NaH is used for the reaction liquid ₂ PO ₄ The pH was adjusted to 7, and then extracted 3 times with 100mL of DCM, and the organic layers were combined and washed successively with saturated brineAnhydrous Na ₂ SO ₄ Drying, suction filtering and spin drying the filtrate to obtain 12g of yellow oily liquid. LRMS (EI) m/z:287 (M + H) ⁺ (without purification, can be directly put into the next step)

1.5 Synthesis of 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxylic acid

12g of 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a]Pyridine-3-carboxylic acid ethyl ester was dissolved in 100mL EtOH, and 58mL of 2N KOH aqueous solution was added, followed by stirring and refluxing for 2h. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, firstly, part of EtOH is removed by spinning, then EA is used for extracting reaction liquid, then 2N HCl is used for adjusting the pH value of an aqueous layer to 3, a brown solid is separated out, and the filtration is carried out to obtain 10g of solid. LRMS (EI) m/z:259 (M + H) ⁺

1.6 Synthesis of 4- (2-fluoro-4-nitrophenoxy) -6,7-dimethoxyquinoline

5g of 4-chloro-6,7-dimethoxyquinoline, 4.2g of 2-fluoro-4-nitrophenol and 7.69g of g K are added into a 100mL eggplant-shaped bottle ₂ CO ₃ And 50mL of DMF, followed by stirring at 100 ℃ overnight. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, a large amount of water was added to the reaction solution to precipitate a yellow solid, which was then filtered under suction to obtain 6.5g of a solid. LRMS (EI) m/z:345 (M + H) ⁺

1.7 Synthesis of 4- ((6,7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline

6.5g of 4- (2-fluoro-4-nitrophenoxy) -6,7-dimethoxyquinoline are dissolved in 80mL EtOH/H ₂ O (1: 1), 5.26g of iron powder and 5.03g of NH were added ₄ Cl, then stirred at reflux for 2h. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered through celite, the solid was washed with an appropriate amount of EA, the filtrate was separated into an organic layer, the aqueous layer was extracted with 100mL of EA for 3 times, the organic layers were combined, and the organic layer was washed with saturated brine sequentially and anhydrous Na ₂ SO ₄ Drying, suction filtering and spin drying the filtrate to obtain 5g of yellow solid. LRMS (EI) m/z:315 (M + H) ⁺ (without purification, can be directly put into the next step)

1.8 Synthesis of the end product DC621001

Into a 25mL eggplant-shaped bottle was added 100mg of 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a]Pyridine-3-carboxylic acid, 128mg 4- ((6,7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline, 221mg HATU,0.16mL DIPEA and 15mL DCM, then stirred at room temperature overnight. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, the reaction mixture was diluted with 25mL of water, the organic layer was separated, the aqueous layer was extracted with 25mL of DCM for 3 times, the organic layers were combined, and the organic layer was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, suction filtering, spin drying the filtrate, purifying to obtain 180mg of white solid with yield of 84%. ¹ HNMR(400MHz，DMSO-d6)δ10.83(s，1H)，8.51(d，J＝5.3Hz，1H)，8.00(dd，J＝13.1，2.3Hz，1H)，7.65-7.38(m，8H)，7.36(dd，J＝9.0，1.8Hz，1H)，6.51(d，J＝5.2Hz，1H)，3.96(s，6H)，3.59(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.04-1.92(m，2H)，1.88-1.78(m，2H).LRMS(EI)m/z：555(M+H) ⁺ .

Example 2N- (6- ((6,7-dimethoxyquinolin-4-yl) oxy) pyridin-3-yl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621002)

2.6 Synthesis of 6,7-dimethoxy-4- ((5-nitropyridin-2-yl) oxy) quinoline

Dissolving 5g of 6, 7-dimethoxyquinoline-4-alcohol in 80mL of DMF, slowly adding 3g of NaH under stirring at 0 ℃, stirring for half an hour, and then addingThen, 3.8g of 2-fluoro-5-nitropyridine was added thereto, and the mixture was allowed to stand at room temperature and stirred. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, a large amount of saturated aqueous ammonium chloride solution was added to the reaction solution to quench excess NaH, the aqueous layer was extracted with 100mL EA 3 times, the organic layers were combined, and the organic layer was washed with saturated brine, anhydrous Na ₂ SO ₄ Drying, suction filtering, and spin drying the filtrate to obtain yellow solid. LRMS (EI) m/z:328 (M + H) ⁺ (the reaction mixture was directly subjected to the next step without purification)

The rest steps are as in example 1, and the product DC621002 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.71(s，1H)，8.55(d，J＝5.1Hz，1H)，8.50(d，J＝2.6Hz，1H)，8.27(dd，J＝8.8，2.7Hz，1H)，7.59(t，J＝7.5Hz，2H)，7.52(d，J＝7.4Hz，1H)，7.46(d，J＝7.3Hz，2H)，7.40(d，J＝13.1Hz，2H)，7.31(d，J＝8.8Hz，1H)，6.84(d，J＝5.2Hz，1H)，3.95(s，3H)，3.88(s，3H)，3.58(t，J＝5.7Hz，2H)，3.20(t，J＝6.1Hz，2H)，2.02-1.93(m，2H)，1.88-1.72(m，2H).LRMS(EI)m/z：538(M+H) ⁺ .

Example 3N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621004)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621004 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.55(s，1H)，7.70(s，1H)，7.68(s，1H)，7.65-7.54(m，3H)，7.52(d，J＝7.3Hz，1H)，7.49-7.44(m，2H)，7.39(s，1H)，7.27(s，1H)，7.25(s，1H)，3.99(s，3H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.4Hz，2H)，2.03-1.95(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：538(M+H) ⁺ .

Example 4N- (4- (imidazo [1,2-a ] pyrazin-8-yloxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621006)

Replacement of 2-fluoro-4-nitrophenol for paranitrophenol, 4-chloro-6,7-dimethoxyquinoline for 8-chloroimidazo [1,2-a]Pyrazine, other required raw materials, reagents and preparation methods are the same as example 1, and a product DC621006 is obtained with a yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.32(d，J＝4.6Hz，1H)，8.16(d，J＝1.0Hz，1H)，7.76(d，J＝1.0Hz，1H)，7.70-7.63(m，2H)，7.62-7.55(m，2H)，7.54-7.43(m，3H)，7.32(d，J＝4.6Hz，1H)，7.28-7.18(m，2H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.3Hz，2H)，2.02-1.94(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：467(M+H) ⁺ .

Example 5N- (4- ([ 1,2,4] triazolo [4,3-b ] pyridazin-6-yloxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621007)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 6-chloro- [1,2,4]Triazolo [4,3-b]Pyridazine, other needed raw materials, reagents and preparation method are the same as example 1, and the product DC621007 is obtained with yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.67(s，1H)，9.40(d，J＝0.6Hz，1H)，8.41(dd，J＝9.8，0.6Hz，1H)，7.73-7.63(m，2H)，7.59(t，J＝7.5Hz，2H)，7.54-7.44(m，3H)，7.34-7.25(m，3H)，3.57(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.03-1.94(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：468(M+H) ⁺ .

Example 6-oxo-1-phenyl-N- (4- (pyrazolo [1,5-a ] pyrimidin-5-yloxy) phenyl) -1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621008)

Replacement of 2-fluoro-4-nitrophenol for paranitrophenol, 4-chloro-6,7-dimethoxyquinoline for 5-chloropyrazolo [1,5-a]The pyrimidine, other needed raw materials, reagents and preparation method are the same as example 1, and the product DC621008 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，9.05(d，J＝7.5Hz，1H)，8.06(d，J＝2.2Hz，1H)，7.67(d，J＝8.9Hz，2H)，7.59(t，J＝7.5Hz，2H)，7.55-7.43(m，3H)，7.21(d，J＝8.9Hz，2H)，6.79(d，J＝7.5Hz，1H)，6.41-6.27(m，1H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.3Hz，2H)，2.04-1.95(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：467(M+H) ⁺ .

Example 7N- (3-fluoro-4- (imidazo [1,2-a ] pyridin-8-yloxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621009)

Replacement of 4-chloro-6,7-dimethoxyquinoline with imidazo [1,2-a]Pyridine-8-alcohol, 2-fluoro-4-nitrophenol is replaced by 1,2-difluoro-4-nitrobenzene, and the other required raw materials, reagents and preparation method are the same as example 2, and the product DC621009 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.75(s，1H)，8.33(d，J＝6.0Hz，1H)，8.03(d，J＝1.1Hz，1H)，8.00-7.88(m，1H)，7.64-7.55(m，3H)，7.54-7.43(m，3H)，7.29-7.16(m，2H)，6.82-6.76(m，1H)，6.52(d，J＝7.5Hz，1H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.02-1.95(m，2H)，1.87-1.79(m，2H).LRMS(EI)m/z：484(M+H) ⁺ .

Example 8N- (6- (imidazo [1,2-a ] pyridin-8-yloxy) pyridin-3-yl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621010)

Replacement of 4-chloro-6,7-dimethoxyquinoline with imidazo [1,2-a]Pyridine-8-alcohol, 2-fluoro-4-nitrophenol is replaced by 2-fluoro-5-nitropyridine, and the other required raw materials, reagents and preparation method are the same as example 2, so that the product DC621010 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.44(dd，J＝6.7，0.9Hz，1H)，8.24(d，J＝2.7Hz，1H)，8.15(dd，J＝8.8，2.7Hz，1H)，7.99(d，J＝1.1Hz，1H)，7.58(t，J＝7.5Hz，2H)，7.54-7.41(m，4H)，7.13(d，J＝8.8Hz，1H)，7.03(dd，J＝7.4，0.8Hz，1H)，6.89(t，J＝7.1Hz，1H)，3.56(t，J＝5.8Hz，2H)，3.19(t，J＝6.3Hz，2H)，2.13-1.94(m，2H)，1.87-1.73(m，2H).LRMS(EI)m/z：467(M+H) ⁺ .

Example 9N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621011)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation method are the same as example 1, and the product DC621011 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.57(s，1H)，7.93(dd，J＝12.9，2.3Hz，1H)，7.63-7.56(m，3H)，7.55-7.46(m，3H)，7.44-7.39(m，2H)，7.31(dd，J＝8.8，1.7Hz，1H)，4.00(s，3H)，3.99(s，3H)，3.59(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.07-1.95(m，2H)，1.89-1.77(m，2H).LRMS(EI)m/z：556(M+H) ⁺ .

Example 10N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621012)

The 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation method are the same as example 1, and the product DC621012 is obtained with the yield of 85%. ¹ HNMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.56(s，1H)，7.93(dd，J＝12.9，2.2Hz，1H)，7.64-7.57(m，3H)，7.55-7.38(m，5H)，7.31(d，J＝10.2Hz，1H)，4.42-4.28(m，4H)，3.85-3.69(m，4H)，3.59(t，J＝5.8Hz，2H)，3.37(s，3H)，3.36(s，3H)，3.22(t，J＝6.1Hz，2H)，2.07-1.95(m，2H)，1.89-1.77(m，2H).LRMS(EI)m/z：644(M+H) ⁺ .

Example 11N- (4- (N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621013)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that a product DC621013 is obtained with the yield of 85%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.54(s，1H)，7.69(d，J＝8.9Hz，2H)，7.63-7.56(m，3H)，7.55-7.44(m，3H)，7.41(s，1H)，7.26(d，J＝8.9Hz，2H)，4.43-4.26(m，4H)，3.81-3.73(m，4H)，3.58(t，J＝5.8Hz，2H)，3.37(s，3H)，3.36(s，3H)，3.23(t，J＝6.3Hz，2H)，2.05-1.94(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：626(M+H) ⁺ .

Example 12N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621014)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621014 is obtained, and the yield is 85%. ¹ HNMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.57(s，1H)，7.93(dd，J＝12.9，2.4Hz，1H)，7.60(t，J＝7.4Hz，3H)，7.53(t，J＝4.0Hz，3H)，7.52-7.41(m 7H)，7.32(d，J＝7.2Hz，1H)，5.37(s，2H)，4.00(s，3H)，3.59(t，J＝5.9Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.04-1.95(m，2H)，1.87-1.79(m，2H).LRMS(EI)m/z：632(M+H) ⁺ .

Example 13N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621015)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 1, so that the product DC621015 is obtained with the yield of 85%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.54(s，1H)，7.73-7.66(m，2H)，7.65-7.57(m，3H)，7.55-7.41(m，8H)，7.39-7.35(m，1H)，7.29-7.23(m，2H)，5.35(s，2H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.3Hz，2H)，2.03-1.94(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z：614(M+H) ⁺ .

Example 14N- (3-fluoro-4- (quinolin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621016)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloroquinoline, and other needed raw materials, reagents and preparationThe method is the same as example 1, and the product DC621016 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.80(s，1H)，8.87(d，J＝2.9Hz，1H)，8.05-7.88(m，3H)，7.70-7.64(m，2H)，7.62-7.54(m，3H)，7.53-7.43(m，3H)，7.40-7.29(m，2H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.04-1.94(m，2H)，1.87-1.78(m，2H).LRMS(EI)m/z：495(M+H) ⁺ .

Example 15N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methoxyphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621017)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621017 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.71(s，1H)，8.51(s，1H)，7.63-7.55(m，3H)，7.54-7.50(m，2H)，7.49-7.45(m，2H)，7.38(s，1H)，7.19(s，2H)，3.99(s，3H)，3.97(s，3H)，3.68(s，3H)，3.58(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.05-1.96(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：568(M+H) ⁺ .

Example 16N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methoxyphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621018)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621018 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.71(s，1H)，8.50(s，1H)，7.62-7.54(m，4H)，7.53-7.44(m，3H)，7.40(s，1H)，7.18(s，2H)，4.39-4.26(m，4H)，3.80-3.73(m，4H)，3.68(s，3H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.23(t，J＝6.3Hz，2H)，2.07-1.93(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：656(M+H) ⁺ .

Example 17N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methylphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621019)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621019 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.52(s，1H)，7.63-7.56(m，4H)，7.55-7.50(m，2H)，7.49-7.45(m，2H)，7.39(s，1H)，7.16(d，J＝8.7Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.3Hz，2H)，2.07(s，3H)，2.02-1.95(m，2H)，1.86-1.79(m，2H).LRMS(EI)m/z：552(M+H) ⁺ .

Example 18N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methylphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621020)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621020 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.51(s，1H)，7.64(s，1H)，7.63-7.56(m，3H)，7.55-7.50(m，2H)，7.49-7.44(m，2H)，7.42(s，1H)，7.16(d，J＝8.7Hz，1H)，4.39-4.29(m，4H)，3.79-3.75(m，4H)，3.57(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.3Hz，2H)，2.07(s，3H)，2.03-1.94(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：640(M+H) ⁺ .

Example 19N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -2-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621021)

3.6 Synthesis of 4- (3-fluoro-4-nitrophenoxy) -6,7-dimethoxyquinazoline

In a 100mL eggplant-shaped bottle, 5g of 4-chloro-6,7-dimethoxyquinoline, 4.2g of 3-fluoro-4-nitrophenol and 50mL of PhCl were added, followed by stirring at 140 ℃ overnight. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, phCl was removed by spinning off, and a yellow solid was precipitated and filtered to obtain 6.5g of a solid. LRMS (EI) M/z 346 (M + H) ⁺

The rest steps are as in example 1, and the product DC621021 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.57(s，1H)，8.50(t，J＝9.0Hz，1H)，7.59(t，J＝7.5Hz，2H)，7.56-7.51(m，2H)，7.50-7.46(m，2H)，7.44-7.39(m，2H)，7.16(d，J＝9.0Hz，1H)，3.99(s，3H)，3.97(s，3H)，3.58(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.04-1.94(m，2H)，1.88-1.78(m，2H).LRMS(EI)m/z：556(M+H) ⁺ .

Example 20- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621022)

2-fluoro-4-nitrophenol is replaced by paranitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 1, so that a product DC621022 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.46(s，1H)，8.55(s，1H)，7.67-7.60(m，4H)，7.59-7.51(m，2H)，7.39(s，1H)，7.26(d，J＝8.9Hz，2H)，3.99(s，3H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.1Hz，2H)，2.06-1.93(m，2H)，1.89-1.75(m，2H).LRMS(EI)m/z：574(M+H) ⁺ .

Example 21- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621023)

Replacing 4-chloro-6,7-dimethoxyquinoline with 4-chloro-6,7-dimethoxyquinazoline and replacing phenylhydrazine with phenylhydrazineThe 2,5-difluorophenylhydrazine is prepared, and the other needed raw materials, reagents and preparation methods are the same as the example 1, so that the product DC621023 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.57(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.69-7.52(m，4H)，7.45-7.37(m，2H)，7.35-7.28(m，1H)，4.00(s，3H)，3.98(s，3H)，3.60(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.05-1.93(m，2H)，1.89-1.75(m，2H).LRMS(EI)m/z：592(M+H) ⁺ .

Example 22- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621024)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621024 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.56(s，1H)，7.92(dd，J＝12.8，2.4Hz，1H)，7.68-7.52(m，5H)，7.44(s，1H)，7.40(d，J＝8.8Hz，1H)，7.35-7.28(m，1H)，4.38-4.31(m，4H)，3.80-3.72(m，4H)，3.53(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.04-1.95(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：680(M+H) ⁺ .

Example 23- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621025)

2-fluoro-4-nitrophenol is replaced by paranitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline), phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621025 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.46(s，1H)，8.54(s，1H)，7.73-7.49(m，6H)，7.41(s，1H)，7.34-7.21(m，2H)，4.37-4.28(m，4H)，3.79-3.73(m，4H)，3.59(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.04-1.93(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z：662(M+H) ⁺ .

Example 24- (2,5-difluorophenyl) -N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621026)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621026 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.56(s，1H)，7.92(dd，J＝12.8，2.3Hz，1H)，7.69-7.59(m，3H)，7.58-7.51(m，4H)，7.47-7.37(m，4H)，7.35-7.29(m，1H)，5.36(s，2H)，3.99(s，3H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.05-1.93(m，2H)，1.87-1.75(m，2H).LRMS(EI)m/z：668(M+H) ⁺ .

Example 25- (2,5-difluorophenyl) -N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621027)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 1, so that the product DC621027 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.46(s，1H)，8.54(s，1H)，7.73-7.49(m，9H)，7.44(t，J＝7.3Hz，2H)，7.41-7.34(m，1H)，7.26(d，J＝8.9Hz，2H)，5.35(s，2H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.1Hz，2H)，2.06-1.91(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：650(M+H) ⁺ .

Example 26- (2,5-difluorophenyl) -N- (3-fluoro-4- (quinolin-4-yloxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621028)

Replacing 4-chloro-6,7-dimethoxyquinoline with 4-chloroquinoline and phenylhydrazine withThe 2,5-difluorophenylhydrazine is prepared, and the other needed raw materials, reagents and preparation methods are the same as example 1, so that the product DC621028 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.87(d，J＝2.9Hz，1H)，8.05-7.91(m，3H)，7.76-7.49(m，6H)，7.45-7.24(m，2H)，3.59(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.04-1.94(m，2H)，1.86-1.75(m，2H).LRMS(EI)m/z：531(M+H) ⁺ .

Example 27- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methoxyphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621029)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621029 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.49(s，1H)，8.51(s，1H)，7.70-7.51(m，5H)，7.38(s，1H)，7.19(s，2H)，3.99(s，3H)，3.97(s，3H)，3.68(s，3H)，3.53(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.03-1.95(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：604(M+H) ⁺ .

Example 28- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methoxyphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621030)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621030 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.49(s，1H)，8.50(s，1H)，7.71-7.51(m，5H)，7.40(s，1H)，7.19(s，2H)，4.43-4.26(m，4H)，3.79-3.71(m，4H)，3.68(s，3H)，3.52(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.2Hz，2H)，2.05-1.93(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z：692(M+H) ⁺ .

Example 29- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methylphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621031)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621031 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.42(s，1H)，8.52(s，1H)，7.70-7.48(m，6H)，7.39(s，1H)，7.16(d，J＝8.7Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.07(s，3H)，2.02-1.95(m，2H)，1.88-1，76(m，2H).LRMS(EI)m/z：588(M+H) ⁺ .

Example 30- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methylphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621032)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621032 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.42(s，1H)，8.52(s，1H)，7.67-7.50(m，6H)，7.42(s，1H)，7.17(d，J＝8.7Hz，1H)，4.39-4.31(m，4H)，3.80-3.73(m，4H)，3.59(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.07(s，3H)，2.01-1.93(m，2H)，1.88-1.72(m，2H).LRMS(EI)m/z：676(M+H) ⁺ .

Example 31N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621033)

2-fluoro-4-nitrophenol is replaced by paranitrophenol, and 4-chloro-substituted benzene6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so as to obtain the product DC621033 with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.55(s，1H)，7.72-7.60(m，4H)，7.58-7.50(m，2H)，7.47-7.41(m，1H)，7.39(s，1H)，7.30-7.23(m，2H)，3.99(s，3H)，3.98(s，3H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.04-1.93(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：556(M+H) ⁺ .

Example 32N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621034)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621034 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.57(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.69-7.60(m，2H)，7.58-7.50(m，2H)，7.47-7.38(m，3H)，7.33-7.28(m，1H)，4.00(s，3H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.02-1.94(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：574(M+H) ⁺ .

Example 33N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621035)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621035 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.56(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.69-7.59(m，3H)，7.54(t，J＝8.7Hz，1H)，7.48-7.38(m，3H)，7.33-7.28(m，1H)，4.42-4.27(m，4H)，3.79-3.72(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.02-1.92(m，2H)，1.85-1.78(m，2H).LRMS(EI)m/z：662(M+H) ⁺ ..

Example 34N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621036)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline), phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 1, so that a product DC621036 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.54(s，1H)，7.71-7.59(m，5H)，7.53(t，J＝9.2Hz，1H)，7.47-7.40(m，2H)，7.26(d，J＝8.9Hz，2H)，4.39-4.24(m，4H)，3.79-3.73(m，4H)，3.53(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.1Hz，2H)，2.03-1.94(m，2H)，1.86-1.76(m，2H).LRMS(EI)m/z：644(M+H) ⁺ .

Example 35N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621037)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621037 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.56(s，1H)，7.92(dd，J＝12.8，2.4Hz，1H)，7.69-7.58(m，3H)，7.57-7.51(m，4H)，7.47-7.35(m，5H)，7.33-7.28(m，1H)，5.36(s，2H)，3.99(s，3H)，3.60(t，J＝5.8Hz，2H)，3.20(t，J＝6.1Hz，2H)，2.02-1.93(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：650(M+H) ⁺ .

Example 36N- (3-fluoro-4- (quinolin-3-yloxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621038)

Replacement of 4-chloro-6,7-dimethoxyquinoline with 4And (3) substituting phenylhydrazine into 2-fluorophenylhydrazine by chloroquinoline, and obtaining a product DC621038 with the yield of 80% by using the rest needed raw materials, reagents and preparation method as in example 1. ¹ HNMR(400MHz，DMSO-d6)δ10.65(s，1H)，8.87(d，J＝2.9Hz，1H)，8.05-7.89(m，3H)，7.70-7.50(m，6H)，7.44(t，J＝7.6Hz，1H)，7.39-7.28(m，2H)，3.54(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.01-1.93(m，2H)，1.86-1.76(m，2H).LRMS(EI)m/z：513(M+H) ⁺ .

Example 37N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methoxyphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621039)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621039 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.51(s，1H)，7.67-7.60(m，2H)，7.53(t，J＝9.0Hz，3H)，7.44(t，J＝7.7Hz，1H)，7.38(s，1H)，7.19(s，2H)，3.99(s，3H)，3.97(s，3H)，3.68(s，3H)，3.50(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.02-1.95(m，2H)，1.84-1.77(m，2H).LRMS(EI)m/z：586(M+H) ⁺ .

Example 38N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methoxyphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621040)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621040 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.50(s，1H)，7.70-7.60(m，2H)，7.58-7.50(m，3H)，7.48-7.38(m，2H)，7.18(s，2H)，4.38-4.27(m，4H)，3.80-3.72(m，4H)，3.68(s，3H)，3.50(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.1Hz，2H)，2.03-1.93(m，2H)，1.86-1.76(m，2H).LRMS(EI)m/z：674(M+H) ⁺ .

Example 39N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methylphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621041)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621041 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.50(s，1H)，8.53(s，1H)，7.69-7.58(m，4H)，7.57-7.49(m，2H)，7.44(t，J＝7.7Hz，1H)，7.39(s，1H)，7.16(d，J＝8.7Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.54(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.07(s，3H)，2.01-1.96(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：570(M+H) ⁺ .

Example 40N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methylphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621042)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621042 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.50(s，1H)，8.52(s，1H)，7.68-7.58(m，4H)，7.56-7.49(m，2H)，7.47-7.40(m，2H)，7.16(d，J＝8.7Hz，1H)，4.40-4.29(m，4H)，3.79-3.73(m，4H)，3.54(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.07(s，3H)，2.02-1.93(m，2H)，1.83-1.77(m，2H).LRMS(EI)m/z：658(M+H) ⁺ .

Example 41N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621043)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621043 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.57(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.69-7.60(m，2H)，7.58-7.50(m，2H)，7.47-7.38(m，3H)，7.33-7.28(m，1H)，4.00(s，3H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.03-1.93(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：574(M+H) ⁺ .

Example 42N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621044)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621044 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.77(s，1H)，8.56(s，1H)，7.92(dd，J＝12.9，2.3Hz，1H)，7.61(s，1H)，7.59-7.50(m，2H)，7.48-7.37(m，4H)，7.34-7.27(m，1H)，4.40-4.29(m，4H)，3.79-3.73(m，4H)，3.56(t，J＝5.7Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.20(t，J＝6.2Hz，2H)，2.01-1.93(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：662(M+H) ⁺ .

Example 43N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621045)

2-fluoro-4-nitrophenol is replaced by p-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline), phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621045 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.65(s，1H)，8.52(d，J＝12.9Hz，1H)，7.71-7.65(m，2H)，7.60(s，1H)，7.57-7.52(m，2H)，7.48-7.39(m，3H)，7.29-7.23(m，2H)，4.45-4.22(m，4H)，3.79-3.74(m，4H)，3.56(t，J＝5.9Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.03-1.94(m，2H)，1.85-1.78(m，2H).LRMS(EI)m/z：644(M+H) ⁺ .

Example 44N- (4- ((7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621046)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7-benzyloxy-6-methoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621046 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.77(s，1H)，8.56(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.59(s，1H)，7.58-7.51(m，5H)，7.47-7.37(m，7H)，7.31-7.21(m，1H)，5.36(s，2H)，3.99(s，3H)，3.56(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.03-1.93(m，2H)，1.85-1.77(m，2H).LRMS(EI)m/z：650(M+H) ⁺ .

Example 45N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methoxyphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621047)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621047 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.51(s，1H)，7.58-7.52(m，4H)，7.48-7.40(m，2H)，7.38(s，1H)，7.21-7.15(m，2H)，3.99(s，3H)，3.97(s，3H)，3.68(s，3H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.02-1.92(m，2H)，1.86-1.74(m，2H).LRMS(EI)m/z：586(M+H) ⁺ .

Example 46N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methoxyphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621048)

2-fluoro-4-nitrophenol is replaced by 2-methoxy-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621048 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.50(s，1H)，7.58-7.51(m，4H)，7.48-7.38(m，3H)，7.18(s，2H)，4.37-4.30(m，4H)，3.81-3.73(m，4H)，3.68(s，3H)，3.56(t，J＝5.7Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.04-1.92(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z：674(M+H) ⁺ .

Example 47N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-methylphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621049)

2-fluoro-4-nitrophenol is replaced by 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621049 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.61(s，1H)，8.52(s，1H)，7.59(d，J＝3.1Hz，2H)，7.57-7.49(m，3H)，7.44(t，J＝8.8Hz，2H)，7.39(s，1H)，7.16(d，J＝8.7Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.07(s，3H)，2.02-1.95(m，2H)，1.85-1.77(m，2H).LRMS(EI)m/z：570(M+H) ⁺ .

Example 48N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-methylphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621050)

Replacing 2-fluoro-4-nitrophenol with 2-methyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline with 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazineThe 4-fluorophenylhydrazine is replaced, and the other needed raw materials, reagents and preparation methods are the same as example 1, so that the product DC621050 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.61(s，1H)，8.51(s，1H)，7.64(s，1H)，7.59(d，J＝2.3Hz，1H)，7.58-7.50(m，3H)，7.48-7.40(m，3H)，7.16(d，J＝8.7Hz，1H)，4.38-4.30(m，4H)，3.79-3.73(m，4H)，3.56(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.3Hz，2H)，2.07(s，3H)，2.02-1.95(m，2H)，1.86-1.76(m，2H).LRMS(EI)m/z：658(M+H) ⁺ .

Example 49N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -2-fluorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621051)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation method are the same as example 21, and the product DC621051 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.57(s，1H)，8.50(t，J＝9.0Hz，1H)，7.63-7.56(m，3H)，7.53(d，J＝7.3Hz，1H)，7.51-7.45(m，2H)，7.44-7.39(m，2H)，7.21-7.11(m，1H)，4.40-4.26(m，4H)，3.79-3.73(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.2Hz，2H)，2.03-1.95(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：644(M+H) ⁺ .

Example 50N- (3-fluoro-4- ((5-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621052)

Replacement of 4-chloro-6,7-dimethoxyquinoline with 4-chloro-5-phenyl-7H-pyrrolo [2,3-d]The pyrimidine, other needed raw materials, reagents and preparation method are the same as example 1, and the product DC621052 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ12.54(s，1H)，10.78(s，1H)，8.33(s，1H)，7.89(dd，J＝12.8，2.3Hz，1H)，7.79-7.75(m，3H)，7.59(t，J＝7.5Hz，2H)，7.54-7.44(m，3H)，7.43-7.35(m，3H)，7.30-7.23(m，2H)，3.57(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.03-1.95(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：561(M+H) ⁺ .

Example 51- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621053)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as example 21, so that the product DC621053 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.45(s，1H)，8.52(s，1H)，7.67-7.50(m，6H)，7.42(s，1H)，7.17(d，J＝8.7Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.55(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.01-1.95(m，2H)，1.88-1.74(m，2H).LRMS(EI)m/z：592(M+H) ⁺ .

Example 52- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621054)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621054 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.67(s，1H)，8.57(s，1H)，8.48(t，J＝9.0Hz，1H)，7.69-7.54(m，4H)，7.46-7.39(m，2H)，7.20-7.13(m，1H)，4.38-4.29(m，4H)，3.79-3.73(m，4H)，3.53(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.3Hz，2H)，2.05-1.93(m，2H)，1.89-1.75(m，2H).LRMS(EI)m/z：680(M+H) ⁺ .

Example 53- (2,5-difluorophenyl) -N- (3-fluoro-4- ((5-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621055)

Replacement of 4-chloro-6,7-dimethoxyquinoline with 4-chloro-5-phenyl-7H-pyrrolo [2,3-d]Pyrimidine, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those of example 1, so that the product DC621055 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ12.54(s，1H)，10.55(s，1H)，8.33(s，1H)，7.88(dd，J＝12.8，2.2Hz，1H)，7.82-7.74(m，3H)，7.68-7.53(m，3H)，7.45-7.35(m，3H)，7.28(d，J＝7.5Hz，2H)，3.57(t，J＝5.8Hz，2H)，3.21(t，J＝6.0Hz，2H)，2.07-1.96(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：597(M+H) ⁺ .

Example 54N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -2-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621056)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 21, so that a product DC621056 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.75(s，1H)，8.58(s，1H)，8.50(t，J＝9.0Hz，1H)，7.70-7.60(m，2H)，7.57-7.50(m，2H)，7.47-7.38(m，3H)，7.19-7.14(m，1H)，3.99(s，3H)，3.97(s，3H)，3.52(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.03-1.93(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：574(M+H) ⁺ .

Example 55N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -2-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621057)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621057 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.74(s，1H)，8.57(s，1H)，8.49(t，J＝9.0Hz，1H)，7.69-7.61(m，2H)，7.59(s，1H)，7.58-7.50(m，1H)，7.47-7.39(m，3H)，7.20-7.13(m，1H)，4.38-4.26(m，4H)，3.79-3.73(m，4H)，3.52(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.1Hz，2H)，2.03-1.93(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：662(M+H) ⁺ .

Example 56N- (3-fluoro-4- ((5-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621058)

Replacement of 4-chloro-6,7-dimethoxyquinoline with 4-chloro-5-phenyl-7H-pyrrolo [2,3-d]Pyrimidine, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621058 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ12.54(s，1H)，10.63(s，1H)，8.33(s，1H)，7.88(dd，J＝12.8，2.3Hz，1H)，7.77(d，J＝6.9Hz，3H)，7.70-7.58(m，2H)，7.53(t，J＝8.7Hz，1H)，7.46-7.34(m，4H)，7.27(t，J＝7.4Hz，2H)，3.54(t，J＝5.8Hz，2H)，3.20(t，J＝6.1Hz，2H)，2.02-1.93(m，2H)，1.86-1.76(m，2H).LRMS(EI)m/z：579(M+H) ⁺ .

Example 57N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -2-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621059)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 21, so that a product DC621059 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.75(s，1H)，8.58(s，1H)，8.50(t，J＝9.0Hz，1H)，7.70-7.60(m，2H)，7.57-7.50(m，2H)，7.47-7.38(m，3H)，7.19-7.14(m，1H)，3.99(s，3H)，3.97(s，3H)，3.53(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.03-1.96(m，2H)，1.87-1.75(m，2H).LRMS(EI)m/z：574(M+H) ⁺ .

Example 58N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -4-fluorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621060)

2-fluoro-4-nitrophenol is replaced by 3-fluoro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621060 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.85(s，1H)，8.56(s，1H)，8.50(t，J＝9.0Hz，1H)，7.61-7.50(m，3H)，7.47-7.39(m，4H)，7.21-7.12(m，1H)，4.37-4.29(m，4H)，3.79-3.73(m，4H)，3.56(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.20(t，J＝6.3Hz，2H)，2.03-1.94(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：662(M+H) ⁺ .

Example 59N- (3-fluoro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621061)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]The quinazoline, the other required raw materials, reagents and preparation method are the same as example 1, and the product DC621061 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.80(s，1H)，8.59(s，1H)，7.93(dd，J＝12.9，2.4Hz，1H)，7.83(s，1H)，7.59(t，J＝7.4Hz，2H)，7.54-7.44(m，4H)，7.41(t，J＝8.8Hz，1H)，7.31(dd，J＝8.9，1.5Hz，1H)，4.40-4.30(m，4H)，3.84-3.79(m，2H)，3.76-3.72(m，2H)，3.64(s，4H)，3.58(t，J＝5.9Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.02-1.94(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：642(M+H) ⁺ .

Example 60N- (3-chloro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621062)

2-fluorine-4-Nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]The quinazoline, the other required raw materials, reagents and preparation method are the same as example 1, and the product DC621062 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.79(s，1H)，8.57(s，1H)，8.12(d，J＝2.3Hz，1H)，7.83(s，1H)，7.62-7.56(m，3H)，7.55-7.41(m，5H)，4.41-4.29(m，4H)，3.85-3.79(m，2H)，3.77-3.72(m，2H)，3.65(s，4H)，3.49(t，J＝5.9Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.02-1.95(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：658(M+H) ⁺ .

Example 61- (2,5-difluorophenyl) -N- (3-fluoro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621063)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]Quinazoline, phenyl hydrazine replaced by 2,5-difluorophenyl hydrazine, the other required raw materials, reagents and preparation method are the same as example 1, the product DC621063 is obtained, the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.59(s，1H)，7.92(dd，J＝12.7，1.9Hz，1H)，7.83(s，1H)，7.69-7.50(m，4H)，7.42(t，J＝8.7Hz，1H)，7.32(dd，J＝8.7，1.3Hz，1H)，4.42-4.26(m，4H)，3.84-3.78(m，2H)，3.77-3.70(m，2H)，3.64(s，4H)，3.47(t，J＝5.9Hz，2H)，3.21(t，J＝5.9Hz，2H)，2.04-1.94(m，2H)，1.87-1.77(m，2H).LRMS(EI)m/z：678(M+H) ⁺ .

Example 62- (2,5-difluorophenyl) -N- (3-chloro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621064)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13,14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]And (3) replacing phenylhydrazine with 2,5-difluorophenylhydrazine by quinazoline, and obtaining a product DC621064 with the yield of 80% by using the rest required raw materials, reagents and the preparation method which are the same as those in example 1. ¹ HNMR(400MHz，DMSO-d6)δ10.56(s，1H)，8.57(s，1H)，8.12(d，J＝2.3Hz，1H)，7.83(s，1H)，7.69-7.52(m，4H)，7.50-7.41(m，2H)，4.39-4.30(m，4H)，3.84-3.79(m，2H)，3.77-3.72(m，2H)，3.65(s，4H)，3.49(t，J＝5.9Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.03-1.95(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：694(M+H) ⁺ .

Example 63N- (3-fluoro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621065)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]Quinazoline, the phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the other required raw materials, reagents and preparation methods are the same as example 1, to obtain the product DC621065 with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.59(s，1H)，7.92(dd，J＝12.9，2.1Hz，1H)，7.83(s，1H)，7.73-7.61(m，2H)，7.57-7.51(m，2H)，7.43(dd，J＝18.6，8.4Hz，2H)，7.31(d，J＝8.6Hz，1H)，4.41-4.29(m，4H)，3.85-3.79(m，2H)，3.77-3.72(m，2H)，3.65(s，4H)，3.47(t，J＝5.8Hz，2H)，3.21(t，J＝6.1Hz，2H)，2.04-1.92(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：660(M+H) ⁺ .

Example 64N- (3-chloro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621066)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]Quinazoline, phenylhydrazineThe 2-fluorophenylhydrazine is replaced, and the other needed raw materials, reagents and preparation methods are the same as example 1, so that the product DC621066 is obtained, and the yield is 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.57(s，1H)，8.12(d，J＝2.3Hz，1H)，7.83(s，1H)，7.70-7.59(m，2H)，7.57-7.50(m，2H)，7.49-7.41(m，3H)，4.40-4.29(m，4H)，3.86-3.79(m，2H)，3.78-3.71(m，2H)，3.65(s，4H)，3.48(t，J＝5.8Hz，2H)，3.20(t，J＝6.1Hz，2H)，2.03-1.94(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z：676(M+H) ⁺ .

Example 65N- (3-fluoro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621067)

4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]Quinazoline, replacing phenylhydrazine with 4-fluorophenylhydrazine, the other required raw materials, reagents and preparation method are the same as example 1, and the product DC621067 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.77(s，1H)，8.58(s，1H)，7.92(dd，J＝12.9，2.4Hz，1H)，7.83(s，1H)，7.58-7.52(m，3H)，7.48-7.37(m，3H)，7.33-7.28(m，1H)，4.39-4.31(m，4H)，3.84-3.79(m，2H)，3.77-3.72(m，2H)，3.64(s，4H)，3.56(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.01-1.94(m，2H)，1.87-1.78(m，2H).LRMS(EI)m/z：660(M+H) ⁺ .

Example 66N- (3-chloro-4- ((7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododecane [2,3-g ] quinazolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621068)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10]Tetraoxacyclododecane [2,3-g]Quinazoline, phenyl hydrazine is replaced by 4-fluorophenylhydrazine, the other required raw materials, reagents and preparation method are the same as example 1, the product DC621068 is obtained, the yield is high80％。 ¹ HNMR(400MHz，DMSO-d6)δ10.76(s，1H)，8.57(s，1H)，8.12(d，J＝2.2Hz，1H)，7.83(s，1H)，7.58-7.51(m，3H)，7.49-7.41(m，4H)，4.38-4.30(m，4H)，3.85-3.78(m，2H)，3.77-3.71(m，2H)，3.65(s，4H)，3.56(t，J＝5.8Hz，2H)，3.20(t，J＝6.3Hz，2H)，2.01-1.94(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：676(M+H) ⁺ .

Example 67N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-chlorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621069)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621069 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.79(s，1H)，8.55(s，1H)，8.12(d，J＝2.4Hz，1H)，7.62-7.56(m，3H)，7.54-7.50(m，1H)，7.49-7.41(m，5H)，4.00(s，3H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.02-1.96(m，2H)，1.87-1.79(m，2H).LRMS(EI)m/z：572(M+H) ⁺ .

Example 68N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-chlorophenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621070)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621070 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.46(s，1H)，8.05(s，1H)，7.72(d，J＝2.9Hz，1H)，7.60-7.46(m，3H)，7.41-7.31(m，3H)，7.29-7.23(m，1H)，7.03(d，J＝15.0Hz，1H)，4.43-4.29(m，4H)，3.84-3.67(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.1Hz，2H)，2.06-1.96(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：660(M+H) ⁺ .

Example 69N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621071)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621071 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.45(s，1H)，7.87(s，1H)，7.85(d，J＝3.1Hz，1H)，7.56-7.46(m，3H)，7.41-7.28(m，4H)，6.80(d，J＝15.0Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.06-1.95(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：606(M+H) ⁺ .

Example 70N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621072)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621072 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.46(s，1H)，7.86(d，J＝3.1Hz，1H)，7.77(s，1H)，7.64-7.46(m，2H)，7.44-7.27(m，5H)，6.81(d，J＝15.0Hz，1H)，4.37-4.26(m，4H)，3.80-3.75(m，4H)，3.59(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.3Hz，2H)，2.07-1.93(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：694(M+H) ⁺ .

Example 71N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) naphthalen-1-yl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621073)

Replacing 2-fluoro-4-nitrophenol with 4-nitro-1-naphthol, replacing 4-chloro-6,7-dimethoxyquinoline with 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materialsThe reagents and preparation method are the same as example 21, and the product DC621073 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.45(s，1H)，8.24(dd，J＝14.9，3.0Hz，1H)，7.97(dd，J＝14.8，3.1Hz，1H)，7.80(s，1H)，7.69-7.46(m，3H)，7.44-7.28(m，5H)，6.81(d，J＝15.0Hz，1H)，6.05(d，J＝14.8Hz，1H)，3.99(s，3H)，3.97(s，3H)，3.58(t，J＝5.8Hz，2H)，3.23(t，J＝6.3Hz，2H)，2.03-1.95(m，2H)，1.87-1.78(m，2H).LRMS(EI)m/z：588(M+H) ⁺ .

Example 72N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621074)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 21, so that the product DC621074 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.46(s，1H)，8.25(dd，J＝14.9，3.0Hz，1H)，8.10(s，1H)，7.98(dd，J＝14.9，3.0Hz，1H)，7.68-7.47(m，3H)，7.44-7.30(m，5H)，6.82(d，J＝15.0Hz，1H)，6.06(d，J＝15.0Hz，1H)，4.38-4.27(m，4H)，3.78-3.71(m，4H)，3.56(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.3Hz，2H)，2.04-1.95(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：676(M+H) ⁺ .

Example 73N- (5- (6,7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621075)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 1, so that the product DC621075 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.82(d，J＝15.0Hz，1H)，8.42(s，1H)，8.12(d，J＝2.9Hz，1H)，7.66(s，1H)，7.58-7.41(m，2H)，7.35-7.29(m，4H)，7.28-7.23(m，1H)，3.99(s，3H)，3.98(s，3H)，3.59(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.04-1.94(m，2H)，1.88-1.78(m，2H).LRMS(EI)m/z：539(M+H) ⁺ .

Example 74N- (5- (6,7-bis (2-methoxyethoxy) quinazolin-4-yl) pyridin-2-yl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621076)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621076 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.84(d，J＝14.8Hz，1H)，8.44(s，1H)，8.14(d，J＝3.1Hz，1H)，8.02(s，1H)，7.69(s，1H)，7.55-7.46(m，2H)，7.40-7.24(m，4H)，4.39-4.25(m，4H)，3.78-3.71(m，4H)，3.59(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.02-1.95(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：627(M+H) ⁺ .

Example 75 (R) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621077)

The 4-chloro-6,7-dimethoxyquinoline is replaced by (R) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, and the rest of the required raw materials, reagents and preparation method are the same as example 1, and the product DC621077 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.44(s，1H)，7.81(s，1H)，7.65-7.42(m，3H)，7.39-7.28(m，4H)，7.13(dd，J＝15.0，3.0Hz，1H)，6.84(dd，J＝14.9，10.0Hz，1H)，5.03-4.95(m，1H)，4.23-4.13(m，1H)，4.07-4.01(m，1H)，3.91(s，3H)3.87-3.80(m，1H)，3.78-3.73(m，1H)，3.58(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.44-2.31(m，1H)，2.19-2.10(m，1H)，2.02-1.95(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：612(M+H)+.

Example 76 (S) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621078)

4-chloro-6,7-dimethoxyquinoline is replaced by (S) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, and the other required raw materials, reagents and preparation methods are the same as example 1, and the product DC621078 is obtained with a yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.42(s，1H)，7.82(s，1H)，7.66-7.41(m，3H)，7.37-7.27(m，4H)，7.15(dd，J＝15.0，3.0Hz，1H)，6.86(dd，J＝14.9，10.0Hz，1H)，5.05-4.97(m，1H)，4.21-4.12(m，1H)，4.06-4.02(m，1H)，3.93(s，3H)3.86-3.80(m，1H)，3.77-3.72(m，1H)，3.59(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.45-2.30(m，1H)，2.18-2.11(m，1H)，2.04-1.93(m，2H)，1.85-1.75(m，2H).LRMS(EI)m/z：612(M+H) ⁺ .

Example 77- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-chlorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621079)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as in example 1, so that the product DC621079 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.56(s，1H)，8.56(s，1H)，8.12(d，J＝2.4Hz，1H)，7.68-7.53(m，4H)，7.50-7.45(m，1H)，7.44-7.39(m，2H)，4.00(s，3H)，3.98(s，3H)，3.55(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.04-1.94(m，2H)，1.89-1.76(m，2H).LRMS(EI)m/z：608(M+H) ⁺ .

Example 78- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-chlorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621080)

Replacing 2-fluoro-4-nitrophenol with 2-chloro-4-nitrophenol, and reacting 4-chloro-6,7-dimethoxyquinolineThe quinoline is replaced by 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621080 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.46(s，1H)，8.05(s，1H)，7.72(d，J＝3.1Hz，1H)，7.51(s，1H)，7.26(dd，J＝15.0，2.9Hz，1H)，7.18-7.07(m，1H)，7.05-6.92(m，2H)，6.64-6.54(m，1H)，4.39-4.32(m，4H)，3.82-3.74(m，4H)，3.55(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.24(t，J＝6.2Hz，2H)，2.06-1.97(m，2H)，1.85-1.76(m，2H).LRMS(EI)m/z：696(M+H) ⁺ .

Example 79 1- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621081)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621081 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.46(s，1H)，7.86(d，J＝3.1Hz，1H)，7.76(s，1H)，7.38(dd，J＝14.9，3.0Hz，1H)，7.35(s，1H)，7.16-7.07(m，1H)，7.03-6.95(m，1H)，6.81(d，J＝15.0Hz，1H)，6.67-6.52(m，1H)，3.99(s，3H)，3.98(s，3H)，3.58(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.06-1.95(m，2H)，1.88-1.73(m，2H).LRMS(EI)m/z：642(M+H) ⁺ .

Example 80- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621082)

Replacing 2-fluoro-4-nitrophenol with 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline with 4-chloro-6,7-bis ((2-methoxyethoxy) quinazoline, phenylhydrazine with 2,5-difluorophenylhydrazine, and the rest of required raw materials, reagents and preparationsThe preparation method is the same as example 1, and the product DC621082 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.68(s，1H)，8.45(s，1H)，7.85(d，J＝3.1Hz，1H)，7.79(s，1H)，7.43(s，1H)，7.37(dd，J＝15.0，2.9Hz，1H)，7.17-7.07(m，1H)，7.02-6.93(m，1H)，6.80(d，J＝15.0Hz，1H)，6.63-6.54(m，1H)，4.38-4.30(m，4H)，3.83-3.74(m，4H)，3.58(t，J＝5.7Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.24(t，J＝6.2Hz，2H)，2.05-1.93(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：730(M+H) ⁺ .

Example 81- (2,5-difluorophenyl) -N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) naphthalen-1-yl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621083)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621083 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.42(s，1H)，8.44(s，1H)，8.24(dd，J＝14.9，3.0Hz，1H)，7.97(dd，J＝14.9，3.0Hz，1H)，7.82(s，1H)，7.67-7.55(m，2H)，7.43-7.32(m，1H)，7.17-7.08(m，1H)，7.02-6.93(m，1H)，6.81(d，J＝15.0Hz，1H)，6.63-6.52(m，1H)，6.05(d，J＝15.0Hz，1H)，4.00(s，3H)，3.98(s，3H)，3.56(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.03-1.94(m，2H)，1.89-1，78(m，2H).LRMS(EI)m/z：624(M+H) ⁺ .

Example 82- (2,5-difluorophenyl) -N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) naphthalen-1-yl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621084)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621084 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.42(s，1H)，8.46(s，1H)，8.25(dd，J＝14.9，3.0Hz，1H)，8.10(s，1H)，7.98(dd，J＝14.9，3.1Hz，1H)，7.67-7.58(m，1H)，7.48-7.31(m，2H)，7.18-7.08(m，1H)，7.03-6.94(m，1H)，6.82(d，J＝15.0Hz，1H)，6.64-6.53(m，1H)，6.06(d，J＝15.0Hz，1H)，4.38-4.30(m，4H)，3.80-3.72(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.23(t，J＝6.2Hz，2H)，2.03-1.95(m，2H)，1.85-1.71(m，2H).LRMS(EI)m/z：712(M+H) ⁺ .

Example 83- (2,5-difluorophenyl) -N- (5- (6,7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621085)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621085 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.45(s，1H)，8.85(d，J＝15.0Hz，1H)，8.45(s，1H)，8.15(d，J＝2.9Hz，1H)，7.68(s，1H)，7.35(s，1H)，7.28(dd，J＝15.0，3.1Hz，1H)，7.16-7.07(m，1H)，7.02-6.93(m，1H)，6.63-6.52(m，1H)，4.00(s，3H)，3.98(s，3H)，3.57(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.02-1.94(m，2H)，1.87-1.75(m，2H).LRMS(EI)m/z：575(M+H) ⁺ .

Example 84- (2,5-difluorophenyl) -N- (5- (6,7-bis (2-methoxyethoxy) quinazolin-4-yl) pyridin-2-yl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621086)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621086 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.67(s，1H)，8.86(d，J＝15.0Hz，1H)，8.46(s，1H)，8.16(d，J＝3.1Hz，1H)，8.02(s，1H)，7.53(s，1H)，7.29(dd，J＝15.0，3.1Hz，1H)，7.18-7.08(m，1H)，7.03-6.92(m，1H)，6.64-6.54(m，1H)，4.37-4.29(m，4H)，3.78-3.72(m，4H)，3.55(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.23(t，J＝6.3Hz，2H)，2.02-1.93(m，2H)，1.86-1.75(m，2H).LRMS(EI)m/z：663(M+H) ⁺ .

Example 85 (R) -1- (2,5-difluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621087)

4-chloro-6,7-dimethoxyquinoline is replaced by (R) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621087 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.45(s，1H)，7.77(s，1H)，7.61(s，1H)，7.57(dd，J＝15.9，2.9Hz，1H)，7.18-7.06(m，2H)，7.02-6.93(m，1H)，6.85(dd，J＝15.0，10.1Hz，1H)，6.64-6.53(m，1H)，5.04-4.96(m，1H)，4.22-4.13(m，1H)，4.07-4.02(m，1H)，3.93(s，3H)3.86-3.80(m，1H)，3.79-3.73(m，1H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.42-2.31(m，1H)，2.18-2.10(m，1H)，2.02-1.94(m，2H)，1.88-1.79(m，2H).LRMS(EI)m/z：648(M+H) ⁺ .

Example 86 (S) -1- (2,5-difluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621088)

4-chloro-6,7-dimethoxyquinoline is replaced by (S) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 2,5-difluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, and the product DC621088 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.88(s，1H)，8.43(s，1H)，7.75(s，1H)，7.63(s，1H)，7.59(dd，J＝15.9，2.9Hz，1H)，7.17-7.07(m，2H)，7.01-6.93(m，1H)，6.86(dd，J＝15.0，10.1Hz，1H)，6.62-6.53(m，1H)，5.03-4.96(m，1H)，4.21-4.13(m，1H)，4.08-4.02(m，1H)，3.95(s，3H)3.87-3.80(m，1H)，3.79-3.71(m，1H)，3.54(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.42-2.33(m，1H)，2.18-2.11(m，1H)，2.02-1.95(m，2H)，1.89-1.79(m，2H).LRMS(EI)m/z：648(M+H) ⁺ .

Example 87N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-chlorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621089)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621089 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.64(s，1H)，8.56(s，1H)，8.12(d，J＝2.3Hz，1H)，7.70-7.60(m，2H)，7.58-7.50(m，2H)，7.49-7.40(m，4H)，4.00(s，3H)，3.98(s，3H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.03-1.93(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：590(M+H) ⁺ .

Example 88N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-chlorophenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621090)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621090 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.44(s，1H)，8.01(s，1H)，7.70(d，J＝2.9Hz，1H)，7.41(s，1H)，7.24(dd，J＝15.0，2.9Hz，1H)，7.06-6.93(m，3H)，6.92-6.82(m，1H)，6.70-6.55(m，1H)，4.41-4.27(m，4H)，3.79-3.71(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.2Hz，2H)，2.01-1.92(m，2H)，1.86-1.78(m，2H).LRMS(EI)m/z：678(M+H) ⁺ .

Example 89N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621091)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621091 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.45(s，1H)，8.04-7.73(m，2H)，7.57(s，1H)，7.37(dd，J＝14.9，3.0Hz，1H)，7.10-6.95(m，2H)，6.93-6.83(m，1H)，6.80(d，J＝15.0Hz，1H)，6.68-6.56(m，1H)，3.99(s，3H)，3.97(s，3H)，3.50(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.02-1.95(m，2H)，1.84-1.77(m，2H).LRMS(EI)m/z：624(M+H) ⁺ .

Example 90N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621092)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621092 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.50(s，1H)，8.45(s，1H)，8.01(s，1H)，7.85(d，J＝3.1Hz，1H)，7.40(s，1H)，7.37(dd，J＝15.0，3.1Hz，1H)，7.06-6.95(m，2H)，6.92-6.83(m，1H)，6.80(d，J＝15.0Hz，1H)，6.67-6.56(m，1H)，4.40-4.28(m，4H)，3.79-3.73(m，4H)，3.56(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.23(t，J＝6.2Hz，2H)，2.02-1.94(m，2H)，1.83-1.75(m，2H).LRMS(EI)m/z：712(M+H) ⁺ .

Example 91N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) naphthalen-1-yl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621093)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 21, so that the product DC621093 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.45(s，1H)，8.24(dd，J＝14.9，3.0Hz，1H)，7.97(dd，J＝14.9，3.0Hz，1H)，7.89(s，1H)，7.68-7.53(m，2H)，7.42-7.34(m，1H)，7.08-6.94(m，2H)，6.92-6.84(m，1H)，6.81(d，J＝15.0Hz，1H)，6.65-6.56(m，1H)，6.05(d，J＝15.0Hz，1H)，3.98(s，3H)，3.97(s，3H)，3.54(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.03-1.95(m，2H)，1.84-1.75(m，2H).LRMS(EI)m/z：606(M+H) ⁺ .

Example 92N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) naphthalen-1-yl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621094)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621094 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.45(s，1H)，8.24(dd，J＝14.9，3.0Hz，1H)，8.07(s，1H)，7.97(dd，J＝14.9，3.0Hz，1H)，7.66-7.58(m，1H)，7.47-7.29(m，2H)，7.06-6.95(m，2H)，6.92-6.83(m，1H)，6.81(d，J＝15.0Hz，1H)，6.70-6.56(m，1H)，6.05(d，J＝15.0Hz，1H)，4.39-4.27(m，4H)，3.81-3.72(m，4H)，3.53(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.24(t，J＝6.1Hz，2H)，2.02-1.93(m，2H)，1.85-1.76(m，2H).LRMS(EI)m/z：694(M+H) ⁺ .

Example 93N- (5- (6,7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621095)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621095 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.75(s，1H)，8.85(d，J＝15.0Hz，1H)，8.45(s，1H)，8.15(d，J＝2.9Hz，1H)，7.83(s，1H)，7.72(s，1H)，7.28(dd，J＝15.0，2.9Hz，1H)，7.07-6.94(m，2H)，6.91-6.85(m，1H)，6.67-6.56(m，1H)，3.99(s，3H)，3.98(s，3H)，3.54(t，J＝5.8Hz，2H)，3.24(t，J＝6.2Hz，2H)，2.02-1.93(m，2H)，1.85-1.77(m，2H).LRMS(EI)m/z：557(M+H) ⁺ .

Example 94N- (5- (6,7-bis (2-methoxyethoxy) quinazolin-4-yl) pyridin-2-yl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621096)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621096 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.74(s，1H)，8.86(d，J＝15.0Hz，1H)，8.46(s，1H)，8.16(d，J＝3.1Hz，1H)，7.85(s，1H)，7.40(s，1H)，7.29(dd，J＝14.9，3.0Hz，1H)，7.15-6.95(m，2H)，6.94-6.79(m，1H)，6.67-6.56(m，1H)，4.36-4.26(m，4H)，3.79-3.74(m，4H)，3.55(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.23(t，J＝6.1Hz，2H)，2.02-1.93(m，2H)，1.86-1.75(m，2H).LRMS(EI)m/z：645(M+H) ⁺ .

Example 95 (R) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621097)

Replacement of 4-chloro-6,7-dimethoxyquinoline with (R) -4-chloro-6-methoxy-7- ((tetrahydrofuran)Pyran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 2-phenylhydrazine, and the other required raw materials, reagents and preparation methods are the same as example 1, to obtain the product DC621097 with a yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.46(s，1H)，7.72(s，1H)，7.58(dd，J＝16.0，3.0Hz，1H)，7.42(s，1H)，7.15(dd，J＝15.0，3.0Hz，1H)，7.09-6.95(m，2H)，6.93-6.81(m，2H)，6.67-6.57(m，1H)，5.05-4.96(m，1H)，4.21-4.13(m，1H)，4.06-4.02(m，1H)，3.94(s，3H)，3.85-3.80(m，1H)，3.78-3.73(m，1H)，3.54(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.44-2.31(m，1H)，2.18-2.11(m，1H)，2.02-1.95(m，2H)，1.88-1.77(m，2H).LRMS(EI)m/z：630(M+H) ⁺ .

Example 96 (S) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621098)

4-chloro-6,7-dimethoxyquinoline is replaced by (S) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 2-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that a product DC621098 is obtained, with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.88(s，1H)，8.45(s，1H)，7.73(s，1H)，7.56(dd，J＝16.0，3.0Hz，1H)，7.44(s，1H)，7.13(dd，J＝15.0，3.0Hz，1H)，7.09-6.97(m，2H)，6.93-6.84(m，2H)，6.67-6.59(m，1H)，5.07-4.96(m，1H)，4.23-4.13(m，1H)，4.06-4.01(m，1H)，3.96(s，3H)，3.86-3.80(m，1H)，3.78-3.71(m，1H)，3.56(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.42-2.31(m，1H)，2.18-2.11(m，1H)，2.04-1.95(m，2H)，1.89-1.77(m，2H).LRMS(EI)m/z：630(M+H) ⁺ .

Example 97N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-chlorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621099)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline,the phenylhydrazine is replaced by the 4-fluorophenylhydrazine, and the other needed raw materials, reagents and preparation methods are the same as the example 1, so that the product DC621099 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.76(s，1H)，8.55(s，1H)，8.12(d，J＝2.3Hz，1H)，7.58-7.53(m，3H)，7.49-7.40(m，5H)，4.00(s，3H)，3.98(s，3H)，3.56(t，J＝5.8Hz，2H)，3.20(t，J＝6.3Hz，2H)，2.02-1.94(m，2H)，1.85-1.78(m，2H).LRMS(EI)m/z：590(M+H) ⁺ .

Example 98N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-chlorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621100)

2-fluoro-4-nitrophenol is replaced by 2-chloro-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline), phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621100 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.46(s，1H)，8.04(s，1H)，7.72(d，J＝3.1Hz，1H)，7.41(s，1H)，7.26(dd，J＝14.9，3.0Hz，1H)，7.07-6.95(m，3H)，6.88(dd，J＝15.0，10.0Hz，2H)，4.42-4.27(m，4H)，3.79-3.72(m，4H)，3.57(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.2Hz，2H)，2.02-1.92(m，2H)，1.87-1.78(m，2H).LRMS(EI)m/z：678(M+H) ⁺ .

Example 99N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621101)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621101 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.46(s，1H)，7.90(s，1H)，7.86(d，J＝3.1Hz，1H)，7.66(s，1H)，7.38(dd，J＝14.9，3.0Hz，1H)，7.05-6.95(m，2H)，6.94-6.75(m，3H)，3.98(s，3H)，3.97(s，3H)，3.53(t，J＝5.8Hz，2H)，3.20(t，J＝6.2Hz，2H)，2.01-1.95(m，2H)，1.85-1.77(m，2H).LRMS(EI)m/z：624(M+H) ⁺ .

Example 100N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-trifluoromethylphenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621102)

2-fluoro-4-nitrophenol is replaced by 2-trifluoromethyl-4-nitrophenol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621102 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.50(s，1H)，8.46(s，1H)，8.02(s，1H)，7.86(d，J＝3.1Hz，1H)，7.45-7.32(m，2H)，7.15-6.95(m，2H)，6.94-6.70(m，3H)，4.40-4.29(m，4H)，3.79-3.72(m，4H)，3.58(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.24(t，J＝6.2Hz，2H)，2.03-1.94(m，2H)，1.84-1.75(m，2H).LRMS(EI)m/z：712(M+H) ⁺ .

Example 101N- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) naphthalen-1-yl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621103)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as those in example 21, so that the product DC621103 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.44(s，1H)，8.23(dd，J＝14.9，3.0Hz，1H)，7.96(dd，J＝14.9，3.0Hz，1H)，7.83(s，1H)，7.66-7.48(m，2H)，7.42-7.33(m，1H)，7.04-6.95(m，2H)，6.89-6.78(m，3H)，6.04(d，J＝14.8Hz，1H)，3.99(s，3H)，3.97(s，3H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.02-1.95(m，2H)，1.86-1.75(m，2H).LRMS(EI)m/z：606(M+H) ⁺ .

Example 102N- (4- ((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) naphthalen-1-yl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621104)

2-fluoro-4-nitrophenol is replaced by 4-nitro-1-naphthol, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 21, so that the product DC621104 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.46(s，1H)，8.25(dd，J＝14.9，3.0Hz，1H)，8.06(s，1H)，7.98(dd，J＝14.8，3.1Hz，1H)，7.62(d，J＝3.1Hz，1H)，7.49-7.26(m，2H)，7.09-6.95(m，2H)，6.94-6.74(m，3H)，6.06(d，J＝15.0Hz，1H)，4.38-4.27(m，4H)，3.83-3.72(m，4H)，3.51(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.22(t，J＝6.1Hz，2H)，2.02-1.94(m，2H)，1.87-1.76(m，2H).LRMS(EI)m/z 694(M+H) ⁺ .

Example 103N- (5- (6,7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621105)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as those in example 1, so that the product DC621105 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.75(s，1H)，8.86(d，J＝15.0Hz，1H)，8.46(s，1H)，8.16(d，J＝3.1Hz，1H)，7.85(s，1H)，7.62(s，1H)，7.29(dd，J＝15.0，3.1Hz，1H)，7.12-6.95(m，2H)，6.94-6.81(m，2H)，3.99(s，3H)，3.97(s，3H)，3.56(t，J＝5.8Hz，2H)，3.23(t，J＝6.2Hz，2H)，2.02-1.94(m，2H)，1.85-1.76(m，2H).LRMS(EI)m/z：557(M+H) ⁺ .

Example 104N- (5- (6,7-bis (2-methoxyethoxy) quinazolin-4-yl) pyridin-2-yl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621106)

2-fluoro-4-nitrophenol is replaced by 5-hydroxy-2-nitropyridine, 4-chloro-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-di ((2-methoxyethoxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the rest of the required raw materials, reagents and preparation method are the same as example 1, so that the product DC621106 is obtained with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.74(s，1H)，8.85(d，J＝15.0Hz，1H)，8.45(s，1H)，8.15(d，J＝3.1Hz，1H)，7.84(s，1H)，7.40(s，1H)，7.28(dd，J＝15.0，2.9Hz，1H)，7.11-6.94(m，2H)，6.92-6.82(m，2H)，4.36-4.25(m，4H)，3.79-3.73(m，4H)，3.57(t，J＝5.8Hz，2H)，3.36(s，3H)，3.36(s，3H)，3.21(t，J＝6.1Hz，2H)，2.02-1.94(m，2H)，1.86-1.77(m，2H).LRMS(EI)m/z：645(M+H) ⁺ .

Example 105 (R) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621107)

4-chloro-6,7-dimethoxyquinoline is replaced by (R) -4-chloro-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 4-phenylhydrazine, and the rest of the required raw materials, reagents and preparation methods are the same as example 1, so that the product DC621107 is obtained, with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.89(s，1H)，8.44(s，1H)，7.76(d，J＝8.8Hz，2H)，7.57(dd，J＝15.9，2.9Hz，1H)，7.14(dd，J＝15.0，3.1Hz，1H)，7.07-6.93(m，2H)，6.91-6.77(m，3H)，5.05-4.97(m，1H)，4.22-4.13(m，1H)，4.06-4.01(m，1H)，3.95(s，3H)，3.86-3.80(m，1H)，3.78-3.72(m，1H)，3.56(t，J＝5.8Hz，2H)，3.22(t，J＝6.2Hz，2H)，2.44-2.33(m，1H)，2.19-2.11(m，1H)，2.02-1.96(m，2H)，1.88-1.76(m，2H).LRMS(EI)m/z：630(M+H) ⁺ .

Example 106 (S) -N- (3-fluoro-4- ((6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a ] pyridine-3-carboxamide (DC 621108)

4-chloro-6,7-dimethoxyquinoline is replaced by (S) -4-Chlorine-6-methoxy-7- ((tetrahydrofuran-3-yl) oxy) quinazoline, phenylhydrazine is replaced by 4-fluorophenylhydrazine, and the other required raw materials, reagents and preparation method are the same as example 1, so as to obtain the product DC621108 with the yield of 80%. ¹ HNMR(400MHz，DMSO-d6)δ10.88(s，1H)，8.45(s，1H)，7.75(d，J＝8.8Hz，2H)，7.56(dd，J＝15.9，2.9Hz，1H)，7.15(dd，J＝15.0，3.1Hz，1H)，7.05-6.93(m，2H)，6.92-6.78(m，3H)，5.06-4.97(m，1H)，4.21-4.13(m，1H)，4.07-4.01(m，1H)，3.93(s，3H)，3.87-3.80(m，1H)，3.78-3.73(m，1H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.42-2.33(m，1H)，2.18-2.11(m，1H)，2.03-1.96(m，2H)，1.88-1.78(m，2H).LRMS(EI)m/z：630(M+H) ⁺ .

Comparative example 1N- (4- ((4,6-dimethoxy-1,3,5-triazin-2-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydro [1,5-a ] pyridine-3-carboxamide (DC 621003)

Synthesis of key intermediate 2,4-dimethoxy-6- (4-nitrophenoxy) -1,3,5-triazine

5g of 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4.4g of p-nitrophenol and 18.6g of Cs are added into a 100mL eggplant-shaped bottle ₂ CO ₃ And 75mL DMF, then stirred at room temperature overnight. The reaction was monitored by Thin Layer Chromatography (TLC). After the reaction, a large amount of water was added to the reaction solution to precipitate a yellow solid, which was then filtered under suction to obtain 7g of a solid. LRMS (EI) m/z:279 (M + H) ⁺ . (the reaction mixture was directly subjected to the next step without purification)

The rest steps are as in example 1, and the product DC621003 is obtained with the yield of 82%. ¹ H NMR(400MHz，DMSO-d6)δ10.67(s，1H)，7.69-7.62(m，2H)，7.62-7.55(m，2H)，7.53-7.43(m，3H)，7.21-7.13(m，2H)，3.90(s，6H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.3Hz，2H)，2.01-1.95(m，2H)，1.87-1.74(m，2H). ¹³ C NMR(101MHz，DMSO-d6)δ173.7，173.3，163.1，161.5，153.9，147.1，137.1，133.1，129.8，129.3，127.7，122.4，120.1，96.5，55.7，46.8，23.8，22.2，19.0.LRMS(EI)m/z 489(M+H) ⁺ .

Comparative example 2N- (4- ((2-methylpyrimidin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1,2,4,5,6,7-hexahydro [1,5- α ] pyridine-3-carboxamide (DC 621005)

2-chloro-4,6-dimethoxy-1,3,5-triazine is replaced by 4-chloro-2-methylpyrimidine, and the rest of the required raw materials, reagents and preparation method are the same as example 107, and the product DC621005 is obtained with a yield of 83%. ¹ H NMR(400MHz，DMSO-d6)δ10.67(s，1H)，8.53(d，J＝5.8Hz，1H)，7.67(d，J＝8.9Hz，2H)，7.58(t，J＝7.5Hz，2H)，7.54-7.44(m，3H)，7.16(d，J＝8.9Hz，2H)，6.84(d，J＝5.8Hz，1H)，3.56(t，J＝5.8Hz，2H)，3.21(t，J＝6.2Hz，2H)，2.44(s，3H)，2.04-1.92(m，2H)，1.87-1.73(m，2H). ¹³ C NMR(101MHz，DMSO-d6)δ169.4，168.1，163.1，161.5，159.5，153.9，147.6，136.8，133.1，129.8，129.3，127.7，122.5，120.6，105.4，96.5，46.8，25.9，23.9，22.2，19.1.LRMS(EI)m/z 442(M+H) ⁺ .

Pharmacological Activity test examples

Experimental example 1: screening for influence of compound on enzyme activity of receptor tyrosine kinase AXL

The detection method comprises the following steps: enzyme-linked immunosorbent assay (ELISA)

Test receptor tyrosine kinase: AXL

Test batch: 2 batches

Reagents, consumables and instruments: the kinase used in the experiment is expressed and purified protein kinase zone recombinant protein by using an insect baculovirus expression system in the laboratory; polyglutamic acid-tyrosine peptide fragment [ Poly (Glu, tyr) _4∶1 Sodium vanadate from Sigma(ii) a Anti-phosphorylation mab PY99 was purchased from Santa Cruz; horseradish peroxidase-labeled goat anti-mouse secondary antibody was purchased from Calbiochem; ATP and OPD were purchased from shanghai life; all other reagents were purchased from national chemical group, inc. The reaction microplate (# 2592) was purchased from Corning corporation. The full-wavelength enzyme standard instrument for the experimental reading plate is a product of Molecular Device company, and the model is as follows: spectraMax 190; the experimental water is distilled water produced by national medicine group.

Compound preparation: centrifuging compound 12000g for 5min, adding DMSO to prepare 10 ^-2 And (5) storing liquid M, uniformly vortexing, and then carrying out ultrasonic treatment for 10min for later use, and storing at-40 ℃. Compounds were diluted from stock solutions to 100-fold the tested concentration with DMSO at the time of testing (DMSO concentration in the system was 1%).

The test method comprises the following steps:

1. the enzyme reaction substrate Poly (Glu, tyr) 4: 1 was diluted to 20. Mu.g/mL with PBS (10 mM sodium phosphate buffer, 150mM NaCl, pH 7.2-7.4) free of potassium ions, coated with 125. Mu.L/well of an ELISA plate, and reacted at 37 ℃ for 12-16 hours. The liquid in the wells was discarded. The plate was washed with T-PBS (0.1% Tween-20 in PBS without potassium ion, 200. Mu.L/well) three times for 5 minutes each. The microplate was dried in an oven at 37 ℃ for 1-2 hours.

2. Reaction buffer (50mM HEPES pH 7.4, 50mM MgCl) was added to each well ₂ ，0.5mM MnCl ₂ ，0.2mM Na ₃ VO ₄ 1mM DTT) of the test compound, 1. Mu.L of the test compound was added to each well, and 50. Mu.L of the AXL kinase domain recombinant protein diluted in the reaction buffer was added to start the reaction, with no ATP control well being provided for each experiment. The reaction was carried out on a shaker (100 rpm) at 37 ℃ for 1 hour. The wells were discarded and the plate washed three times with T-PBS.

3. The diluted PY99 antibody (diluted 1: 500 with BSA in 5mg/mL T-PBS) was added thereto at 100. Mu.L/well, followed by shaking reaction at 37 ℃ for 0.5 hour. The wells were discarded and the plate washed three times with T-PBS.

4. Horseradish peroxidase-labeled goat-anti-mouse secondary antibody diluent (antibody diluted with T-PBS containing BSA 5mg/ml 1: 2000) was added thereto at 100. Mu.L/well, followed by shaking reaction at 37 ℃ for 0.5 hour. The wells were discarded and the plate washed three times with T-PBS.

5.2 mg/ml of O was addedPD developing solution 100. Mu.L/well [ with content 0.03% ]H ₂ O ₂ 0.1M citric acid-sodium citrate buffer (pH = 5.4) and reacted at 25 ℃ for 1-10 minutes in the absence of light.

6. 2M H was added ₂ SO ₄ The reaction was stopped at 50. Mu.L/well and read on a VERSAmax wavelength-tunable microplate reader at 490nm.

7. Analysis of results

IC ₅₀ The values were determined by regression with a four parameter method using a microplate reader random plus software.

TABLE 1 inhibition ratio (%), of the enzyme activity of the compound on receptor tyrosine kinase AXL

Note: "/" not measured.

And (4) conclusion: applicants found that compounds with bicyclic ring A had superior activity, and when the ring A was monocyclic, as in the control compounds DC621003 and DC621005, there was almost no activity at 1000, 100, 10 nM. Preliminary in vitro enzyme activity inhibition detection shows that 25 compounds have good AXL kinase inhibition activity, and the inhibition rate of the compounds on AXL under 10nM concentration exceeds 50% (shown in Table 1). We completed IC's of 8 compounds such as DC621001 ₅₀ Measuring and finding out the inhibition IC ₅₀ Below 10nM, has potent AXL inhibitory activity superior to the positive drugs R428 and Cabozantinib.

Experimental example 2: kinase Spectrum Selectivity study of Compounds

In view of the potent AXL inhibitory activity of the compounds, we selected one of the compounds DC621044 and screened 369 kinase patterns in order to investigate the selectivity of the compounds on the kinase patterns.

The results are shown in figure 1 and in the following table:

the research result shows that the compound DC621044 has good selectivity for AXL kinase. Among the 369 kinases screened, the compound DC621044 only has certain inhibition on MER and TYRO3 kinases in the same family as AXL kinase and c-Met kinase with higher homology, and basically has no inhibition effect on other kinases, thereby showing good kinase spectrum selectivity. DC621044 has better selectivity than AXL inhibitors R428 and Cabozantinib which have been reported in the art, and provides a better basis for the development of selective AXL inhibitors.

Experimental example 3: in vitro study of c-Met kinase inhibitory Activity

Based on the screening result of 369 kinase spectrums of the compound DC621044, the compound is found to have certain inhibitory activity to c-Met, and partial compounds are further screened for the inhibitory activity to the c-Met kinase. As shown in Table 2, 18 compounds showed good c-Met inhibitory activity, with an inhibition rate of c-Met kinase exceeding 50% at a concentration of 10 nM.

TABLE 2 inhibition of receptor tyrosine kinase c-Met enzyme activity by compounds

Experimental example 4: effect of Compounds on the proliferative Effect of BaF3/TEL-AXL cells

On the basis of the results of the above-mentioned studies on the enzyme activity, we further investigated the effect of the compounds on cell proliferation mediated by the receptor tyrosine kinase AXL. As shown in Table 3, a plurality of compounds such as compounds DC621024, DC621044 and DC621051 exhibited potent cell proliferation inhibitory effects at a cell proliferation inhibitory rate of BaF3/TEL-AXL of > 70% at a concentration of 1 nM.

TABLE 3 inhibition of BaF3/TEL-AXL cell proliferation by compounds

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (17)

1. A cyclo-pyrazolone formamide compound with a structure shown in the following general formula I, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof:

wherein:

n is an integer of 0 to 2;

x and Y are each independently CH, Z is CH or N;

R ¹ and R ² Are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy radicalA cyano group; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ An alkyl group;

the ring is selected from the group consisting of:

wherein R is ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² Each of 1 to 4 substituents selected from the group consisting of: H. deuterium (D), tritium (T), halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, cyano, nitro, amino, C ₁ -C ₆ Amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heterocyclyloxy; wherein, the aromatic heterocyclic group and the heterocyclic group respectively and independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; or two adjacent substituents together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S;

R ³ selected from hydrogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, and hydroxymethyl;

q is 1,2, 3 or 4;

r is 0, 1 or 2;

s is selected from the group consisting of: 0.1, 2,3 or 4;

ar is selected from the group consisting of: substituted or unsubstituted C ₆ -C ₁₂ Aryl, substituted or unsubstituted 5-12 membered heteroaryl;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkoxycarbonyl, halogen-substituted C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy.

2. The cyclo-pyrazolone carboxamide according to claim 1, or the racemate, the R-isomer, the S-isomer, the pharmaceutically acceptable salts thereof or the mixtures thereof, wherein R ¹ And R ² Each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ An alkoxy group.

3. The cyclo-pyrazolone carboxamide according to claim 1, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixtures thereof,the ring is selected from the group consisting of:

wherein R is ⁴ 、R ⁵ 、R ¹¹ 、R ¹² Each of 1 to 4 substituents selected from the group consisting of: H. d, T halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, toSubstituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, cyano, nitro, amino, C ₁ -C ₆ Amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heterocyclyloxy; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

4. The cyclo-pyrazolone carboxamide according to claim 2, characterized in that it is the racemate, the R-isomer, the S-isomer, the pharmaceutically acceptable salts or the mixtures thereofThe ring is selected from the group consisting of:

5. the cyclo-pyrazolone carboxamide according to claim 4, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixtures thereof, characterized in that: r ⁴ 、R ⁵ Each of 1 to 4 substituents selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted 3-12 membered heterocyclyloxy; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

6. A fused pyrazolone formamide compound with a structure shown in the following general formula I, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof:

wherein:

n is an integer of 0 to 2;

x and Y are each independently CH, Z is CH or N;

r is as described ¹ And R ² Each independently is 1 to 3 substituents selected from the group consisting of: hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, cyano, hydroxy; or two R ¹ The carbon atoms adjacent thereto and the atoms to which they are attached may together form a group selected from: a benzene ring, a 5-8 membered heteroaromatic ring;

the ring is selected from the group consisting of:

wherein R is ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² Each of 1 to 4 substituents selected from the group consisting of: H. deuterium (D), tritium (T), halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, cyano, nitro, amino, C ₁ -C ₆ Amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heterocyclyloxy; wherein the aromatic heterocyclic group and the heterocyclic group each independently contain 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen; or two adjacent substituents together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S;

R ³ selected from hydrogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, and hydroxymethyl;

q is 1,2, 3 or 4;

r is 0, 1 or 2;

s is selected from the group consisting of: 0.1, 2,3 or 4;

ar is selected from the group consisting of: substituted or unsubstituted C ₆ -C ₁₂ Aryl, substituted or unsubstituted 5-12 membered heteroaryl;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkoxycarbonyl, halogen-substituted C ₁ -C ₆ Alkoxy radical, C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl.

7. The cyclo-pyrazolone carboxamide according to claim 6, or the racemate, the R-isomer, the S-isomer, the pharmaceutically acceptable salts thereof, or mixtures thereof,the ring is selected from the group consisting of:

wherein R is ⁴ 、R ⁵ 、R ¹¹ 、R ¹² Each of 1 to 4 substituents selected from the group consisting of: H. d, T halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted C ₃ -C ₈ Cycloalkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkylamino, cyano, nitro, amino, C ₁ -C ₆ Amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heterocyclyloxy; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

8. The cyclic pyrazolone carboxamides of claim 6 or racemates, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereofThe ring is selected from the group consisting of:

9. the ring-fused pyrazolone carboxamide according to claim 8, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixtures thereof, characterized in that: r ⁴ 、R ⁵ Each of 1 to 4 substituents selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ Alkoxy, -O [ (CH) ₂ ) _q O] _r R ³ 、-NH[(CH ₂ ) _q O] _r R ³ 、-NH(C＝O)[(CH ₂ ) _q O] _r R ³ 、-NH(SO ₂ )[(CH ₂ ) _q O] _r R ³ 、-O(CH ₂ ) _s Ar, substituted or unsubstituted 3-12 membered heterocyclyloxy; or two adjacent of the above groups together with the atoms to which they are attached may form a structure selected from the group consisting of: a substituted or unsubstituted 6-20 membered heterocyclic ring, said heterocyclic ring optionally comprising 1,2, 3 or 4 heteroatoms selected from N, O or S.

10. The fused pyrazolone carboxamide according to claim 6, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof, wherein: said R ¹ Each independently is 1 to 3 substituents selected from the group consisting of: fluorine, chlorine, bromine, iodine, methoxy, trifluoromethyl.

11. Cyclopyrazolone carboxamides according to claim 6A compound or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof, characterized in that: said R ² 1 to 3 fluorines.

12. A cyclic pyrazolone carboxamide compound, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof, characterized in that it is selected from the following compounds:

13. a process for the preparation of a compound as claimed in claim 1 or 6, comprising the steps of:

reacting a compound of formula 1-8 with a compound of formula 2-4 in an inert solvent to provide a compound of formula I;

wherein the definition of each substituent is as defined in claim 1 or 6.

14. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound according to any one of claims 1 to 12, or one or more of pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and optionally pharmaceutically acceptable adjuvants.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable excipient comprises: excipients, adjuvants, carriers and/or diluents.

16. A kinase inhibitor, wherein said inhibitor comprises: an inhibitory effective amount of one or more of the compounds of any one of claims 1-12, or a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixtures thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, and/or diluent; and the kinase is selected from the group consisting of: AXL, c-Met, or a combination thereof.

17. Use of a compound according to any one of claims 1 to 12 for the preparation of a pharmaceutical composition for the treatment or prevention of a disease associated with kinase activity; or for the preparation of kinase inhibitors;

wherein the kinase is selected from the group consisting of: AXL, c-Met, or a combination thereof.