CN108239071B

CN108239071B - Amide and thioamide derivatives, and preparation method and application thereof

Info

Publication number: CN108239071B
Application number: CN201611223917.3A
Authority: CN
Inventors: 赵冬梅; 程卯生; 郝晨洲; 郭靖; 张巧玲; 王凯; 王健; 黄万旭; 李丰; 李晓东
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2016-12-27
Filing date: 2016-12-27
Publication date: 2020-12-04
Anticipated expiration: 2036-12-27
Also published as: CN108239071A; WO2018121400A1

Abstract

The invention belongs to the technical field of medicines, relates to amide and thioamide derivatives, and a preparation method and application thereof, and particularly relates to derivatives shown in a general formula (I), geometric isomers thereof, pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, and a preparation method thereof. The derivatives have activity as protein kinase inhibitors, in particular as inhibitors of PAK kinase.

Description

Amide and thioamide derivatives, and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and relates to novel amide/thioamide derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, a preparation method of the derivatives and application of the derivatives as a therapeutic agent, especially as a PAK inhibitor.

Background

The treatment of tumor has become a worldwide problem, and the research and development of high-efficiency and low-toxicity anti-tumor drugs are imminent. The targeted antitumor drug has the characteristics of good specificity, strong effectiveness, low toxic and side effects and the like, and has great success in tumor treatment.

Protein kinases are the largest family of human gene-encoded proteins and are closely associated with tumor development, invasion, metastasis, angiogenesis and chemotherapy resistance. Because part of the kinases are only highly expressed in tumor cells, the inhibition of the kinases does not affect the biological function of normal cells, so that the antitumor drug taking the protein kinases as targets has the advantages of high selectivity and low toxicity. Therefore, protein kinases have become important targets for the development of antitumor drugs.

2001 Bcr-Abl kinase inhibitor imatinib

Is approved by FDA to treat chronic granulocytic leukemia and becomes the first protein kinase inhibitor antineoplastic drug on the market. In the next fifteen short years, 42 protein kinase inhibitors have been marketed, and only 8 FDA-approved small molecule kinase inhibitors for tumor therapy have been marketed since 2013. The research on protein kinase inhibitors with antitumor activity has received a great deal of attention from the biopharmaceutical industry.

PAKs (p 21-activated kinases) are a class of serine/threonine protein kinases belonging to the STE20 family. PAK4 is representative of class II PAKs, and can affect a plurality of downstream proteins related to cell cycle, migration, invasion and apoptosis, thereby causing abnormal differentiation, angiogenesis, proliferation and the like of tumor cells. Therefore, PAK4 is a potential tumor therapy target.

PAKs include six family members (PAK1-PAK6) and are divided into two classes according to their structure and mode of activation: class I PAKs (PAK1, PAK2, PAK3), class II PAKs (PAK4, PAK5, PAK 6). Among these, PAK4 is the most studied of PAKs in class II.

The full length of the PAK4(p21 activated kinase 4) kinase includes 591 amino acid residues, which are divided into three major domains: the protein Kinase comprises a P21 binding Domain (P21-binding Domain, PBD), a self-inhibition Domain (AID) and a Kinase Domain (KD) or a Catalytic Domain (Catalytic Domain), wherein the P21 binding Domain and the self-inhibition Domain are positioned at the N-end of the Kinase, and the Kinase Domain is positioned at the conserved C-end of the Kinase. There is significant structural diversity between class I PAKs and class II PAKs, e.g., class II PAKs do not contain regions rich in acidic amino acid residues and PIX/Cool binding domains; the homology of the kinase domains of two subfamilies is only about 50%, the structural difference is large, and the homology in the same subfamily is respectively as high as 92-96% and 79-86%, and the structures are relatively similar.

PAK is a main target protein of guanosine triphosphatase (Rho-GTPases) Cdc42 and Rac1 in the Rho family, and regulates and controls various biological functions such as cytoskeleton recombination, cell migration movement, apoptosis, mitosis, cell differentiation and the like through participating in multiple signal paths in cells. Besides being involved in regulating normal physiological activities of cells, PAK is closely related to the occurrence and development of various diseases, especially tumors. In an RAS-Cdc42/Rac1-PAK signal channel in a cell, Cdc42/Rac1 respectively control the generation of cell filopodia and lamellipodia, and PAK is used as a downstream main effector and plays an important role in the processes of malignant transformation of cells and invasion and metastasis of tumor cells.

The research shows that the PAK kinase, particularly PAK1 and PAK4, has the phenomena of gene amplification, over-expression and abnormal activation in various tumor cells, thereby causing canceration and uncontrollable proliferation, invasion and metastasis of the cells. For example, PAK1 is highly expressed in cell lines of breast, kidney, colon, etc.; in a squamous skin carcinoma tumor-bearing murine model, PAK1 deletion will significantly attenuate tumorigenic development by down-regulating the MAPK and PI3K pathways; PAK1 can also phosphorylate BAD protein, and inhibit apoptosis of tumor cells; phosphorylated DLC1(Dynein light chain 1), promoting cell survival and malignant phenotypes; mediates the expression of mammary epithelial cell cyclinD1, and promotes the generation and development of breast cancer. On the other hand, more than 70% of various human cancer cell lines highly express PAK4, including breast cancer, pancreatic cancer, colon cancer, lung cancer, ovarian cancer and the like, the activation of PAK4 can lead to the anchorage-independent growth of tumor cells, and the PAK4 inactivated mutant can inhibit malignant transformation caused by Ras. The mechanism of upregulation of PAK4 is primarily gene amplification, particularly in pancreatic, ovarian, oral squamous cell, and breast cancers. PAK4 is expressed in a variety of solid tumors, the most prominent feature being its increased expression of mRNA or protein by increased transcription or gene amplification. However, the study also reported that genetic mutation of PAK4 (E329K) was associated with colon cancer.

Studies have shown that the protein Ras is mutated and overexpressed in about 30% of tumors, including malignancies such as pancreatic, colon, and lung cancers. Ras activates the Rho family small G protein Rac1/Cdc42 through PI-3k, thereby activating PAKs. Activated PAKs further influence downstream cell signaling pathways, promoting tumor survival, angiogenesis, migratory invasion, etc. Research shows that PAK4 can activate the survival signal channel of tumor cells through NF-kB, and promote the survival of the tumor cells; PAK4 can promote the migration of gastric cancer cells through LIMK1-Cofilin signal pathway; PAK4 can also promote melanin generation through CREB and Wnt/beta-catenin signal channel, which causes diseases such as pigmentation disorder; the PAK4/Raf/MEK/ERK signal channel exists in the liver cancer cell, and the proliferation of the liver cancer cell can be inhibited through PAK 4.

The PAK4 is closely related to the occurrence and development of various tumors, inhibits the abnormal function of PAK4, can effectively inhibit the invasion and metastasis and the hyperproliferation of tumor cells, and promotes the apoptosis of the tumor cells. Therefore, the research of the PAK4 inhibitor has important value.

Because of the close association of PAK with tumors, the current study of small molecule PAK inhibitors is in a rapidly progressing stage. Most of the PAK inhibitors found are ATP competitive PAK inhibitors acting on kinase domains, and the ATP competitive inhibitors have the characteristics of high affinity and definite action sites and are the most studied types of kinase inhibitors at present. However, the kinase domain of the kinase catalyzes the same biochemical reaction and has the conservation of structure and sequence, and the realization of the selectivity of the inhibitor among the kinases is a common problem encountered in the current research of ATP competitive inhibitors; meanwhile, the ATP binding cavity of PAK has the individual characteristics of large space and high flexibility, so that the discovery of the PAK subtype selective inhibitor is a remarkably challenging research. However, with the rapid development of related disciplines, more and more high-selectivity ATP competitive kinase inhibitors have been discovered and are the mainstream trend in the current kinase inhibitor research field.

At present, the research on inhibition of PAKs is still in the initial stage, and only PF-3758309 developed by the company Perey enters phase I clinical research. PF-3758309 is a PAKs inhibitor with pyrrolopyrazole structure reported in 2009 by the pfeiffer company, and is the only PAKs inhibitor entering clinical research, and PAK4IC thereof₅₀＝19nM，PAK1IC₅₀14 nM. In an in vitro tumor inhibition experiment and an in vivo model study of tumor-bearing mice, PF-3758309 obviously inhibits tumor cell proliferation and promotes tumor cell apoptosis. However, phase I clinical studies of PF-3758309 were forced to terminate due to poor oral bioavailability (about 1%), adverse gastrointestinal effects, etc. The compound which is reported by gene tack company 2014 and has benzimidazole structure and selectively acts on class II PAKs can generate selective inhibition effect on PAK4 (PAK1 IC)₅₀＝5.4μM，PAK4IC₅₀7.5 nM). Although such compounds still have the defects of weak cellular activity and poor druggability, the research preliminarily proves the possibility of discovering the subtype selective PAK inhibitor.

In conclusion, targeted antitumor drugs represented by protein kinase inhibitors have become the mainstream of research and development of antitumor drugs at home and abroad. PAK4 is a new target for tumor therapy due to its important role in tumor development, migration and invasion. At present, the research on the PAK4 inhibitor is still in the initial stage, and the research and development of the high-activity and high-selectivity inhibitor have important significance. However, no PAK inhibitor drug is currently on the market, and the development of a compound with a novel structure and better drug effect is still needed. The invention designs and synthesizes the compound with the structure shown in the general formula (I), and finds that the compound with the structure shows better PAK4 inhibitory activity and has good selectivity of PAK 4/1.

The invention content is as follows:

the invention aims to provide a novel amide/thioamide derivative shown in a general formula (I), a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;

wherein the A ring moiety is selected from

R₁Selected from hydrogen, C₁-C₆Alkyl, C substituted by halogen₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, C substituted by halogen₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy, six-membered aryl, benzyl, wherein said aryl, benzyl may be further substituted by 1-6R_xAnd (4) substitution.

The B ring is selected from a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocycle, a 5-7 membered saturated aliphatic ring and a 5-7 membered unsaturated aliphatic ring. The B ring may be further substituted by 1-4R₂And (4) substituting.

R₂Selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine), C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, halogenated C₁-C₆An alkyl group.

In the general formula (I)

Z of the moiety is selected from O or S.

The C ring is a 4-7 membered heterocyclic group, a 5-7 membered unsaturated heterocyclic group, a 4-7 membered bicyclic heterocyclic group, the above ring containing at least 1 nitrogen (N) atom, and the nitrogen atom being a moiety of an acyl or thioacyl group

Forming an amide bond.The ring also includes an additional 0-2 heteroatoms of N, O or S. The ring may be further substituted with 1-4 Rx. R_xThe chiral carbon atom formed after substitution can be in the R configuration, the S configuration or the racemic form.

R_xis-H, hydroxy, halogen, nitro, amino, cyano, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkoxy, optionally hydroxy, amino or halo (C)₁-C₆) Alkyl or (C)₁-C₆) Alkoxy, mono-or di (C)₁-C₆Alkyl) substituted amino, (C)₁-C₆) Alkylamido, free, salified, esterified and amidated carboxyl, (C)₁-C₆) Alkylsulfinyl (C)₁-C₆) Alkylsulfonyl group, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkanoyl, carbamoyl, mono-or di (C)₁-C₆Alkyl) substituted carbamoyl, (C)₁-C₃) An alkylenedioxy group.

The invention prefers novel amide/thioamide derivatives shown in the general formula (I), and geometrical isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein

Wherein the A ring moiety is selected from

R₁Selected from hydrogen, C₁-C₆Alkyl, C substituted by halogen₃-C₆Cycloalkyl, C substituted by halogen₃-C₆Cycloalkyl radical, C₂-C₄Alkoxy, six-membered aryl, benzyl, wherein said aryl, benzyl may be further substituted by 1-6R_xAnd (4) substitution.

The B ring is selected from a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocycle. The B ring may be further substituted by 1-4R₂And (4) substituting.

R₂Selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine))，C₁-C₄Alkyl radical, C₁-C₄Alkoxy, methoxy, hydroxy, halogen substituted C₁-C₄An alkyl group.

In the general formula (I)

Z of the moiety is selected from O, S.

Ring C is a 4-7 membered heterocyclic group, the ring containing at least 1 nitrogen (N) atom, the nitrogen atom being in communication with an acyl or thioacyl moiety

Forming an amide bond. The ring also includes an additional 0-2 heteroatoms of N, O, S. The ring may be further substituted with 1-4 Rx. R_xThe chiral carbon atom formed after substitution can be in the R configuration, the S configuration or the racemic form.

The invention preferably selects the novel amide/thioamide derivatives shown in the general formula (I), and geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

wherein the A ring moiety is selected from

R₁Selected from hydrogen, C₁-C₆Alkyl, C substituted by halogen₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, C substituted by halogen₃-C₆Cycloalkyl radical, C₂-C₄Alkoxy, six-membered aryl, benzyl, wherein said aryl, benzyl may be further substituted by 1-6R_xAnd (4) substitution.

R₂Selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxyl and trifluoromethyl.

In the general formula (I)

Z of the moiety is selected from O, S.

Ring C is a 6-membered heterocyclic group, the ring containing at least 1 nitrogen (N) atom, and the nitrogen atom being part of an acyl or thioacyl group

Forming an amide bond. The ring also includes 0-1 heteroatoms of N, O, S. The ring may be further substituted by 1-4R_xAnd (4) substitution. R_xThe chiral carbon atom formed after substitution can be in the R configuration, the S configuration or the racemic form.

Wherein the A ring moiety is selected from

R₁Selected from hydrogen, C₁-C₃Alkyl, C substituted by halogen₁-C₃Alkyl radical, C₃-C₅Cycloalkyl, C substituted by halogen₃-C₅Cycloalkyl, phenyl, benzyl, wherein said phenyl, benzyl may be further substituted by 1-6R_xAnd (4) substitution.

The B ring is a benzene ring, and the benzene ring and the adjacent pyrimidine ring form a benzopyrimidine ring which is further substituted by 1-4R₂And (4) substituting. R₂Selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxyl and trifluoromethyl.

In the general formula (I)

Z of the moiety is selected from O, S.

The C ring is preferably a piperazine ring

And a ring with an acyl or thioacyl moiety

Forming an amide bond. The ring may be further substituted with 1-2 Rx groups selected from hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C)₃-C₆) Cycloalkyl, halogenated (C)₃-C₆) A cycloalkyl group. The chiral carbon atom formed after Rx substitution may beR configuration, S configuration or racemic form.

The invention preferably selects the novel amide/thioamide derivatives shown in the general formula (I), and geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

Wherein the A ring moiety is selected from

R₁Selected from hydrogen, C₁-C₃Alkyl, C substituted by halogen₁-C₃Alkyl radical, C₃-C₅Cycloalkyl, C substituted by halogen₃-C₅Cycloalkyl, phenyl, wherein said phenyl may be further substituted with 1-2 Rx.

The B ring is selected from benzene ring, the 6-position or 7-position of the benzo pyrimidine ring formed by the benzene ring and the adjacent pyrimidine ring can be further substituted by R₂And (4) substituting. R₂Selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl, and the like. Further preferably a chlorine atom.

In the general formula (I)

Z of the moiety is selected from O, S.

The C ring is piperazine ring

And a ring with an acyl or thioacyl moiety

Forming an amide bond. The most preferred ranges for ring C are as follows:

furthermore, some of the compounds of formula (I) of the present invention have basic groups and can form pharmaceutically acceptable salts with acids according to conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Most preferred is hydrochloric acid.

In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have weak or even no activity, but which, upon administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.

The compounds of formula (I) may be in unsolvated form as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds of formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the present invention.

The compounds of formula (I) may exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are mutually converted via a low energy barrier.

"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "aryl" refers to an organic group derived from an aromatic hydrocarbon by removal of two hydrogen atoms at one or different positions, such as phenyl, naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which refers to an organic group having aromatic character and obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, and the like; heterocyclyl means a monocyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl, thiazolidinyl, and the like.

The invention can contain the derivatives of the general formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and the derivatives, the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.

Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.

The derivatives of formula (I) which may be comprised by the present invention may be synthesized by methods well known in the art including chemistry, in particular in accordance with the teachings of the present invention.

The starting materials are generally available from commercial sources such as the reagent companies avastin, dary, etc. or are prepared using methods well known to those skilled in the art.

The room temperature in the present invention means an ambient temperature of 10 to 30 ℃.

The positive progress effects of the invention are as follows: the invention provides an amide/thioamide derivative completely different from the prior art, a preparation method, a pharmaceutical composition and application thereof. The amide/thioamide compounds have good selective inhibition effect on PAK4 kinase, and can be used for preventing, treating or adjunctively treating various diseases related to the expression or activity of PAK4 kinase.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of formula I according to the invention can be prepared according to the methods of synthetic schemes 1-3, all the variables used in these schemes being as defined in the claims.

Synthesis scheme 1

As shown in scheme 1, the synthesis of a portion of the compounds essentially has several steps:

step a: the intermediate I-2 is obtained by acylation reaction of the raw material I-1.

Step b: and (3) carrying out oxalyl chloride monoethyl ester acylation reaction on the intermediate I-2 to obtain an intermediate I-3.

Step c: the intermediate I-3 is reacted with sodium ethoxide for cyclization to obtain an intermediate I-4.

Step d: and carrying out alkaline hydrolysis reaction on the intermediate I-4 to obtain an intermediate I-5.

Step e: and performing chlorination reaction on the intermediate I-5 to obtain an intermediate I-6.

Step f: and carrying out selective acylation reaction on the intermediate I-6 and the corresponding amine C fragment to obtain an intermediate I-7. The corresponding amines may be amine fragments with suitable protecting groups.

Step g: the intermediate I-7 is reacted with the A ring segment through aromatic nucleophilic substitution reaction, and then the corresponding protecting group is removed to obtain the final product.

Preferred conditions are as follows:

in step a, the reactants are dissolved in anhydrous tetrahydrofuran solvent, triphosgene is added, and the reaction is carried out for 12 hours under the condition of heating reflux. And cooling to room temperature, adding 1N ammonia water, reacting at 65 ℃ for 1 hour, cooling to room temperature, separating out a white solid, and performing suction filtration to obtain an intermediate I-2.

In step b, the reactants are dissolved in anhydrous tetrahydrofuran solvent, triethylamine is added at 0 ℃, and oxalyl chloride monoethyl ester is added dropwise with stirring. After the dropwise addition, the temperature is raised to room temperature for half an hour, and white solid is separated out. Adding a small amount of water, evaporating to remove tetrahydrofuran, adding ethyl acetate for extraction, and drying the organic layer to obtain an intermediate I-3.

In the step c, the reactant is dissolved in ethanol, sodium ethoxide is added at the temperature, the temperature is raised to room temperature after the addition is finished, the reaction is carried out for 12 hours, the PH value is adjusted to be neutral by 2N hydrochloric acid, and the white solid is filtered by suction to obtain an intermediate I-4.

In the step d, the reactant is dissolved in an ethanol-water (1-1) mixed solvent, sodium hydroxide is added, heating reflux is carried out for 2 hours, 2N hydrochloric acid is added to adjust the pH value to be acidic, and a white solid is filtered by suction to obtain an intermediate I-5.

In step e, the reactant is dissolved in chloroform, and thionyl chloride is added to be heated and refluxed for 3 hours to evaporate the solvent and the thionyl chloride to obtain an intermediate I-6.

In the step f, dissolving the reactant in anhydrous dichloromethane, cooling to-35 ℃, adding corresponding amine, stirring for 1 hour, adding water to quench the reaction, extracting dichloromethane, drying an organic layer, and purifying by silica gel column chromatography to obtain an intermediate I-7.

In step g, the reaction is dissolved in DMF, the corresponding A-ring fragment and potassium iodide are added, the temperature is raised to 65 ℃, the mixture is stirred for 10 hours and poured into water, and the precipitate is purified by silica gel column chromatography to obtain the final compound. If the compound contains protecting groups, then removing the corresponding protecting groups under corresponding conventional deprotection reaction conditions to obtain the final product. Wherein the A-ring fragment is as defined above.

The protecting group is a molecule containing 2 or more functional groups in organic synthesis, and in order to prevent a functional group from being damaged by reaction, a certain reagent is commonly used for protecting the functional group, and the protecting agent is removed after the reaction is finished. The protecting group includes t-butyloxycarbonyl (Boc), benzyl (Bn), etc.

Synthesis scheme 2

As shown in scheme 2, some of the compounds can be synthesized by the following steps:

preferred conditions are as follows:

in step e, the reactant is dissolved in tetrahydrofuran or toluene, Lawson reagent is added, heating reflux is carried out for 3 hours, the solvent is removed by evaporation, and the compound final product is obtained by silica gel column chromatography purification.

Synthesis scheme 3

And (3) ring A fragment synthesis:

when the ring segment A is substituted imidazole, the synthesis may be carried out by method A, step i, of substituted 4-nitroimidazole with alkyl halide (R)₁-X) reacting in DMF or acetonitrile by heating to generate 1-substituted 4-nitroimidazole derivative, and reducing by hydrogen in step j to obtain imidazole fragment.

Or a method B can be adopted, namely the substituted 4-nitroimidazole in the step k is subjected to nitration reaction for 1 hour at zero degree centigrade by nitric acid acetic anhydride, and the 1-nitro substituted 4-nitroimidazole is obtained by extraction and drying. 1-nitro-4-nitroimidazole via reaction with an amine fragment (R)₁-NH₂) Dissolving the reaction in water-ethanol mixture (1-1), stirring overnight at room temperature, extracting, drying, and purifying by silica gel column chromatography to obtain 1-R₁Substituted 4-nitroimidazole derivatives. Reducing by hydrogen in the step m to obtain 1-R₁Substituted 4-aminoimidazole fragments. Wherein, A ring segment and R₁As defined above.

When the A-ring fragment is a substituted pyrazole, the following method can be employed:

preferred conditions are as follows:

in the step n, adding sodium hydrogen into anhydrous tetrahydrofuran, heating to 65 ℃, and dropwise adding R₁Refluxing a mixture of substituted carboxylic ester and acetonitrile for 12 hours, cooling to room temperature, extracting with diethyl ether for 3 times, adjusting pH of a water layer to acidity with 2N hydrochloric acid, extracting with ethyl acetate, drying, and purifying by silica gel column chromatography to obtain R₁Substituted beta-carbonyl nitriles.

In step o, R is₁Dissolving substituted beta-carbonyl nitrile in ethanol, adding hydrazine hydrate and methanesulfonic acid, heating and refluxing for 1 hour, cooling to room temperature, evaporating to remove solvent, and purifying by silica gel column chromatography to obtain R₁Substituted 3-aminopyrazoles.

The specific implementation mode is as follows:

without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The examples provided below are therefore intended to illustrate but not to limit the scope of the invention.

The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art or in accordance with the methods described herein. The reagents used are, without particular reference, analytically or chemically pure.

Mass spectra used for compound structure confirmation were determined using an Agilent 1100 LC/MSD. The column chromatography purification product adopts silica gel of 100-200 meshes or 200-300 meshes produced by Qingdao ocean chemical plant.

TABLE 1 structural formulas of examples 1-55

Example 1: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

The synthetic route is as follows:

reagents and conditions: a) tetrahydrofuran, acetonitrile, sodium hydrogen, 66 ℃; b) refluxing ethanol, methanesulfonic acid and hydrazine hydrate; c) triphosgene, tetrahydrofuran, 65 ℃; 2.1N ammonia water at 65 ℃; d) tetrahydrofuran, oxalyl chloride monoethyl ester, at 0 ℃ to room temperature; e) sodium ethoxide, ethanol, 0 ℃ to room temperature; f) sodium hydroxide, ethanol, water, room temperature; g) refluxing chloroform and thionyl chloride; h) dichloromethane, triethylamine, N-Boc-piperazine at-35 ℃; i) 5-methyl-3-aminopyrazole, DMF, 65 ℃; j)2N hydrogen chloride-ethyl acetate solution at room temperature.

a) 8.80g (100mmol) of ethyl acetate (I-1) and 12.3g (300mmol) of acetonitrile were dissolved in 180mL of anhydrous tetrahydrofuran, and 12.5g (300mmol) of sodium hydride was added portionwise with stirring at 0 ℃ and the reaction was heated to reflux for 1.5 h. The reaction solution was slowly poured into 200mL of ice water at room temperature, the pH was adjusted to 2-3 with 2N hydrochloric acid, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3.68g of a pale yellow oily substance (I-2) with a yield of 45.4%. GC-MS M/z 83.1[ M ] +.

b) 0.83g (10.0mmol) of 3-oxobutyronitrile (I-2) and 0.70mL (10.0mmol) of hydrazine hydrate are dissolved in 50mL of anhydrous ethanol, 96.0mg (1.0mmol) of methanesulfonic acid is added to the mixed solution, the mixture is heated to reflux for 45min, and the reaction is detected to be complete by TLC (iodophor). The solvent was evaporated under reduced pressure to give a yellow oil, which was purified by silica gel chromatography (petroleum ether: ethyl acetate: 3:1) to give 0.82g of a pale yellow oil (I-3) in 84.5% yield. GC-MS M/z 97.1[ M ] +.

c) 2.00g (11.6mmol) of 2-amino-5-chlorobenzoic acid (I-4) was dissolved in 20mL of dry tetrahydrofuran, 1.20g (3.90mmol) of triphosgene was added with stirring, the temperature was raised to 60 ℃ for reaction for 12 hours, and the completion of the reaction was monitored by TLC. And cooling to room temperature, evaporating to remove the solvent under reduced pressure, adding 1N ammonia water, heating to 60 ℃, reacting for 1h, separating out a white solid, and monitoring the reaction completion by TLC. Cooling to room temperature, filtering, washing with water (10 mL. times.3), drying the filter cake to constant weight to obtain 1.68g of white powdery solid with yield of 84.9%. 1H-NMR (400MHz, DMSO-d6):7.85(s,1H),7.60(d, J ═ 2.44Hz,1H),7.18-7.16(m,2H),6.72(d, J ═ 8.80Hz,1H),6.40(br, 2H).

d) 1.68g (9.85mmol) of 2-amino-5-chlorobenzamide (I-5) and 1.63Ml (11.8mmol) of triethylamine were dissolved in 34mL of dry tetrahydrofuran, and 1.15mL (10.8mmol) of oxalyl chloride monoethyl ester was added dropwise to the reaction mixture with stirring at 0 ℃ and then allowed to react at room temperature for 1 hour after completion of the addition, and the completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, and 40mL of ethyl acetate was added to dissolve the solvent, the mixture was washed with water (10mL × 3), and the mixture was washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the mixture was purified by silica gel chromatography (dichloromethane: acetone ═ 50:1) to obtain 2.50g of an off-white powdery solid with a yield of 93.9%.¹H-NMR(400MHz,DMSO-d6):13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。

e) 2.50g (9.24mmol) of ethyl 2- (2-carboxamido-4-chloro-phenyl) aminooxalate (I-6) were dissolvedIn 28mL of ethanol, 7.60mL (11.1mmol) of 10% sodium ethoxide ethanol solution is slowly dropped into the solution under stirring at 0 ℃, the reaction is continued for 3h, and the completion of the reaction is monitored by TLC. The pH was adjusted to 3-4 with 1N hydrochloric acid, a white solid was precipitated, which was filtered, washed with water (10mL × 3), the cake was dried to a constant weight, and purified by silica gel chromatography (dichloromethane: acetone ═ 100:1) to obtain 2.00g of a white powdery solid with a yield of 85.8%.¹H-NMR(400MHz,DMSO-d6):12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。

f) 2.00g (7.92mmol) of ethyl 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylate (I-7) was dissolved in 25mL of ethanol, and 25.5mL (63.4mmol) of 10% aqueous sodium hydroxide was added to the solution with stirring at room temperature, and the reaction was continued for 0.5H, and the completion of the reaction was monitored by TLC. The pH was adjusted to 3 with 2N hydrochloric acid, a white solid was precipitated, filtered under suction, washed with water (10mL × 3), and the cake was dried to a constant weight to obtain 1.70g of an off-white powdery solid with a yield of 95.5%.

g) 0.23g (1.00mmol) of 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylic acid (I-8) was dissolved in 5mL of chloroform, 0.87mL (12.0mmol) of thionyl chloride and a drop of N, N-dimethylformamide were added to the solution, the reaction was warmed to reflux for 0.5H, and the completion of the reaction was monitored by TLC. Cooling to room temperature, and evaporating the solvent under reduced pressure to obtain an intermediate (I-6), and immediately carrying out the next reaction.

h) The intermediate (I-9) was dissolved in 5mL of dry dichloromethane, stirred at-35 deg.C, and then 0.42mL (3.00mmol) of triethylamine and 185mg (1.00mmol) of N-Boc-piperazine were slowly added dropwise to the solution, followed by reaction for 0.5h and TLC to monitor completion of the reaction. After quenching with water, 30mL of dichloromethane, water (10mL × 3) and saturated brine (10mL × 3) were added, and the mixture was dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by silica gel chromatography (dichloromethane: methanol ═ 50:1) to obtain 0.40g of a yellow powdery solid with a yield of 48.7%.¹H-NMR(400MHz,CDCl3):8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。

i) 0.20g (0.49mmol) of 4, 6-dichloro-2- [1- (4-N-tert-butoxycarbonyl) piperazinyl]Formylquinazoline (I-10),47.5mg (0.49mmol) of 5-methyl-3-amino-1H-pyrazole (I-3) and 0.096mL (0.59mmol) of N, N-diisopropylethylamine were dissolved in 4mL1, 4-dioxane, and the reaction was warmed to reflux for 3H to precipitate a pale yellow solid which was monitored by TLC for completion of the reaction. Cooling to room temperature, suction filtering, purifying the filter cake by silica gel chromatography (dichloromethane: methanol 20:1, 0.5% triethylamine) and 10 times methanol hot beating to obtain white powdery solid 0.07g, yield 30.3%.¹H-NMR(400MHz,DMSO-d6):12.28(s,1H),10.71(s,1H),8.89(s,1H),7.89(dd,J＝2.00,8.92Hz,1H),7.79(d,J＝8.92Hz,1H),6.56(s,1H),3.64-3.62(m,2H),3.44(s,2H),3.29-3.27(m,4H),2.27(s,3H),1.40(s,9H)。

j) Dissolving the solid (I-11) in 2mL hydrochloric acid/ethyl acetate, reacting for 6h under stirring at room temperature, separating out a white solid, carrying out suction filtration, and drying a filter cake to constant weight to obtain 0.06g of a white powdery solid with a yield of 96.7%. mp 341.8-342.6 ℃. ESI-MS M/z 372.1[ M + H ] +. 1H-NMR (400MHz, DMSO-d6):11.47(s,1H),9.59(s,2H),9.01(s,1H),8.01(dd, J ═ 8.92Hz,1H),7.91(d, J ═ 2.42,8.84Hz,1H),6.56(s,1H),3.92-3.91(m,2H),3.71(s,2H),3.23(s,2H),3.09(s,2H),2.32(s, 2H).

Example 2: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

The procedure of example 1 was followed to replace the starting material 2-amino-5-chlorobenzoic acid in step c) with 2-aminobenzoic acid,

example 2 was obtained via steps a-j. ESI-MS M/z 338.4[ M + H ] +.

Example 3: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 3 was obtained by following the procedure of example 1, replacing the ethyl acetate feed in step a) with ethyl cyclopropanecarboxylate, the 2-amino-5-chlorobenzoic acid feed in step c) with 2-aminobenzoic acid, and the 5-methyl-3-amino-1H-pyrazole feed in step i) with 5-cyclopropyl-3-amino-1H-pyrazole, via steps a-j. ESI-MS M/z 364.2[ M + H ] +.

Example 4: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-isopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 4 was obtained via steps a-j following the procedure of example 1, replacing the ethyl acetate feed in step a) with ethyl isobutyrate, the 2-amino-5-chlorobenzoic acid feed in step c) with 2-aminobenzoic acid, and the 5-methyl-3-amino-1H-pyrazole feed in step i) with 5-isopropyl-3-amino-1H-pyrazole. ESI-MS M/z 366.1[ M + H ] +.

Example 5: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclobutyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 5 was obtained via steps a-j following the procedure of example 1, replacing the ethyl acetate feed in step a) with ethyl cyclobutyrate, the 2-amino-5-chlorobenzoic acid feed in step c) with 2-aminobenzoic acid, and the 5-methyl-3-amino-1H-pyrazole feed in step i) with 5-cyclobutyl-3-amino-1H-pyrazole. ESI-MS M/z 377.1[ M + H ] +.

Example 6: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-phenyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 6 was obtained by following the procedure of example 1, replacing the ethyl acetate feed in step a) with methyl benzoate, the 2-amino-5-chlorobenzoic acid feed in step c) with 2-aminobenzoic acid, and the 5-methyl-3-amino-1H-pyrazole feed in step i) with 5-phenyl-3-amino-1H-pyrazole feed through steps a-j. ESI-MS M/z 400.3[ M + H ] +.

Example 7: 2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-benzyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 7 was obtained by following the procedure of example 1, replacing the ethyl acetate feed in step a) with methyl phenylacetate, the 2-amino-5-chlorobenzoic acid feed in step c) with 2-aminobenzoic acid, and the 5-methyl-3-amino-1H-pyrazole feed in step i) with 5-benzyl-3-amino-1H-pyrazole in steps a-j. ESI-MS M/z 414.4[ M + H ] +.

Example 8: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 8 was obtained via steps a-j following the procedure of example 1, replacing the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate and replacing the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole. ESI-MS M/z 398.5[ M + H ] +.

Example 9: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-isopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 9 was obtained via steps a-j following the procedure of example 1, substituting ethyl acetate as feed in step a) with ethyl isobutyrate and 5-methyl-3-amino-1H-pyrazole in step i) with 5-isopropyl-3-amino-1H-pyrazole. ESI-MS M/z 400.6[ M + H ] +.

Example 10: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 10 was obtained via steps a-j following the procedure of example 1, replacing the crude ethyl acetate in step a) with ethyl benzoate and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-phenyl-3-amino-1H-pyrazole. ESI-MS M/z 434.5[ M + H ] +.

Example 11: 6-chloro-2- [ 4-morpholinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

The synthetic route is as follows:

reagents and conditions: a) triphosgene, tetrahydrofuran, 65 ℃; 2.1N ammonia water at 65 ℃; b) tetrahydrofuran, oxalyl chloride monoethyl ester, at 0 ℃ to room temperature; c) sodium ethoxide, ethanol, 0 ℃ to room temperature; d) sodium hydroxide, ethanol, water, room temperature; e) refluxing chloroform and thionyl chloride; f) dichloromethane, triethylamine, morpholine, at-35 ℃; g) 5-methyl-3-aminopyrazole, DMF, 65 ℃; h)2N hydrogen chloride-ethyl acetate solution at room temperature.

a) 2.00g (11.6mmol) of 2-amino-5-chlorobenzoic acid (I-1) was dissolved in 20mL of dry tetrahydrofuran, 1.20g (3.90mmol) of triphosgene was added with stirring, the temperature was raised to 60 ℃ for reaction for 12 hours, and the completion of the reaction was monitored by TLC. Cooling to room temperature, evaporating to remove the solvent under reduced pressure, adding 1N ammonia water, heating to 60 ℃ for reaction for 1h, separating out a white solid, and monitoring the reaction completion by TLC. Cooling to room temperature, filtering, washing with water (10 mL. times.3), drying the filter cake to constant weight to obtain 1.68g of white powdery solid with yield of 84.9%.¹H-NMR(400MHz,DMSO-d6):7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。

b) 1.68g (9.85mmol) of 2-amino-5-chlorobenzamide (I-2) and 1.63Ml (11.8mmol) of triethylamine were dissolved in 34mL of dry tetrahydrofuran, and 1.15mL (10.8mmol) of oxalyl chloride monoethyl ester was added dropwise to the reaction mixture with stirring at 0 ℃ and then allowed to react at room temperature for 1 hour after completion of the addition, and the completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, and 40mL of ethyl acetate was added to dissolve the solvent, the mixture was washed with water (10mL × 3), and the mixture was washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the mixture was purified by silica gel chromatography (dichloromethane: acetone ═ 50:1) to obtain 2.50g of an off-white powdery solid with a yield of 93.9%.¹H-NMR(400MHz,DMSO-d6):13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。

c) 2.50g (9.24mmol) of ethyl 2- (2-carboxamido-4-chloro-phenyl) aminooxalate (I-3) are dissolved in 28mL of ethanol, 7.60mL (11.1mmol) of 10% sodium ethoxide ethanol solution is slowly added dropwise to the solution with stirring at 0 ℃ and the reaction is continued for 3h, and the reaction is monitored by TLC to be complete. The pH was adjusted to 3-4 with 1N hydrochloric acid, a white solid was precipitated, which was filtered, washed with water (10mL × 3), the cake was dried to a constant weight, and purified by silica gel chromatography (dichloromethane: acetone ═ 100:1) to obtain 2.00g of a white powdery solid with a yield of 85.8%.¹H-NMR(400MHz,DMSO-d6):12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。

d) 2.00g (7.92mmol) of ethyl 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylate (I-4) was dissolved in 25mL of ethanol, 25.5mL (63.4mmol) of 10% aqueous sodium hydroxide was added to the solution with stirring at room temperature, the reaction was continued for 0.5H, and the completion of the reaction was monitored by TLC. The pH was adjusted to 3 with 2N hydrochloric acid, a white solid was precipitated, filtered under suction, washed with water (10mL × 3), and the cake was dried to a constant weight to obtain 1.70g of an off-white powdery solid with a yield of 95.5%.

e) 0.23g (1.00mmol) of 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylic acid (I-5) was dissolved in 5mL of chloroform, 0.87mL (12.0mmol) of thionyl chloride and a drop of N, N-dimethylformamide were added to the solution, the reaction was warmed to reflux for 0.5H, and the completion of the reaction was monitored by TLC. Cooling to room temperature, and evaporating the solvent under reduced pressure to obtain an intermediate (I-6), and immediately carrying out the next reaction.

f) The intermediate (I-6) was dissolved in 5mL of dry dichloromethane, stirred at-35 deg.C, and then 0.42mL (3.00mmol) of triethylamine and 0.087mL (1.00mmol) of morpholine were added dropwise slowly to the solution, followed by reaction for 0.5h and TLC to monitor completion of the reaction. After quenching with water, 30mL of dichloromethane, water (10mL × 3) and saturated brine (10mL × 3) were added, and the mixture was dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by silica gel chromatography (dichloromethane: methanol ═ 50:1) to obtain 0.27g of a yellow powdery solid with a yield of 86.5%.

g) 0.15g (0.49mmol) of 4, 6-dichloro-2- (4-morpholinyl) formylquinazoline (I-7), 47.5mg (0.49mmol) of 5-methyl-3-amino-1H-pyrazole (prepared as described above), 0.096mL (0.59mmol) of N, N-diisopropylethylamine and 4mL of 1, 4-dioxane were placed in a sealed tube, the temperature was raised to 130 ℃ and the reaction was carried out for 24H, whereupon a pale yellow solid precipitated and the reaction was monitored by TLC for completion. Filtering, drying the filter cake to constant weight, and thermally pulping by 30 times of methanol to obtain 0.09g of white powdery solid with the yield of 49.4 percent. mp 326.9-327.4 ℃. ESI-MS M/z 373.1[ M + H ]]+。¹H-NMR(400MHz,DMSO-d6):12.29(s,1H),10.71(s,1H),8.89(d,J＝1.88Hz,1H),7.88(dd,J＝2.04,8.92Hz,1H),7.80(d,J＝8.92Hz,1H),6.58(s,1H),3.68-3.66(m,4H),3.54-3.52(m,2H),3.31-3.28(m,2H),2.28(s,3H)。

Example 12: 6-chloro-2- [ 4-methylpiperazino ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 12 was obtained via steps a-g following the procedure of example 11 substituting morpholine in step f) for 4-methylpiperazine. ESI-MS M/z 434.5[ M + H ] +.

Example 13: 6-chloro-2- [ piperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazolines

Example 13 was obtained via steps a-g following the procedure of example 11 substituting morpholine in step f) with piperidine. ESI-MS M/z 371.6[ M + H ] +.

Example 14: 6-chloro-2- [1, 1-dioxothiomorpholinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 14 was obtained via steps a-g following the procedure of example 11, substituting morpholine in step f) with 1, 1-dioxothiomorpholine. ESI-MS M/z 412.7[ M + H ] +.

Example 15: 6-chloro-2- [ 3-oxopiperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 15 was obtained via steps a-g following the procedure of example 11 substituting morpholine in step f) for piperazine 2-one. ESI-MS M/z 386.5[ M + H ] +.

Example 16: 6-chloro-2- [ 4-hydroxypiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 16 was obtained via steps a-g following the procedure of example 11 substituting morpholine in step f) with 4-hydroxypiperidine. ESI-MS M/z 387.5[ M + H ] +.

Example 17: 6-chloro-2- [ 4-hydroxy-4-methylpiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 17 was obtained via steps a-g following the procedure of example 11 substituting morpholine in step f) with 4-hydroxy-4-methylpiperidine. ESI-MS M/z 401.5[ M + H ] +.

Example 18: 6-chloro-2- [ 4-aminopiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 18 was obtained via steps a-g following the procedure of example 1 substituting N-Boc-piperazine with 4-N-Boc-aminopiperidine in step h). ESI-MS M/z 386.5[ M + H ] +.

Example 19: 6-chloro-2- [ 4-hydroxy-4-methylpiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 19 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine with 4-N-Boc-amino-4-methylpiperidine in step h). ESI-MS M/z 400.5[ M + H ] +.

Example 20: 6-chloro-2- [2, 6-diazaspiro [3.3] heptan-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 20 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step i) with 3-N-Boc-amino-mono-oxetane. ESI-MS M/z 358.5[ M + H ] +.

Example 21: 6-chloro-2- [ 3-amino-monoheterocycloalkyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 21 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step i) with tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate. ESI-MS M/z 384.5[ M + H ] +.

Example 22: 6-chloro-2- [ (1R,4R)2, 5-diazabicyclo (2.2.1) heptan-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 22 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with (1R,4R) -2-tert-butoxycarbonyl-2, 5-diazabicyclo (2.2.1) heptane. ESI-MS M/z 384.5[ M + H ] +.

Example 23: 6-chloro-2- [ (hexahydropyrrolo [3,4-c ] pyrrol-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 24 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2-carboxylate. ESI-MS M/z 400.5[ M + H ] +.

Example 24: 6-chloro-2- [ 4-aminopiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 24 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine with 4-N-Boc-amino-4-methylpiperidine in step h). ESI-MS M/z 400.5[ M + H ] +.

EXAMPLE 25(S) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 25 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with (S) -2-methyl-N-Boc-piperazine. ESI-MS M/z 386.6[ M + H ] +.

Example 26: (R) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 26 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with (R) -2-methyl-N-Boc-piperazine. ESI-MS M/z 386.5[ M + H ] +.

Example 27: (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 27 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with (R) -3-methyl-N-Boc-piperazine. ESI-MS M/z 386.6[ M + H ] +.

Example 28: (S) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 28 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with (S) -3-methyl-N-Boc-piperazine. ESI-MS M/z 386.4[ M + H ] +.

Example 29: 6-chloro-2- [3, 5-dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 29 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with 3, 5-dimethyl-N-Boc-piperazine. ESI-MS M/z 400.5[ M + H ] +.

Example 30: 6-chloro-2- [3, 3' -dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 30 was obtained via steps a-j following the procedure of example 1 substituting N-Boc-piperazine in step h) with 3, 3' -dimethyl-N-Boc-piperazine. ESI-MS M/z 400.5[ M + H ] +.

Example 31: 6-chloro-2- [3, 3' -dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with 3, 3' -dimethyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 31 was obtained via steps a-j. ESI-MS M/z 426.5[ M + H ] +.

Example 32: (S) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropa-zolyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with (S) -2-methyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 32 was obtained via steps a-j. ESI-MS M/z 412.6[ M + H ] +.

Example 33: (R) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 33 was obtained via steps a-j following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine in step H) with (R) -2-methyl-N-Boc-piperazine, and substituting 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole. ESI-MS M/z 412.5[ M + H ] +.

Example 34: (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with (R) -3-methyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 34 was obtained via steps a-j. ESI-MS M/z 412.6[ M + H ] +.

Example 35: (S) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with (S) -3-methyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 35 was obtained via steps a-j. ESI-MS M/z 412.4[ M + H ] +.

Example 36: 6-chloro-2- [3, 5-dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with 3, 5-dimethyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 36 was obtained via steps a-j. ESI-MS M/z 426.5[ M + H ] +.

Example 37: (R) -6-chloro-2- [ 3-ethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with (R) -3-ethyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 37 was obtained via steps a-j. ESI-MS M/z 426.6[ M + H ] +.

Example 38: (R) -6-chloro-2- [ 3-isopropyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 38 was obtained by following the procedure of example 1, replacing the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, replacing N-Boc-piperazine in step H) with (R) -3-isopropyl-N-Boc-piperazine, and replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 440.6[ M + H ] +.

Example 39: (R) -6-chloro-2- [ 3-isopropyl-1-piperazinyl ] formyl-4- [1H-3- (5-phenyl) pyrazolyl ] aminoquinazoline hydrochloride

Following the procedure of example 1, substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, substituting N-Boc-piperazine with (R) -3-phenyl-N-Boc-piperazine in step H), and substituting 5-methyl-3-amino-1H-pyrazole with 5-cyclopropyl-3-amino-1H-pyrazole in step i), example 39 was obtained via steps a-j. ESI-MS M/z 474.5[ M + H ] +.

Example 40: 6-chloro-2- [ 1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

The synthetic route is as follows:

reagents and conditions: a) lawson's reagent, toluene, reflux.

a) 124mg (0.33mmol) of 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline was dissolved in 5mL of dry toluene, 404mg (1.00mmol) of Lawson's reagent was added with stirring, the mixture was heated to reflux for 12 hours, and the reaction was monitored by TLC. Cooling to room temperature, evaporating the solvent under reduced pressure, and performing silica gel column chromatography to obtain white powdery solid 32mg with yield of 24.9%. ESI-MS M/z 388.5[ M + H ] +.

Example 41: 6-chloro-2- [ 1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline

Example 41 was obtained via step a by substituting 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline in step g) with 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline according to the method of example 43. ESI-MS M/z 414.5[ M + H ] +.

Example 42: (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

Example 42 was obtained via step a by substituting 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline in step g) with (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline according to the method of example 43. ESI-MS M/z 402.5[ M + H ] +.

Example 43: (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline

Example 43 was obtained via step a by substituting 6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline in step g) with (R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline according to the method of example 43. ESI-MS M/z 428.5[ M + H ] +.

Example 44: (R) -2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 44 was obtained via steps a-j following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-aminobenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole. ESI-MS M/z 378.2[ M + H ] +.

Example 45: (R) -6-fluoro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 45 was obtained by following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-amino 5-fluorobenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 396.2[ M + H ] +.

Example 46: (R) -6-bromo-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 46 was obtained by following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-amino 5-bromobenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 456.2[ M + H ] +.

Example 47: (R) -6-methyl-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 47 was obtained by following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-amino 5-methylbenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 392.2[ M + H ] +.

Example 48: (R) -6-methoxy-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 48 was obtained by following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-amino 5-methoxybenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 408.3[ M + H ] +.

Example 49: (R) -7-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

Example 49 was obtained by following the procedure of example 1 substituting the crude ethyl acetate in step a) with ethyl cyclopropanecarboxylate, the crude 2-amino 5-chlorobenzoic acid in step c) with 2-amino 6-chlorobenzoic acid, the N-Boc-piperazine in step H) with (R) -3-methyl-N-Boc-piperazine, and the 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole via steps a-j. ESI-MS M/z 412.5[ M + H ] +.

Example 50: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-methyl-1H-imidazol 4-yl ] aminoquinazoline hydrochloride

Synthetic routes such asThe following:

reagents and conditions: a) methyl iodide, acetonitrile, potassium carbonate, 65 ℃; b)1) stirring hydrogen and palladium carbon at room temperature 2) adding hydrogen chloride-ethanol solution and ethanol at 0 ℃; c)1) triphosgene, tetrahydrofuran, 65 ℃; 2) 1N ammonia water at 65 ℃; d) tetrahydrofuran, oxalyl chloride monoethyl ester, at 0 ℃ to room temperature; e) sodium ethoxide, ethanol, 0 ℃ to room temperature; f) sodium hydroxide, ethanol, water, room temperature; g) refluxing chloroform and thionyl chloride; h) dichloromethane, triethylamine, N-Boc-piperazine at-35 ℃; i) 5-methyl-3-aminopyrazole, DMF, 65 ℃; j)2N hydrogen chloride-ethyl acetate solution at room temperature.

a) The preparation method comprises the steps of uniformly mixing 11.3g (0.10mol) of 4-nitroimidazole (I-1) and 25mL of DMF (dimethyl formamide), adding 20.7 g (0.15mol) of potassium carbonate, slowly dropwise adding 7.5mL of methyl iodide (0.12mol) into the solution under stirring at room temperature, maintaining the reaction temperature at 65 ℃ for 24 hours, adding 5mL of diethylamine, stirring at room temperature for half an hour, evaporating to remove a solvent, adding 100mL of water and 50mL of ethyl acetate, extracting for 5 times, combining organic phases, drying, concentrating under reduced pressure, and carrying out column chromatography separation to obtain 9.2g of white-like solid with the yield of 72.4%. ESI-MS (m/z): 128[ M + H ]]⁺.

b) Dissolving 6.4g (0.05mol) of 1-methyl-1H-4-4-nitroimidazole (I-2) in 50ml of absolute ethanol, adding 1.0g of 10% palladium carbon, reacting for 6 hours under stirring at room temperature in a hydrogen atmosphere, filtering out the palladium carbon, evaporating to remove the solvent, adding 50ml of hydrogen chloride-ethanol solution, stirring in an ice bath, precipitating a solid, filtering to obtain 5.2g of an off-white solid, and obtaining the yield of 63.5%. ESI-MS (m/z): 98[ M + H ]]⁺.

c) 2.00g (11.6mmol) of 2-amino-5-chlorobenzoic acid (I-4) was dissolved in 20mL of dry tetrahydrofuran, 1.20g (3.90mmol) of triphosgene was added with stirring, the temperature was raised to 60 ℃ for reaction for 12 hours, and the completion of the reaction was monitored by TLC. Cooling to room temperature, evaporating to remove the solvent under reduced pressure, adding 1N ammonia water, heating to 60 ℃ for reaction for 1h, separating out a white solid, and monitoring the reaction completion by TLC. Cooling to room temperature, filtering, washing with water (10 mL. times.3), drying the filter cake to constant weight to obtain 1.68g of white powdery solid with yield of 84.9%.¹H-NMR(400MHz,DMSO-d6):7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。

e) 2.50g (9.24mmol) of ethyl 2- (2-carboxamido-4-chloro-phenyl) aminooxalate (I-6) are dissolved in 28mL of ethanol, 7.60mL (11.1mmol) of 10% sodium ethoxide ethanol solution is slowly added dropwise to the solution with stirring at 0 ℃, the reaction is continued for 3h, and the completion of the reaction is monitored by TLC. The pH was adjusted to 3-4 with 1N hydrochloric acid, a white solid was precipitated, which was filtered, washed with water (10mL × 3), the cake was dried to a constant weight, and purified by silica gel chromatography (dichloromethane: acetone ═ 100:1) to obtain 2.00g of a white powdery solid with a yield of 85.8%.¹H-NMR(400MHz,DMSO-d₆):12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。

h) The intermediate (I-9) was dissolved in 5mL of dry dichloromethane, stirred at-35 deg.C, and then 0.42mL (3.00mmol) of triethylamine and 185mg (1.00mmol) of N-Boc-piperazine were slowly added dropwise to the solution, followed by reaction for 0.5h and TLC to monitor completion of the reaction. After quenching with water, 30mL of dichloromethane, water (10mL × 3) and saturated brine (10mL × 3) were added, and the mixture was dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by silica gel chromatography (dichloromethane: methanol ═ 50:1) to obtain 0.40g of a yellow powdery solid with a yield of 48.7%.¹H-NMR(400MHz,CDCl₃):8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。

i) 0.20g (0.49mmol) of 4, 6-dichloro-2- [1- (4-N-tert-butoxycarbonyl) piperazinyl ] formylquinazoline (I-10), 65.0mg (0.49mmol) of 1-methyl-1H-imidazol-4-amine hydrochloride (I-3) and 0.18mL (1.08mmol) of N, N-diisopropylethylamine were dissolved in 4mL of DMMF and the temperature was raised to 65 ℃ for 12H. Cooled to room temperature, poured into water, filtered and the filter cake purified by silica gel chromatography (dichloromethane: methanol 20:1, 0.5% triethylamine) to give 0.023g of white powdery solid with 10.3% yield.

j) Dissolving the solid (I-11) in 2mL hydrochloric acid/ethyl acetate, reacting for 6h under stirring at room temperature, separating out a yellow solid, performing suction filtration, and drying a filter cake to constant weight to obtain 0.017g of yellow powdery solid with the yield of 95.0%. ESI-MS M/z 372.1[ M + H ] +.

Example 51: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-cyclopropyl-1H-imidazol 4-yl ] aminoquinazoline hydrochloride

The synthetic route is as follows:

reagents and conditions: a) nitric acid, acetic anhydride and acetic acid, wherein the temperature is 0 ℃ to room temperature; b) water, methanol, cyclopropylamine, room temperature; c)1) stirring hydrogen and palladium carbon at room temperature 2) adding hydrogen chloride-ethanol solution and ethanol at 0 ℃; d) triphosgene, tetrahydrofuran, 65 ℃; 2.1N ammonia water at 65 ℃; e) tetrahydrofuran, oxalyl chloride monoethyl ester, at 0 ℃ to room temperature; f) sodium ethoxide, ethanol, 0 ℃ to room temperature; j) sodium hydroxide, ethanol, water, room temperature; h) refluxing chloroform and thionyl chloride; i) dichloromethane, triethylamine, morpholine, at-35 ℃; j) 1-cyclopropyl-1H-imidazole 4-amine hydrochloride, DMF, 65 ℃; k)2N hydrogen chloride-ethyl acetate solution at room temperature.

a) Dispersing 11.3g (0.10mol) of 4-nitroimidazole (I-1) in 200mL of acetic acid, slowly dropwise adding 50mL of nitric acid and 139mL of acetic anhydride into the solution in sequence under the stirring of ice bath, keeping the reaction temperature at 25 ℃ after dropwise adding, reacting for 1 hour, pouring into 1.5L of ice water, extracting for 5 times by 100mL of ethyl acetate, combining organic phases, washing by a sodium bicarbonate solution, drying, and concentrating under reduced pressure to obtain an off-white solid.¹H NMR(400MHz,CDCl₃)8.54(d,J＝1.60Hz,1H),8.40(d,J＝1.56Hz,1H).

b) Dissolving 1, 4-dinitroimidazole (I-2) in 200ml of methanol, adding 200ml of water, dropwise adding 8.6g (0.15mol) of cyclopropylamine, maintaining the reaction temperature at 25 ℃ after dropwise addition, reacting for 24 hours, evaporating the solvent, adding 100ml of water and 50ml of ethyl acetate, extracting for 5 times, combining organic phases, drying, concentrating under reduced pressure, and performing column chromatography to obtain 7.3g of off-white solid with the yield of 47.4%. ESI-MS (m/z): 154[ M + H ]]⁺.¹H NMR(400MHz,CDCl₃)7.76(s,1H),7.47(s,1H),3.45-3.40(m,1H),1.12-0.99(m,4H).

c) Dissolving 4.6g (0.03mol) of 1-cyclopropyl 4-nitroimidazole (I-3) in 50ml of absolute ethanol, adding 0.6g of 10% palladium carbon, reacting for 6 hours under stirring at room temperature in a hydrogen atmosphere, filtering the palladium carbon, removing the solvent by evaporation, adding 30ml of hydrogen chloride-ethanol solution, stirring in an ice bath, precipitating a solid, and filtering to obtain 2.0g of an off-white solid with the yield of 53.8%. ESI-MS (m/z): 124[ M + H ]]⁺.

d) 2.00g (11.6mmol) of 2-amino-5-chlorobenzoic acid (I-5) was dissolved in 20mL of dry tetrahydrofuran, 1.20g (3.90mmol) of triphosgene was added with stirring, the temperature was raised to 60 ℃ for 12h, and the completion of the reaction was monitored by TLC. Cooling to room temperature, evaporating to remove the solvent under reduced pressure, adding 1N ammonia water, heating to 60 ℃ for reaction for 1h, separating out a white solid, and monitoring the reaction completion by TLC. Cooling to room temperature, filtering, washing with water (10 mL. times.3), drying the filter cake to constant weight to obtain 1.68g of white powdery solid with yield of 84.9%.¹H-NMR(400MHz,DMSO-d₆):7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。

e) 1.68g (9.85mmol) of 2-amino-5-chlorobenzamide (I-6) and 1.63Ml (11.8mmol) of triethylamine were dissolved in 34mL of dry tetrahydrofuran, and 1.15mL (10.8mmol) of oxalyl chloride monoethyl ester was added dropwise to the reaction mixture with stirring at 0 ℃ and then allowed to react at room temperature for 1 hour after completion of the addition, and the completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, and 40mL of ethyl acetate was added to dissolve the solvent, the mixture was washed with water (10mL × 3), and the mixture was washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the mixture was purified by silica gel chromatography (dichloromethane: acetone ═ 50:1) to obtain 2.50g of an off-white powdery solid with a yield of 93.9%.¹H-NMR(400MHz,DMSO-d₆):13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。

f) 2.50g (9.24mmol) of ethyl 2- (2-carboxamido-4-chloro-phenyl) aminooxalate (I-7) are dissolved in 28mL of ethanol, 7.60mL (11.1mmol) of 10% sodium ethoxide ethanol solution is slowly added dropwise to the solution with stirring at 0 ℃, the reaction is continued for 3h, and the completion of the reaction is monitored by TLC. The pH was adjusted to 3-4 with 1N hydrochloric acid, a white solid was precipitated, which was filtered, washed with water (10mL × 3), the cake was dried to a constant weight, and purified by silica gel chromatography (dichloromethane: acetone ═ 100:1) to obtain 2.00g of a white powdery solid with a yield of 85.8%.¹H-NMR(400MHz,DMSO-d₆):12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。

g) 2.00g (7.92mmol) of ethyl 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylate (I-8) was dissolved in 25mL of ethanol, and 25.5mL (63.4mmol) of 10% aqueous sodium hydroxide was added to the solution with stirring at room temperature, and the reaction was continued for 0.5H, and the completion of the reaction was monitored by TLC. The pH was adjusted to 3 with 2N hydrochloric acid, a white solid was precipitated, filtered under suction, washed with water (10mL × 3), and the cake was dried to a constant weight to obtain 1.70g of an off-white powdery solid with a yield of 95.5%.

h) 0.23g (1.00mmol) of 6-chloro-4-oxo-3H, 4H-quinazoline-2-carboxylic acid (I-9) was dissolved in 5mL of chloroform, 0.87mL (12.0mmol) of thionyl chloride and a drop of N, N-dimethylformamide were added to the solution, the reaction was warmed to reflux for 0.5H, and the completion of the reaction was monitored by TLC. Cooling to room temperature, and evaporating the solvent under reduced pressure to obtain an intermediate (I-6), and immediately carrying out the next reaction.

i) The intermediate (I-10) was dissolved in 5mL of dry dichloromethane, stirred at-35 ℃ and slowly added dropwise to the solution in this order 0.42mL (3.00mmol) of triethylamine and 185mg (1.00mmol) of N-Boc-piperazine, and the reaction was continued for 0.5h with TLC to monitor completion of the reaction. After quenching with water, 30mL of dichloromethane, water (10mL × 3) and saturated brine (10mL × 3) were added, and the mixture was dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by silica gel chromatography (dichloromethane: methanol ═ 50:1) to obtain 0.40g of a yellow powdery solid with a yield of 48.7%.¹H-NMR(400MHz,CDCl₃):8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。

j) 0.20g (0.49mmol)4, 6-dichloro-2- [1- (4-N-tert-butoxycarbonyl) piperazinyl ] formylquinazoline (I-11), 79mg (0.49mmol) 1-cyclopropyl-1H-imidazol-4-amine hydrochloride (I-4) and 0.18mL (1.08mmol) N, N-diisopropylethylamine were dissolved in 4mL DMF and heated to 65 ℃ for 12H. Cooled to room temperature, poured into water, filtered with suction, and the filter cake purified by silica gel chromatography (dichloromethane: methanol 20:1, 0.5% triethylamine) to give 0.018g of a white powdery solid in 7.2% yield.

k) Dissolving the solid (I-12) in 2mL hydrochloric acid/ethyl acetate, reacting for 6h under stirring at room temperature, separating out a yellow solid, performing suction filtration, and drying a filter cake to constant weight to obtain 0.015g of yellow powdery solid with the yield of 98.0%. ESI-MS M/z 398.5[ M + H ] +.

Example 52: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-trifluoroethyl-1H-imidazol 4-yl ] aminoquinazoline hydrochloride

Example 52 was obtained by following the procedure of example 51 substituting cyclopropylamine as starting material in step b) with trifluoroethylamine and 1-cyclopropyl-1H-imidazol-4-amine hydrochloride in step j) with 1-trifluoroethyl-1H-imidazol-4-amine hydrochloride via steps a-k. ESI-MS M/z 440.5[ M + H ] +.

Example 53: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-cyclopropylmethyl-1H-imidazol-4-yl ] aminoquinazoline hydrochloride

Example 53 was obtained by following the procedure of example 50 by replacing the starting material methyl iodide in step 1) with cyclopropylmethyl bromide and the solvent with DMF and replacing the 1-methyl-1H-imidazol-4-amine hydrochloride in step i) with 1-cyclopropylmethyl-1H-imidazol-4-amine hydrochloride via steps a-j. ESI-MS M/z 440.5[ M + H ] +.

Example 54: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-isopropyl-1H-imidazol 4-yl ] aminoquinazoline hydrochloride

Example 54 was obtained by the method of example 50, substituting raw material methyl iodide in step 1) with isopropyl bromide and the solvent with DMF, and substituting 1-methyl-1H-imidazol-4-amine hydrochloride in step i) with 1-isopropyl-1H-imidazol-4-amine hydrochloride, via steps a-j. ESI-MS M/z 400.5[ M + H ] +.

Example 55: 6-chloro-2- [ 1-piperazinyl ] formyl-4- [ 1-isopropyl-1H-imidazol 4-yl ] aminoquinazoline hydrochloride

Example 57 was obtained via steps a-k following the procedure for example 51 substituting cyclopropylamine, as starting material in step 1), with 3-chloroaniline and 1-methyl-1H-imidazol-4-amine hydrochloride in step j) with 1- (3-chlorophenyl) -1H-imidazol-4-amine hydrochloride. ESI-MS M/z 468.5[ M + H ] +.

Example 56: in vitro enzyme inhibitory Activity Studies of partial products of the invention

Experimental materials:

Tecan

f500 microplate reader.

KinEASE^TMSTK kit (containing biotinylated polypeptide substrate S2, Eu3+ labeled monoclonal antibody directed only to specific phosphorylation sites, Sa-XL665 labeled streptavidin, KinEASE enzyme reaction buffer), 384 shallow well plate, PAK4 full-length protein. PAK4 protein concentration 0.0256 ng/. mu.l, MgCl₂Ethylenediaminetetraacetic acid (EDTA), Dithiothreitol (DL-Dithiothreitol, DTT), DMSO.

The experimental method comprises the following steps:

the first step is as follows: and (3) kinase reaction. A compound sample was first prepared as a 20mM solution in DMSO, and then diluted with a kinase reaction buffer solution to 100. mu.M, 10. mu.M, 1. mu.M, etc., as required for the test. PAK4 kinase (concentration 0.0256 ng/. mu.l), ATP (4. mu.M), biotin-labeled polypeptide substrate S2 (1. mu.M) and compound sample (4. mu.l) were then added to 10. mu.l kinase reaction buffer solution (containing MgCl₂5mM and DTT 1mM) and incubated at room temperature for 40 minutes, the kinase phosphorylates substrate S2. Then, 10. mu.l of a detection reagent containing EDTA was added to detect the phosphorylated product.

The second step is that: detecting the phosphorylated product. Rare earth element europium (Eu)³⁺) The labelled antibody recognises the phosphorylated substrate and XL665 labelled streptavidin binds to the biotin on the substrate. Eu (Eu)³⁺Is a fluorescence donor, XL665 is a fluorescence acceptor, when Eu³⁺Close to XL665, Eu³⁺The energy is transferred to XL665, which generates the HTRF signal.

And (3) a result evaluation method: the fluorescent signal is formed by Eu³⁺620nm and XL665 nm. The ratio of the HTRF signal (665/620) for each well plate reaction was calculated.

TABLE 2 percentage of PAK4 inhibitory Activity of some of the example compounds at 1. mu.M, 0.1. mu.M concentration in vitro

Compound (I)	1μM	0.1μM	Compound (I)	1μM	0.1μM
						Example 1	98％	89％	Example 29	84％	52％
Example 8	100％	99％	Example 32	99％	79％
						Example 11	69％	26％	Example 33	99％	92％
Example 12	46％	25％	Example 34	100％	95％
						Example 16	17％	0％	Example 35	99％	75％
Example 17	5％	0％	Example 36	97％	62％
						Example 18	78％	36％	Example 37	100％	97％
Example 19	64％	22％	Example 44	99％	92％
						Example 24	62％	24％	Example 45	99％	95％
Example 25	96％	72％	Example 46	100％	96％
						Example 26	98％	86％	Example 48	97％	92％
Example 27	99％	93％	Example 49	100％	95％
						Example 28	97％	59％

As shown in the table, some compounds in the compounds of the general formula (I) have obvious inhibition effect on the PAK4 kinase activity.

Example 57: partial product of the invention is tested against PAK4/PAK1 in vitro selectivity

Experimental materials: the kit comprises an EnVision multi-label microplate detector, PAK4 full-length protein, PAK1 full-length protein, polypeptide substrates, buffer solutions Hepes, MgCl2 solution, EGTA, EDTA, Brij-35, DTT and other buffer solution components.

The experimental method comprises the following steps: z' -LYTE^TMKinase assay (Z' -LYTE)^TMKinase Assay), conditions were tested according to kit standards. The test method is divided into a kinase reaction step, a conversion reaction step and a detection step.

The reaction steps are specifically as follows:

1. and determining the reaction conditions of the Ki determination experiment according to the results of the enzyme digestion and ATP Km experiments. Wherein PAK1 Km 180000nM, PAK4Km 3000 nM.

2. Compound solution preparation: compound DMSO solution was diluted from 10mM to 1 mM. The solutions were diluted three times in sequence using an agilent automated pipetting station (Bravo) for a total of 11 concentrations.

3. Enzyme reaction: PAK1 (kinase domain) and PAK4 (kinase domain) proteins, oxa-theophyllone (fluorescence donor) and fluorescein (fluorescence acceptor) labeled polypeptide substrates (Ser/thr19, Ser/thr20), ATP (Km) and test compounds were incubated in the kinase 22 ℃ reaction. The 10. mu.L reaction contained 50mM HEPES (pH 7.5), 0.01% Brij-35,10mM MgCl2,1mM EGTA, 2. mu.M FRET polypeptide substrate, and PAK enzyme (20pM PAK1 KD; 80pM PAK4KD).

After 4.60 minutes, 5. mu.L of Z' -LYTE was added^TMKi was calculated by fitting a non-linear equation to the reaction stopped with a kinase reaction conversion Reagent (Development Reagent). The experimental results are as follows:

table 3 part Ki for compounds of the examples PAK4 and PAK1

As shown in the table, the inhibitory activity of some compounds in the compounds of the general formula (I) on PAK4 and the selectivity of PAK4/PAK1 are obviously superior to those of a typical PAK4 inhibitor PF3758309 and staurosporine, and the compounds have obvious technical progress and advantages.

Example 58: in vitro enzyme inhibitory Activity Studies of partial products of the invention

The compounds of formula (I) of the present invention may be administered alone, but are generally administered in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice, for which reference will now be made to the use of the compounds in the manufacture of various pharmaceutical dosage forms, e.g., tablets, capsules, injections, aerosols, suppositories, films, drops, liniments and ointments, for which reference will be made.

Example 59: tablet formulation

10g of the compound of claim 1 (taking the compound in example 34 as an example) is mixed with 20g of auxiliary materials according to a general pharmaceutical tabletting method, and then the mixture is pressed into 100 tablets, wherein each tablet is 300 mg.

Example 60: capsule preparation

10g of the compound of claim 1 (taking the compound of example 34 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.

Example 61: injection preparation

The compound of claim 1 (example 34) was used 10g, and the mixture was filtered through a 0.65 μm microporous membrane by activated carbon adsorption, and then filled in a nitrogen gas tank to prepare a water-in-needle preparation (2 mL each) in a total of 100 bottles.

Example 62: aerosol formulation

The compound of claim 1 (example 34) is dissolved in propylene glycol 10g, and then 500mL of clear solution is obtained after adding distilled water and other additives.

Example 63: suppository

50 suppositories were prepared by grinding 10g of the compound of claim 1 (example 34) with the appropriate amount of glycerin, mixing well, adding melted glycerin gelatin, grinding well, pouring into lubricant-coated molds.

Example 64: film agent

Using 10g of the compound according to claim 1 (in example 34), polyvinyl alcohol, medicinal glycerin, water and the like were swelled under stirring, dissolved under heating, filtered through a 80-mesh screen, and the compound of example 18 was added to the filtrate and dissolved under stirring to prepare 100 films on a film-coating machine.

Example 65: drop pills

10g of the compound of claim 1 (taking the compound in example 34 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then are dropped into low-temperature liquid paraffin to prepare 1000 pills.

Example 66: external liniment

The compound of claim 1 (example 34) is 10g, mixed with 2.5g of auxiliary materials such as emulsifier according to conventional pharmaceutical method, ground, and added with distilled water to 200 mL.

Example 67: ointment formulation

Prepared by grinding 10g of the compound of claim 1 (taking the compound in example 34 as an example), and then uniformly grinding the ground product with 500g of oil-based substance such as vaseline.

While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

1. An amide/thioamide derivative represented by the general formula (I), a geometric isomer thereof or a pharmaceutically acceptable salt thereof;

wherein ring A is

R₁Selected from hydrogen, C₁-C₆Alkyl, C substituted by halogen₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, C substituted by halogen₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy, six-membered aryl, benzyl, wherein said aryl, benzyl may be further substituted by 1-6R_xSubstitution;

ring B is a benzene ring, and ring B may be further substituted with 1-4R₂Substituted;

R₂selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, halogenated C₁-C₆An alkyl group;

in the general formula (I)

Z of the moiety is selected from O or S;

the C ring is 4-7 membered monocyclic heterocyclic group, 4-7 membered bicyclic heterocyclic group, the above ring contains at least 1 nitrogen atom, and the nitrogen atom and acyl or thioacyl moiety

Forming an amide bond, the ring further comprising an additional 0-2 heteroatoms of N, O, or S, and the ring may be further substituted with 1-4 Rx, R_xThe chiral carbon atom formed after the substitution isR configuration, S configuration or racemic form;

R_xis-H, hydroxy, amino, (C)₁-C₆) Alkyl, mono-or di (C)₁-C₆Alkyl) substituted amino.

2. Amide/thioamide derivatives of the general formula (I) according to claim 1, their geometric isomers or their pharmaceutically acceptable salts,

wherein, the B ring is a benzene ring, and the benzene ring and the adjacent ring form a benzopyrimidine ring which is further substituted by 1-4R₂Substituted, R₂Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, hydroxyl and trifluoromethyl.

3. The following derivatives, and geometric isomers or pharmaceutically acceptable salts thereof:

6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-isopropyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclobutyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-phenyl) pyrazolyl ] aminoquinazoline hydrochloride

2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-benzyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-isopropyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 1-piperazinyl ] formyl-4- [1H-3- (5-phenyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 4-morpholinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 4-methylpiperazino ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ piperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazolines

6-chloro-2- [1, 1-dioxothiomorpholinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 3-oxopiperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 4-hydroxypiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 4-hydroxy-4-methylpiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 4-aminopiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 4-amino-4-methylpiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 3-aminoazetidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [2, 6-diazaspiro [3.3] heptan-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ (1R,4R)2, 5-diazabicyclo (2.2.1) heptan-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ (hexahydropyrrolo [3,4-c ] pyrrol-2-yl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 4-methylaminopiperidinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

(S) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

(S) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [3, 5-dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [3, 3' -dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [3, 3' -dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(S) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropa-zolyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 2-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(S) -6-chloro-2- [ 3-methyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [3, 5-dimethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-ethyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-isopropyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-phenyl-1-piperazinyl ] formyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

6-chloro-2- [ 1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline

6-chloro-2- [ 1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline

(R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-methyl) pyrazolyl ] aminoquinazoline hydrochloride

(R) -6-chloro-2- [ 3-methyl-1-piperazinyl ] thiocarbonyl-4- [1H-3- (5-cyclopropyl) pyrazolyl ] aminoquinazoline hydrochloride

4. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 3 and geometric isomers or pharmaceutically acceptable salts thereof as an active ingredient and a pharmaceutically acceptable excipient.

5. Use of a derivative according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof or a pharmaceutical composition according to claim 4 in the manufacture of a medicament for the prevention or treatment of a disease associated with the expression or activity of PAK4 kinase.

6. Use of the derivative of any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 4 for the preparation of a medicament for the prevention or treatment of tumors.