WO2018121400A1 - Amide and thioamide derivatives and preparation method therefor and use thereof - Google Patents

Abstract

The present invention falls within the technical field of medicine and relates to amide and thioamide derivatives and preparation methods therefor and the use thereof, and particularly relates to derivatives of the general formula (I) and geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof and the preparation methods therefor. The derivatives have an activity as protein kinase inhibitors, especially PAK kinase inhibitors.

Description

Amide and thioamide derivatives and preparation method and application thereof Technical field

The present invention belongs to the field of pharmaceutical synthesis, and relates to a novel class of amide/thioamide derivatives, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, and processes for their preparation and their use as therapeutic agents. It is used as a PAK inhibitor.

Background technique

The treatment of tumors has become a worldwide problem, and the development of high-efficiency and low-toxic anti-tumor drugs is imminent. Targeted anti-tumor drugs have achieved great success in cancer treatment because of their good specificity, strong effectiveness, and low toxic and side effects.

Protein kinase is the largest family of proteins encoded by human genes and is closely related to tumorigenesis, invasion, metastasis, angiogenesis and chemoresistance. Since some kinases are highly expressed only in tumor cells, their inhibition does not affect the biological functions of normal cells, making the anti-tumor drugs targeting protein kinases have the advantages of high selectivity and low toxicity. Therefore, protein kinase has become an important target for the development of anti-tumor drugs.

被FDA批准用于治疗慢性粒细胞白血病，成为第一个上市的蛋白激酶抑制剂类抗肿瘤药物。之后短短的十五年中，已有42个蛋白激酶抑制剂上市，仅2013年以来，FDA批准上市的用于肿瘤治疗的小分子激酶抑制剂已有8个。具有抗肿瘤活性的蛋白激酶抑制剂的研究得到了生物制药行业的高度重视。 2001 Bcr-Abl kinase inhibitor imatinib

Approved by the FDA for the treatment of chronic myeloid leukemia, it became the first listed protein kinase inhibitor antitumor drug. In the short fifteen years, 42 protein kinase inhibitors have been marketed. Since 2013, there have been eight small-molecule kinase inhibitors approved for FDA treatment. The research of protein kinase inhibitors with anti-tumor activity has been highly valued by the biopharmaceutical industry.

PAKs (p21 activated kinase) are a class of serine/threonine protein kinases belonging to the STE20 family. PAK4 is a representative of class II PAKs, which can affect a variety of downstream proteins related to cell cycle, migration, invasion and apoptosis, resulting in abnormal cell differentiation, angiogenesis and proliferation. Therefore, PAK4 has become a potential target for tumor therapy.

PAKs include six family members (PAK1-PAK6), which are classified into two types according to their structure and activation mode: class I PAKs (PAK1, PAK2, PAK3), class II PAKs (PAK4, PAK5, PAK6). Among them, PAK4 is the most in-depth study of class II PAKs.

The full length of PAK4 (p21 activated kinase 4) kinase includes 591 amino acid residues and is mainly divided into three domains: p21-binding domain (PBD), Auto-inhibition domain (AID) and kinase. A domain (Kinase Domain, KD) or a catalytic domain (Catalytic Domain) in which the p21 binding domain and the self-inhibiting domain are located at the N-terminus of the kinase, and the kinase domain is located at the conserved C-terminus of the kinase. There are obvious structural differences between class I PAKs and class II PAKs. For example, class II PAK does not contain a region rich in acidic amino acid residues and a PIX/Cool binding domain; the homology of the two subfamily kinase domains is only about 50%. The structural differences are large, and the homology in the same subfamily is as high as 92-96% and 79-86%, respectively, and the structure is similar.

PAK is a major target protein downstream of the Rho family of guanosine triphosphatase (Rho-GTPases) Cdc42 and Rac1. It regulates and controls various biological functions, such as cytoskeletal reorganization and cell migration, by participating in multiple signaling pathways in cells. Apoptosis, mitosis, cell differentiation, and the like. In addition to being involved in regulating the normal physiological activities of cells, PAK is closely related to the development of various diseases, especially tumors. In the intracellular RAS-Cdc42/Rac1-PAK signaling pathway, Cdc42/Rac1 controls the formation of filopodia and lamellipodia, respectively, and PAK acts as a major effector downstream, in malignant transformation of cells and invasion of tumor cells. It plays an important role in the transfer process.

Studies have shown that PAK kinases, especially PAK1 and PAK4, have gene amplification, overexpression, and abnormal activation in a variety of tumor cells, leading to canceration and uncontrolled proliferation, invasion and metastasis of cells. For example, PAK1 is highly expressed in cell lines such as breast cancer, kidney cancer, and colon cancer; in a squamous skin cancer-bearing mouse model, PAK1 deletion significantly attenuates tumorigenesis by down-regulating MAPK and PI3K pathways; PAK1 can also phosphorylate BAD protein inhibits apoptosis of tumor cells; phosphorylation of DLC1 (Dynein light chain 1) promotes cell survival and malignant phenotype; mediates the expression of cyclinD1 in mammary epithelial cells and promotes the development of breast cancer. On the other hand, more than 70% of human cancer cell lines express PAK4, including breast cancer, pancreatic cancer, colon cancer, lung cancer and ovarian cancer. Activation of PAK4 can lead to anchorage-independent growth of tumor cells, PAK4 loss. The live mutant is able to inhibit the malignant transformation caused by Ras. The mechanism of PAK4 up-regulation is mainly gene amplification, especially in pancreatic cancer, ovarian cancer, oral squamous cell carcinoma and breast cancer. PAK4 is expressed in a variety of solid tumors, the most prominent feature being its increased mRNA or protein expression through increased transcription or gene amplification. However, studies have also reported that the PAK4 gene mutation (E329K) is associated with colon cancer.

Studies have shown that protein Ras mutations are overexpressed in approximately 30% of tumors, including malignant tumors such as pancreatic cancer, colon cancer, and lung cancer. Ras activates the Rho family small G protein Rac1/Cdc42 via PI-3k, thereby activating PAKs. Activated PAKs further affect downstream cell signaling pathway transduction and promote tumor survival, angiogenesis, migration and invasion. Studies have shown that PAK4 can activate the survival signal pathway of tumor cells through NF-κB, and promote the survival of tumor cells; PAK4 can promote the migration of gastric cancer cells through LIMK1-Cofilin signaling pathway; PAK4 can also pass CREB and Wnt/β-catenin signals Pathway, promote melanin production, cause diseases such as pigmentation disorder; PAK4/Raf/MEK/ERK signaling pathway exists in liver cancer cells, and PAK4 can inhibit the proliferation of liver cancer cells.

PAK4 is closely related to the occurrence and development of various tumors, inhibiting the abnormal function of PAK4, and can effectively inhibit the invasion and metastasis, excessive proliferation of tumor cells, and promote the apoptosis of tumor cells. Therefore, the research of PAK4 inhibitors has important value.

Because of the close correlation between PAK and tumors, the current research on small molecule PAK inhibitors is in a rapid development stage. Most of the PAK inhibitors have been found to be ATP-competitive PAK inhibitors acting on the kinase domain. The ATP-competitive inhibitors have high affinity and clear site of action, and are the most studied types of kinase inhibitors. However, the kinase domain of the kinase catalyzes the same biochemical reaction, which is structurally and sequence-conserved. The selective selectivity of the inhibitor between the kinases is a common problem encountered in the current ATP competitive inhibitor research. Meanwhile, the ATP binding cavity of PAK The discovery of PAK subtype selective inhibitors is a highly challenging study with a large spatial and flexible personality. However, with the rapid development of related disciplines, more and more highly selective ATP competitive kinase inhibitors have been discovered, which is the mainstream trend in the field of current kinase inhibitor research.

At present, the research on PAKs inhibition is still in its infancy, and only PF-3758309 developed by Pfizer has entered Phase I clinical research. PF-3758309 is a PARKs inhibitor with pyrrolopyrazine structure reported by Pfizer in 2009. It is the only PAKs inhibitor to enter clinical studies with PAK4IC ₅₀ = 19nM and PAK1IC ₅₀ = 14nM. In in vitro anti-tumor experiments and in vivo model studies of tumor-bearing mice, PF-3758309 significantly inhibited tumor cell proliferation and promoted tumor cell apoptosis. However, Phase I clinical studies of PF-3758309 were forced to terminate due to factors such as poor oral bioavailability (about 1%) and gastrointestinal side effects. Subsequently reported by Genentech in 2014, compounds with a benzimidazole structure that selectively act on class II PAKs can selectively inhibit PAK4 (PAK1IC ₅₀ = 5.4 μM, PAK4 IC ₅₀ = 7.5 nM). Although such compounds still have the disadvantage of weak cell viability and poor drug-forming properties, this study has initially demonstrated the possibility of sub-selective PAK inhibitor discovery.

In summary, targeted anti-tumor drugs represented by protein kinase inhibitors have become the mainstream of anti-tumor drug research and development at home and abroad. PAK4 has become a new target for cancer therapy due to its important role in tumor development, migration and invasion. At present, the research of PAK4 inhibitors is still in its infancy, and the development of highly active and highly selective inhibitors is of great significance. However, there are currently no PAK inhibitor drugs on the market, and there is still a need to develop compounds with better structure and better efficacy. The present invention is designed to synthesize a compound having the structure represented by the general formula (I), and it has been found that a compound having such a structure exhibits a good PAK4 inhibitory activity and has a good selectivity of PAK4/1.

Summary of the invention:

The object of the present invention is to provide a novel amide/thioamide derivative represented by the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;

Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₆ alkyl, halo-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen substituted cycloalkyl C ₃ -C ₆ -alkyl, C ₁ a -C ₄ alkoxy group, a six-membered aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with from 1 to 6 R _x .

The B ring is selected from the group consisting of a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocyclic ring, a 5-7 membered saturated aliphatic ring, and a 5-7 membered unsaturated fatty ring. The B ring can be further substituted with from 1 to 4 R ₂ .

R _{2 is} selected from the group consisting of hydrogen, halogen (fluoro, chloro, bromo, iodo), C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halo C ₁ -C ₆ alkyl.

部分的Z选自O或S。 In general formula (I)

Part of Z is selected from O or S.

形成酰胺键。该环还包括另外0-2个N,O或S的杂原子。该环可进一步被1-4个Rx取代。R _x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。 The C ring is a 4-7 membered heterocyclic group, a 5-7 membered unsaturated heterocyclic group, and a 4-7 membered bicyclic heterocyclic group, and the above ring contains at least one nitrogen (N) atom, and the nitrogen atom and the acyl group or sulfur Acyl moiety

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

R _x is -H, hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxy, amino or halo(C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, singly or di(C ₁ -C ₆ alkane Substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylsulfinyl, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl acyl, carbamoyl, mono- or di-(C) _1- C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy.

The present invention is preferably a novel amide/thioamide derivative of the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein

Wherein the A ring portion is selected from

R _{1 is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl substituted by halogen, C ₃ -C ₆ cycloalkyl substituted by halogen, C ₂ -C ₄ alkoxy, six A aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with 1 to 6 R _x groups.

The B ring is selected from the group consisting of a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocyclic ring. The B ring can be further substituted with from 1 to 4 R ₂ .

R _{2 is} selected from the group consisting of hydrogen, halogen (fluoro, chloro, bromo, iodo), C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, methoxy, hydroxy, halogen-substituted C ₁ -C ₄ alkyl .

部分的Z选自O，S。 In general formula (I)

Part of Z is selected from O, S.

形成酰胺键。该环还包括另外0-2个N,O,S的杂原子。该环可进一步被1-4个Rx取代。R _x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。 The C ring is a 4-7 membered heterocyclic group having at least one nitrogen (N) atom and the nitrogen atom and the acyl or thioacyl moiety

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

R _x is -H, hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxy, amino or halo(C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, singly or di(C ₁ -C ₆ alkane Substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylsulfinyl, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl acyl, carbamoyl, mono- or di-(C) _1- C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy.

Preferred in the invention are novel amide/thioamide derivatives of the formula (I), and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₆ alkyl, halo-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen substituted C ₃ -C ₆ cycloalkyl, C ₂ a -C ₄ alkoxy group, a six-membered aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with from 1 to 6 R _x .

The B ring is selected from the group consisting of a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocyclic ring. The B ring can be further substituted with from 1 to 4 R ₂ .

R _{2 is} selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl.

部分的Z选自O，S。 In general formula (I)

Part of Z is selected from O, S.

形成酰胺键。该环还包括0-1个N,O,S的杂原子。该环可进一步被1-4个R _x取代。R _x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。 The C ring is a 6-membered heterocyclic group having at least one nitrogen (N) atom, and the nitrogen atom and the acyl or thioacyl moiety

An amide bond is formed. The ring also includes 0-1 heteroatoms of N, O, S. The ring can be further substituted with from 1 to 4 R _x . The chiral carbon atom formed after the substitution of R _x may be in the R configuration, the S configuration or the racemic form.

R _x is -H, hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxy, amino or halo(C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, singly or di(C ₁ -C ₆ alkane Substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylsulfinyl, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl acyl, carbamoyl, mono- or di-(C) _1- C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy.

The present invention is preferably a novel amide/thioamide derivative of the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein

Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₃ alkyl, halo substituted C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, halogen substituted C ₃ -C ₅ cycloalkyl, phenyl And a benzyl group, wherein the phenyl group and the benzyl group are further substituted by 1 to 6 R _x .

The B ring is a benzene ring, and the benzopyrimidine ring composed of the benzene ring and its adjacent pyrimidine ring is further substituted with 1-4 R ₂ . R _{2 is} selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl.

部分的Z选自O，S。 In general formula (I)

Part of Z is selected from O, S.

且环与酰基或硫代酰基部分

形成酰胺键。该环可进一步被1-2个Rx取代，Rx选自氢，(C1-C6)烷基，卤代的(C1-C6)烷基，(C ₃-C ₆)环烷基，卤代的(C ₃-C ₆)环烷基。Rx取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。 The C ring is preferably a piperazine ring

Ring and acyl or thioacyl moiety

An amide bond is formed. The ring may be further substituted with 1-2 Rx, Rx is selected from hydrogen, (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C ₃ -C ₆₎ cycloalkyl, halogenated (C ₃ -C ₆ )cycloalkyl. The chiral carbon atom formed after the Rx substitution may be in the R configuration, the S configuration, or the racemic form.

The present invention is preferably a novel amide/thioamide derivative represented by the formula (I), and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₃ alkyl, halo substituted C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, halogen substituted C ₃ -C ₅ cycloalkyl, phenyl Wherein the phenyl group may be further substituted with 1-2 Rx.

The B ring is selected from a benzene ring, and the 6 or 7 position of the benzopyrimidine ring composed of the benzene ring and its adjacent pyrimidine ring may be further substituted by R ₂ . R _{2 is} selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl and the like. Further preferred is a chlorine atom substitution.

部分的Z选自O，S。 In general formula (I)

Part of Z is selected from O, S.

且环与酰基或硫代酰基部分

形成酰胺键。C环最优选的范围如下： C ring is piperazine ring

Ring and acyl or thioacyl moiety

An amide bond is formed. The most preferred range of the C ring is as follows:

Moreover, according to some general methods in the art to which the present invention pertains, a part of the compound of the formula (I) in the present invention has a basic group and can form a pharmaceutically acceptable salt with an acid. The pharmaceutically acceptable addition salts include inorganic acids and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , benzenesulfonic acid, naphthalene disulfonic 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.

Furthermore, the invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) ) is converted to the corresponding biologically active form.

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

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

In the present invention, "halogen" means fluorine, chlorine, bromine or iodo; "alkyl" means a straight or branched alkyl group; "aryl" means two hydrogens at one or different positions in the aromatic hydrocarbon. An organic group obtained by atom, such as phenyl or naphthyl; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more hetero atoms selected from N, O, S, which is a ring The system refers to an organic group which is aromatic and which removes two hydrogen atoms at one or different positions in the cyclic system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1, 2, 3)- and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, fluorenyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, Isoquinolyl, benzimidazolyl, benzoxazolyl, etc.; heterocyclyl refers to a monocyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, Tetrahydropyrrolidinyl, morpholinyl, piperidinyl, tetrahydropyrazolyl, tetrahydroimidazolidinyl, tetrahydrothiazolinyl and the like.

The present invention may contain a derivative of the formula (I), and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, and mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition. And prepared as a clinically acceptable dosage form, and the above pharmaceutically acceptable excipient means any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as allergic reactions.

The pharmaceutical compositions of the present invention can be formulated in a number of dosage forms containing some of the commonly used excipients in the pharmaceutical arts. A plurality of dosage forms as described above may be administered as a medicament such as an injection, a tablet, a capsule, an aerosol, a suppository, a film, a pill, a topical tincture, or an ointment.

The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: a binder, a lubricant, a disintegrant, a solubilizer, a diluent, a stabilizer, a suspending agent, a non-pigment, a flavoring agent. , preservatives, solubilizers and matrices. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.

The derivatives of the present invention which may contain the general formula (I) can be synthesized by a method well known in the chemical art, especially in accordance with the description of the present invention.

The starting materials can generally be obtained from commercial sources such as Aladdin, Darry, and the like, or can be prepared using methods well known to those skilled in the art.

In the present invention, room temperature refers to an ambient temperature of from 10 degrees Celsius to 30 degrees Celsius.

A positive progressive effect of the present invention is that the present invention provides an amide/thioamide derivative which is completely different from the prior art, a preparation method, a pharmaceutical composition and use thereof. The amide/thioamide compound of the present invention has a good selective inhibitory effect on PAK4 kinase and can be used for the prevention, treatment or adjuvant treatment of various diseases associated with the expression or activity of PAK4 kinase.

The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods for their preparation. It is to 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 procedures of Schemes 1-3, all of which are defined in the claims as defined in the claims.

Synthetic route 1

As shown in Route 1, there are several main steps in the synthesis of some compounds:

Step a: The starting material I-1 is subjected to acylation to give Intermediate I-2.

Step b: Intermediate I-2 is acylated with oxalyl chloride monoethyl ester to give intermediate I-3.

Step c: Intermediate I-3 is cyclized by reaction with sodium ethoxide to give Intermediate I-4.

Step d: Intermediate I-4 is subjected to basic hydrolysis to give Intermediate I-5.

Step e: Intermediate I-5 is chlorinated to give intermediate I-6.

Step f: Intermediate 1-6 is subjected to selective acylation with the corresponding amine C fragment to give intermediate I-7. The corresponding amine can be an amine fragment bearing a suitable protecting group.

Step g: Intermediate I-7 is reacted with an A ring fragment by an aromatic nucleophilic substitution reaction, and the corresponding protecting group is removed to obtain the final product.

The preferred conditions are as follows:

In the step a, the reactant was dissolved in an anhydrous tetrahydrofuran solvent, and triphosgene was added thereto, followed by heating under reflux for 12 hours. The mixture was cooled to room temperature, and 1N aqueous ammonia was added thereto, and the mixture was reacted at 65 ° C for 1 hour, and the mixture was cooled to room temperature to precipitate a white solid.

In the step b, the reactant was dissolved in an anhydrous tetrahydrofuran solvent, triethylamine was added at 0 ° C, and oxalyl chloride monoethyl ester was added dropwise with stirring. After the dropwise addition, the mixture was heated to room temperature for half an hour to precipitate a white solid. A small amount of water was added, the tetrahydrofuran was evaporated, ethyl acetate was added and the organic layer was dried to give Intermediate-1.

In the step c, the reactant is dissolved in ethanol, sodium ethoxide is added at a temperature of Celsius, and the mixture is heated to room temperature for 12 hours, 2N hydrochloric acid is adjusted to pH, and the white solid is suction filtered to give the intermediate I-4.

In the step d, the reactant was dissolved in a mixed solvent of ethanol-water (1-1), and the mixture was heated under reflux for 2 hours with 2N hydrochloric acid to adjust the pH to acid.

In the step e, the reactant was dissolved in chloroform, and refluxed with thionyl chloride for 3 hours to evaporate the solvent and the thionyl chloride to afford Intermediate I-6.

In the step f, the reactant is dissolved in anhydrous dichloromethane, the temperature is lowered to -35 ° C, the corresponding amine is added and stirred for 1 hour, the reaction is quenched with water, extracted with dichloromethane, and dried over silica gel. Intermediate I-7 was obtained.

In step g, the reactant is dissolved in DMF, the corresponding A ring fragment and potassium iodide are added, the temperature is raised to 65 ° C, stirred for 10 hours, poured into water, and the precipitate is purified by silica gel column chromatography to obtain the final product of the compound. When the compound contains a protecting group, the corresponding protecting group is removed under the corresponding conventional deprotection reaction conditions to obtain the final product. Among them, the definition of the A loop fragment is as described above.

A protecting group refers to a molecule containing two or more functional groups in organic synthesis. In order to protect one of the functional groups from the reaction, a certain reagent is used to protect it first, and then the protective agent is removed after the reaction is completed. . Protecting groups include tert-butoxycarbonyl (Boc), benzyl (Bn) and the like.

Synthetic route 2

As shown in Route 2, some of the compounds can be synthesized as follows:

The preferred conditions are as follows:

In the step e, the reactant is dissolved in tetrahydrofuran or toluene, heated to reflux with a Lawson reagent for 3 hours, the solvent is distilled off, and purified by silica gel column chromatography to give a compound product.

Synthetic route 3

A loop fragment synthesis:

When the A ring fragment is a substituted imidazole, the synthesis can be carried out by the method A, that is, the step i, the substituted 4-nitroimidazole is reacted with an alkyl halide (R ₁ -X) in DMF or acetonitrile to form a 1-position substituted 4-nitro group. The imidazole derivative is subjected to hydrogen reduction in step j to obtain an imidazole fragment.

Method B can also be employed. The 4-nitroimidazole substituted in step k is nitrated by nitric acid anhydride at zero degrees Celsius for 1 hour, and extracted to obtain a 1-nitro substituted 4-nitroimidazole. 1-Nitro-4-nitroimidazole is dissolved in a water-ethanol mixture (1-1) by reaction with an amine fragment (R ₁ -NH ₂ ), stirred at room temperature overnight, extracted and dried, and purified by silica gel column chromatography. The 1-position R _{1 is} substituted for the 4-nitroimidazole derivative. Hydrogen reduction by the step m gives a 1-position R ₁ substituted 4-aminoimidazole fragment. Among them, the definition of the A loop fragment and R ₁ is as described above.

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

The preferred conditions are as follows:

In the step n, sodium hydride was added to anhydrous tetrahydrofuran, the temperature was raised to 65 ° C, and a mixture of the R ₁ -substituted carboxylic acid ester and acetonitrile was added dropwise, and the mixture was refluxed for 12 hours, cooled to room temperature, and extracted with diethyl ether three times. PH of 2N hydrochloric acid, extracted with ethyl acetate, dried, purified by silica gel column chromatography to give β- R-carbonyl substituted _{1-carbonitrile.}

In the step o, the R ₁ -substituted β-carbonyl nitrile is dissolved in ethanol, hydrazine hydrate and methanesulfonic acid are added, and the mixture is heated under reflux for 1 hour, cooled to room temperature, and the solvent is evaporated, and purified by silica gel column chromatography to give R ₁ substituted. 3-aminopyrazole.

detailed description:

Without further elaboration, it is believed that the invention may The examples provided below are therefore intended to illustrate and not to limit the scope of the invention.

The starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art or prepared according to the methods described herein. The reagents used were of analytical or chemical purity, unless otherwise stated.

The structure of the compound was confirmed to be determined by Agilent 1100 LC/MSD. The column chromatography purification product used was 100-200 mesh or 200-300 mesh silica gel produced by Qingdao Ocean Chemical Plant.

Table 1 Structures of Examples 1-55

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

The synthetic route is:

Reagents and conditions: a) tetrahydrofuran, acetonitrile, sodium hydrogen, 66 degrees Celsius; b) ethanol, methanesulfonic acid, hydrazine hydrate, reflux; c) 1. triphosgene, tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; d) Tetrahydrofuran, oxalyl chloride monoethyl ester, 0 ° C to room temperature; e) sodium ethoxide, ethanol, 0 ° C to room temperature; f) sodium hydroxide, ethanol, water, room temperature; g) chloroform, thionyl chloride, reflux; h) Dichloromethane, triethylamine, N-Boc-piperazine, minus 35 degrees Celsius; i) 5-methyl 3-aminopyrazole, DMF, 65 degrees C; j) 2N hydrogen chloride-ethyl acetate solution at room temperature.

a) 8.80 g (100 mmol) of ethyl acetate (I-1) and 12.3 g (300 mmol) of acetonitrile were dissolved in 180 mL of anhydrous tetrahydrofuran, and 12.5 g (300 mmol) of sodium hydride was added portionwise with stirring at 0 ° C, and the mixture was heated to reflux. 1.5h. The reaction mixture was poured into 200 mL of ice water, and the pH was adjusted to 2-3 with 2N hydrochloric acid. The solvent was obtained as a pale yellow oil (I-2) 3.68 g. GC-MS m/z: 83.1 [M]+.

b) 0.83 g (10.0 mmol) of 3-oxobutyronitrile (I-2) and 0.70 mL (10.0 mmol) of hydrazine hydrate were dissolved in 50 mL of absolute ethanol, and 96.0 mg (1.0 mmol) of methane was added to the mixed solution. The acid was heated to reflux for 45 min, and the reaction was complete by TLC (iodine). The solvent was evaporated under reduced pressure to dryness crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted GC-MS m/z: 97.1 [M]+.

c) 2.00 g (11.6 mmol) of 2-amino-5-chlorobenzoic acid (I-4) was dissolved in 20 mL of dry tetrahydrofuran, and 1.20 g (3.90 mmol) of triphosgene was added with stirring, and the temperature was raised to 60 ° C for 12 h, TLC The reaction was monitored completely. The temperature was reduced to room temperature, the solvent was evaporated under reduced pressure, and then 1N aqueous ammonia was added, and the mixture was warmed to 60 ° C for 1 h to precipitate a white solid. The mixture was cooled to room temperature, suction filtered, washed with water (10 mL×3), and the filter cake was dried to constant weight to obtain white powdery solid 1.68 g, yield 84.9%. 1H-NMR (400MHz, DMSO-d6) δ: 7.85 (s, 1H), 7.60 (d, J = 2.44 Hz, 1H), 7.18-7.16 (m, 2H), 6.72 (d, J = 8.80 Hz, 1H) ), 6.40 (br, 2H).

d) 1.68 g (9.85 mmol) of 2-amino-5-chlorobenzamide (I-5) and 1.63 Ml (11.8 mmol) of triethylamine were dissolved in 34 mL of dry tetrahydrofuran, and the solution was dropped at 0 ° C with stirring. 1.15 mL (10.8 mmol) of oxalyl chloride monoethyl ester was added, and the mixture was added dropwise, and the mixture was allowed to react to room temperature for 1 hour, and the reaction was completely monitored by TLC. The solvent was evaporated under reduced pressure, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Methyl chloride: acetone = 50:1), obtained as a white powdery solid, 2.50 g, yield 93.9%. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 13.02 (s, 1H), 8.56 (d, J = 8.96Hz, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.97 (d, J = 2.44 Hz, 1H), 7.66 (dd, J = 2.44, 8.92 Hz, 1H), 4.30 (q, J = 7.12 Hz, 2H), 1.31 (t, J = 7.12 Hz, 3H).

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

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

g) 0.23 g (1.00 mmol) of 6-chloro-4-oxo-3H,4H-quinazoline-2-carboxylic acid (I-8) was dissolved in 5 mL of chloroform, and 0.87 mL was added to the solution ( 12.0 mmol) of thionyl chloride and a drop of N,N-dimethylformamide were heated to reflux for 0.5 h, and the reaction was monitored by TLC. The temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure to give Intermediate (I-6).

h) The intermediate (I-9) was dissolved in 5 mL of dry dichloromethane, and stirring was carried out at -35 ° C, and 0.42 mL (3.00 mmol) of triethylamine and 185 mg (1.00 mmol) of N- were slowly added dropwise to the solution. Boc-piperazine, the reaction was continued for 0.5 h, and the reaction was monitored by TLC. After quenching with water, add 30 mL of dichloromethane, wash with water (10 mL×3), wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, and evaporate the solvent and purify on silica gel column (dichloromethane:methanol = 50:1), 0.40 g of a yellow powdery solid was obtained, yield 48.7%. ^{1 H-NMR (400MHz, CDCl3} ) δ: 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) 0.20 g (0.49 mmol) of 4,6-dichloro-2-[1-(4-N-tert-butoxycarbonyl)piperazinyl]formylquinazoline (I-10), 47.5 mg (0.49) Ment) 5-methyl-3-amino-1H-pyrazole (I-3) and 0.096 mL (0.59 mmol) of N,N-diisopropylethylamine dissolved in 4 mL of 1,4-dioxane The reaction was refluxed for 3 h, and a pale yellow solid was precipitated. The mixture was cooled to room temperature, suction filtered, and the filter cake was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 0.5% triethylamine) and 10 times methanol to give a white powdery solid 0.07 g, yield 30.3% . ^{1 H-NMR (400MHz, DMSO} -d6) δ: 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=8.92 Hz, 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) The above solid (I-11) was dissolved in 2 mL of hydrochloric acid/ethyl acetate, and the mixture was stirred for 6 hr at room temperature to precipitate a white solid, which was filtered with suction, and the filter cake was dried to a constant weight to give a white powdery solid 0.06 g. 96.7%. Mp 341.8 ~ 342.6 degrees Celsius. ESI-MS m/z: 372.1 [M+H]+. 1H-NMR (400MHz, DMSO-d6) δ: 11.47 (s, 1H), 9.59 (s, 2H), 9.01 (s, 1H), 8.01 (dd, J = 8.92 Hz, 1H), 7.91 (d, J) = 2.42, 8.84 Hz, 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 starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid according to the method of Example 1.

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

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoformate, and the starting material 2-amino-5-chlorobenzoic acid was replaced with 2-aminobenzoic acid in step c). The 5-methyl-3-amino-1H-pyrazole was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 3 was obtained via step aj. ESI-MS m/z: 364.2 [M+H]+.

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

According to the method of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl isobutyrate, and the starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid. The 5-methyl-3-amino-1H-pyrazole was replaced with 5-isopropyl-3-amino-1H-pyrazole, and Example 4 was obtained via step aj. ESI-MS m/z: 366.1 [M+H]+.

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

According to the method of Example 1, the ethyl acetate in the step a) was replaced with ethyl cyclobutyrate, and the starting material 2-amino-5-chlorobenzoic acid in the step c) was replaced with 2-aminobenzoic acid. The 5-methyl-3-amino-1H-pyrazole was replaced with 5-cyclobutyl-3-amino-1H-pyrazole, and Example 5 was obtained via step aj. ESI-MS m/z: 377.1 [M+H]+.

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

In accordance with the method of Example 1, the ethyl acetate of the starting material in step a) was replaced with methyl benzoate, and the starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid. Step i) The 5-methyl-3-amino-1H-pyrazole was replaced with 5-phenyl-3-amino-1H-pyrazole, and Example 6 was obtained via step aj. ESI-MS m/z: 400.3 [M+H]+.

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

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with methyl phenylacetate, and the starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid. Step i) The 5-methyl-3-amino-1H-pyrazole was replaced with 5-benzyl-3-amino-1H-pyrazole, and Example 7 was obtained via step aj. ESI-MS m/z: 414.4 [M+H]+.

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

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl- 3-Amino-1H-pyrazole, Example 8 was obtained via step aj. ESI-MS m/z: 398.5 [M+H]+.

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

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl isobutyrate, and the 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-isopropyl- 3-Amino-1H-pyrazole, Example 9 was obtained via step aj. ESI-MS m/z: 400.6 [M+H]+.

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

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl benzoate, and the 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-phenyl-3-. Amino-1H-pyrazole, Example 10 was obtained via step aj. 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) 1. triphosgene, tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; b) tetrahydrofuran, oxalyl chloride monoethyl ester, 0 degrees Celsius to room temperature; c) sodium ethoxide, ethanol, 0 degrees Celsius to room temperature; d) sodium hydroxide, ethanol, water, room temperature; e) chloroform, thionyl chloride, reflux; f) dichloromethane, triethylamine, morpholine, minus 35 degrees Celsius; g) 5-methyl 3-aminopyridinium Azole, DMF, 65 ° C; h) 2N hydrogen chloride-ethyl acetate solution at room temperature.

a) 2.00 g (11.6 mmol) of 2-amino-5-chlorobenzoic acid (I-1) was dissolved in 20 mL of dry tetrahydrofuran, and 1.20 g (3.90 mmol) of triphosgene was added thereto with stirring, and the temperature was raised to 60 ° C for 12 h, TLC The reaction was monitored completely. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. <1>1N aqueous ammonia, and then warmed to 60 C for 1 hr. The mixture was cooled to room temperature, suction filtered, washed with water (10 mL×3), and the filter cake was dried to constant weight to obtain white powdery solid 1.68 g, yield 84.9%. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 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) 1.68 g (9.85 mmol) of 2-amino-5-chlorobenzamide (I-2) and 1.63 Ml (11.8 mmol) of triethylamine were dissolved in 34 mL of dry tetrahydrofuran, and the solution was dropped at 0 ° C with stirring. 1.15 mL (10.8 mmol) of oxalyl chloride monoethyl ester was added, and the mixture was added dropwise, and the mixture was allowed to react to room temperature for 1 hour, and the reaction was completely monitored by TLC. The solvent was evaporated under reduced pressure, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Methyl chloride: acetone = 50:1), obtained as a white powdery solid, 2.50 g, yield 93.9%. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 13.02 (s, 1H), 8.56 (d, J = 8.96Hz, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.97 (d, J = 2.44 Hz, 1H), 7.66 (dd, J = 2.44, 8.92 Hz, 1H), 4.30 (q, J = 7.12 Hz, 2H), 1.31 (t, J = 7.12 Hz, 3H).

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

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

e) 0.23 g (1.00 mmol) of 6-chloro-4-oxo-3H,4H-quinazoline-2-carboxylic acid (I-5) was dissolved in 5 mL of chloroform, and 0.87 mL was added to the solution ( 12.0 mmol) of thionyl chloride and a drop of N,N-dimethylformamide were heated to reflux for 0.5 h, and the reaction was monitored by TLC. The temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure to give Intermediate (I-6).

f) Dissolve the intermediate (I-6) in 5 mL of dry dichloromethane, stir at -35 ° C, and slowly add 0.42 mL (3.00 mmol) of triethylamine and 0.087 mL (1.00 mmol) to the solution. The morpholine was continued for 0.5 h, and the reaction was monitored by TLC. After quenching with water, add 30 mL of dichloromethane, wash with water (10 mL×3), wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, and evaporate the solvent and purify on silica gel column (dichloromethane:methanol = 50:1), 0.27 g of a yellow powdery solid was obtained, yield 86.5%.

g) 0.15 g (0.49 mmol) of 4,6-dichloro-2-(4-morpholinyl)formylquinazoline (I-7), 47.5 mg (0.49 mmol) 5-methyl-3-amino -1H-pyrazole (prepared as described above), 0.096 mL (0.59 mmol) of N,N-diisopropylethylamine and 4 mL of 1,4-dioxane were placed in a sealed tube and heated to 130 ° C for 24 h. A pale yellow solid precipitated and the reaction was monitored by TLC. After suction filtration, the cake was dried to constant weight, and hot-battered by 30 times methanol to obtain 0.09 g of a white powdery solid, yield 49.4%. Mp 326.9 ~ 327.4 degrees Celsius. ESI-MS m/z: 373.1 [M+H]+. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 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 = 8.92 Hz, 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-methylpiperazinyl]formyl-4-[1H-3-(5-methyl)pyrazolyl]aminoquinazoline

Following the procedure of Example 11, the morpholine in step f) was replaced with 4-methylpiperazine, and Example 12 was obtained via steps a-g. ESI-MS m/z: 434.5 [M+H]+.

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

Following the procedure of Example 11, morpholine was replaced with piperidine in step f) and Example 13 was obtained via steps a-g. ESI-MS m/z: 371.6 [M+H]+.

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

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

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

Substituting morpholine in step f) with piperazine 2-one according to the procedure of Example 11 gave Example 15 via steps a-g. ESI-MS m/z: 386.5 [M+H]+.

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

Following the procedure of Example 11, the morpholine in step f) was replaced with 4-hydroxypiperidine, and Example 16 was obtained via steps a-g. 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

Following the procedure of Example 11, morpholine was replaced with 4-hydroxy-4-methylpiperidine in step f), and Example 17 was obtained via steps a-g. ESI-MS m/z: 401.5 [M+H]+.

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

Following the procedure of Example 1, N-Boc-piperazine was replaced with 4-N-Boc-aminopiperidine in step h), and Example 18 was obtained from step a-g. 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 salt

Following the procedure of Example 1, N-Boc-piperazine was replaced with 4-N-Boc-amino 4-methylpiperidine in step h), and Example 19 was obtained from step a-j. 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]amine Riquiazoline hydrochloride

Following the procedure of Example 1, N-Boc-piperazine was replaced with 3-N-Boc-aminomonoheterocyclobutane in step i), and Example 20 was obtained via steps a-j. ESI-MS m/z: 358.5 [M+H]+.

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

Following the procedure of Example 1, N-Boc-piperazine in step i) was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and Example 21 was obtained via steps a-j. 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

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (1R,4R)-2-tert-butoxycarbonyl-2,5-diazabicyclo(2.2.1) heptane, stepwise Example 22 was obtained from aj. 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]amine Riquiazoline hydrochloride

Substituting N-Boc-piperazine in step h) with t-butyl hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate according to the procedure of Example 1 gave Example 24 via steps a-j. ESI-MS m/z: 400.5 [M+H]+.

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

Following the procedure of Example 1, N-Boc-piperazine was replaced with 4-N-Boc-amino 4-methylpiperidine in step h), and Example 24 was obtained via steps a-j. 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

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (S)-2-methyl-N-Boc-piperazine, obtained in steps a-j

Example 25. 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]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (R)-2-methyl-N-Boc-piperazine, obtained in steps a-j

Example 26. 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]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (R)-3-methyl-N-Boc-piperazine, obtained in steps a-j

Example 27. 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]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (S)-3-methyl-N-Boc-piperazine, obtained in steps a-j

Example 28. 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

Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with 3,5-dimethyl-N-Boc-piperazine, obtained in steps a-j

Example 29. 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]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, N-Boc-piperazine was replaced with 3,3'-dimethyl-N-Boc-piperazine in step h), and Example 30 was obtained via steps a-j. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the N-Boc-piperazine in step h) was replaced with 3,3'-dimethyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 31 was obtained via step aj. ESI-MS m/z: 426.5 [M+H]+.

Example 32: (S)-6-Chloro-2-[2-methyl-1-piperazinyl]formyl-4-[1H-3-(5-cyclopropan)pyrazolyl]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoformate, and the N-Boc-piperazine in step h) was replaced with (S)-2-methyl-N-Boc- Piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole, gave Example 32 via step aj. 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]aminoquinic Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the N-Boc-piperazine in step h) was replaced with (R)-2-methyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 33 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyclopropanoate, and the N-Boc-piperazine in step h) was replaced with (R)-3-methyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 34 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyclopropanoate, and the N-Boc-piperazine in step h) was replaced with (S)-3-methyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 35 was obtained via step aj. 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]aminopyrazole Porphyrin hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyclopropanoate, and the N-Boc-piperazine in step h) was replaced with 3,5-dimethyl-N-Boc-peri The oxazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 36 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the N-Boc-piperazine in step h) was replaced with (R)-3-ethyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 37 was obtained via step aj. 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]amino Quinazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyclopropanoate, and the N-Boc-piperazine in step h) was replaced with (R)-3-isopropyl-N-Boc. -piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 38 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the N-Boc-piperazine in step h) was replaced with (R)-3-phenyl-N-Boc- Piperazine, 5-methyl-3-amino-1H-pyrazole in step i) was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 39 was obtained via step aj. ESI-MS m/z: 474.5 [M+H]+.

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

The synthetic route is:

Reagents and conditions: a) Lawson's reagent, toluene, reflux.

a) Add 124 mg (0.33 mmol) of 6-chloro-2-[1-piperazinyl]formyl-4-[1H-3-(5-methyl)pyrazolyl]aminoquinazoline to 5 mL To dry toluene, 404 mg (1.00 mmol) of Lawson's reagent was added under stirring, and the mixture was heated to reflux for 12 h, and the reaction was monitored by TLC. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. ESI-MS m/z: 388.5 [M+H]+.

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

6-Chloro-2-[1-piperazinyl]formyl-4-[1H-3-(5-methyl)pyrazolyl]aminoquinazoline in step g) according to the procedure of Example 43 Replaced with 6-chloro-2-[1-piperazinyl]formyl-4-[1H-3-(5-cyclopropyl)pyrazolyl]aminoquinazoline, Example 41 was obtained via step a. ESI-MS m/z: 414.5 [M+H]+.

Example 42: (R)-6-Chloro-2-[3-methyl-1-piperazinyl]thioformyl-4-[1H-3-(5-methyl)pyrazolyl]amino Quinazoline

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

Example 43: (R)-6-Chloro-2-[3-methyl-1-piperazinyl]thioformyl-4-[1H-3-(5-cyclopropyl)pyrazolyl]amine Quinazoline

6-Chloro-2-[1-piperazinyl]formyl-4-[1H-3-(5-methyl)pyrazolyl]aminoquinazoline in step g) according to the procedure of Example 43 Replaced with (R)-6-chloro-2-[3-methyl-1-piperazinyl]formyl-4-[1H-3-(5-cyclopropyl)pyrazolyl]aminoquinazoline Example 43 was obtained via step a. 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 salt

Following the method of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoformate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid. Step h) Substituting N-Boc-piperazine for (R)-3-methyl-N-Boc-piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl -3-Amino-1H-pyrazole, Example 44 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the method of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 5-fluorobenzoic acid. In step h), replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole, Example 45 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 5-bromobenzoic acid. In step h), replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole, Example 46 was obtained via step aj. 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]amino Quinazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 5-methylbenzoic acid. Substituting N-Boc-piperazine in step h) with (R)-3-methyl-N-Boc-piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5 -cyclopropyl-3-amino-1H-pyrazole, Example 47 was obtained via step aj. 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]amine Riquiazoline hydrochloride

Following the procedure of Example 1, the ethyl acetate in step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 5-methoxybenzoic acid. Substituting N-Boc-piperazine in step h) with (R)-3-methyl-N-Boc-piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole, Example 48 was obtained via step aj. 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]aminoquine Oxazoline hydrochloride

In accordance with the method of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 6-chlorobenzoic acid. In step h), replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole, Example 49 was obtained via step aj. 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

The synthetic route is as follows:

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

a) Mix 4-nitroimidazole (I-1) 11.3 g (0.10 mol) with 25 ml DMF, add potassium carbonate 20.7 (0.15 mol), and slowly add 7.5 mL of methyl iodide (0.12 mol) to the solution while stirring at room temperature. After maintaining the reaction temperature at 65 ° C for 24 hours, 5 ml of diethylamine was added, and the mixture was stirred at room temperature for half an hour, and the solvent was evaporated, and then, 100 ml of water and 50 ml of ethyl acetate were added, and the organic phase was combined, dried and concentrated under reduced pressure. Column chromatography gave 9.2 g of an off-white solid, yield 72.4%. ESI-MS (m/z): 128 [M+H] ⁺ .

b) 1-methyl-1H-4-4-nitroimidazole (I-2) 6.4 g (0.05 mol) was dissolved in 50 ml of absolute ethanol, and 10 g of 10% palladium carbon was added thereto, and the reaction was stirred under a hydrogen atmosphere at room temperature. After 6 hours, the palladium carbon was filtered off, the solvent was evaporated, and 50 ml of a hydrogen chloride-ethanol solution was added thereto, and the mixture was stirred in an ice bath to precipitate a solid, which was filtered to give 5.2 g of a white solid. ESI-MS (m/z): 98 [M+H] ⁺ .

c) 2.00 g (11.6 mmol) of 2-amino-5-chlorobenzoic acid (I-4) was dissolved in 20 mL of dry tetrahydrofuran, and 1.20 g (3.90 mmol) of triphosgene was added with stirring, and the temperature was raised to 60 ° C for 12 h, TLC The reaction was monitored completely. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. <1>1N aqueous ammonia, and then warmed to 60 C for 1 hr. The mixture was cooled to room temperature, suction filtered, washed with water (10 mL×3), and the filter cake was dried to constant weight to obtain white powdery solid 1.68 g, yield 84.9%. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 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) 1.68 g (9.85 mmol) of 2-amino-5-chlorobenzamide (I-5) and 1.63 Ml (11.8 mmol) of triethylamine were dissolved in 34 mL of dry tetrahydrofuran, and the solution was dropped at 0 ° C with stirring. 1.15 mL (10.8 mmol) of oxalyl chloride monoethyl ester was added, and the mixture was added dropwise, and the mixture was allowed to react to room temperature for 1 hour, and the reaction was completely monitored by TLC. The solvent was evaporated under reduced pressure, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Methyl chloride: acetone = 50:1), obtained as a white powdery solid, 2.50 g, yield 93.9%. ^{1 H-NMR (400MHz, DMSO} -d6) δ: 13.02 (s, 1H), 8.56 (d, J = 8.96Hz, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.97 (d, J = 2.44 Hz, 1H), 7.66 (dd, J = 2.44, 8.92 Hz, 1H), 4.30 (q, J = 7.12 Hz, 2H), 1.31 (t, J = 7.12 Hz, 3H).

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

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

g) 0.23 g (1.00 mmol) of 6-chloro-4-oxo-3H,4H-quinazoline-2-carboxylic acid (I-8) was dissolved in 5 mL of chloroform, and 0.87 mL was added to the solution ( 12.0 mmol) of thionyl chloride and a drop of N,N-dimethylformamide were heated to reflux for 0.5 h, and the reaction was monitored by TLC. The temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure to give Intermediate (I-6).

h) The intermediate (I-9) was dissolved in 5 mL of dry dichloromethane, and stirring was carried out at -35 ° C, and 0.42 mL (3.00 mmol) of triethylamine and 185 mg (1.00 mmol) of N- were slowly added dropwise to the solution. Boc-piperazine, the reaction was continued for 0.5 h, and the reaction was monitored by TLC. After quenching with water, add 30 mL of dichloromethane, wash with water (10 mL×3), wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, and evaporate the solvent and purify on silica gel column (dichloromethane:methanol = 50:1), 0.40 g of a yellow powdery solid was obtained, yield 48.7%. ^{1 H-NMR (400MHz, CDCl} 3) δ: 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) 0.20 g (0.49 mmol) of 4,6-dichloro-2-[1-(4-N-tert-butoxycarbonyl)piperazinyl]formylquinazoline (I-10), 65.0 mg (0.49) Methyl) 1-methyl-1H-imidazol-4-amine hydrochloride (I-3) and 0.18 mL (1.08 mmol) of N,N-diisopropylethylamine dissolved in 4 mL of DMF, warmed to 65 ° C for 12 h . The temperature was lowered to room temperature, poured into water, and suction filtered, and the filter cake was purified by silica gel column chromatography (dichloromethane: methanol = 20:1, 0.5% triethylamine) to give white powdery solid (0.02 g).

j) The above solid (I-11) was dissolved in 2 mL of hydrochloric acid / ethyl acetate, and the mixture was stirred for 6 hr at room temperature to precipitate a yellow solid, which was filtered with suction, and the filter cake was dried to constant weight to obtain a yellow powdery solid of 0.017 g. 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, acetic acid, 0 degrees Celsius to room temperature; b) water, methanol, cyclopropylamine, room temperature; c) 1). hydrogen, palladium carbon, stirring at room temperature 2). hydrogen chloride-ethanol solution, ethanol , 0 degrees Celsius; d) 1. triphosgene, tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; e) tetrahydrofuran, oxalyl chloride monoethyl ester, 0 degrees Celsius to room temperature; f) sodium ethoxide, ethanol, 0 degrees Celsius to room temperature; j) sodium hydroxide, ethanol, water, room temperature; h) chloroform, thionyl chloride, reflux; i) dichloromethane, triethylamine, morpholine, minus 35 degrees Celsius; j) 1-cyclopropyl-1H- Imidazole 4-amine hydrochloride, DMF, 65 ° C; k) 2N hydrogen chloride-ethyl acetate solution, room temperature.

a) Dissolving 11.3 g (0.10 mol) of 4-nitroimidazole (I-1) in 200 ml of acetic acid, slowly adding 50 mL of nitric acid and 139 ml of acetic anhydride to the solution while stirring in an ice bath, and maintaining the reaction temperature at 25 ° C after the dropwise addition. After 1 hour, it was poured into 1.5 L of ice water, and extracted with 100 ml of ethyl acetate. The organic phase was combined, washed with sodium bicarbonate, dried and concentrated under reduced pressure to give a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.54 (d, J = 1.60 Hz, 1H), 8.40 (d, J = 1.56 Hz, 1H).

b) Dissolve 1,4-dinitroimidazole (I-2) in 200 ml of methanol, add 200 ml of water, add 8.6 g (0.15 mol) of cyclopropylamine dropwise, and continue to react at a temperature of 25 ° C for 24 hours. In addition to the solvent, 100 ml of water was added, and 50 ml of ethyl acetate was added for 5 times. The organic phase was combined, dried and concentrated under reduced pressure. ESI-MS (m/z): 154 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.47 (s, 1H), 3.45-3.40 (m, 1H) , 1.12-0.99 (m, 4H).

c) Dissolving 4.6 g (0.03 mol) of 1-cyclopropyl 4-nitroimidazole (I-3) in 50 ml of absolute ethanol, adding 0.6 g of 10% palladium carbon, and reacting for 6 hours under stirring in a hydrogen atmosphere at room temperature. The solvent was distilled off except for palladium carbon, and 30 ml of a hydrogen chloride-ethanol solution was added thereto, and the mixture was stirred in an ice bath to precipitate a solid. ESI-MS (m/z): 124 [M+H] ⁺ .

d) 2.00 g (11.6 mmol) of 2-amino-5-chlorobenzoic acid (I-5) was dissolved in 20 mL of dry tetrahydrofuran, and 1.20 g (3.90 mmol) of triphosgene was added with stirring, and the temperature was raised to 60 ° C for 12 h, TLC The reaction was monitored completely. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. <1>1N aqueous ammonia, and then warmed to 60 C for 1 hr. The mixture was cooled to room temperature, suction filtered, washed with water (10 mL×3), and the filter cake was dried to constant weight to obtain white powdery solid 1.68 g, yield 84.9%. ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 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) 1.68 g (9.85 mmol) of 2-amino-5-chlorobenzamide (I-6) and 1.63 Ml (11.8 mmol) of triethylamine were dissolved in 34 mL of dry tetrahydrofuran, and the solution was dropped at 0 ° C with stirring. 1.15 mL (10.8 mmol) of oxalyl chloride monoethyl ester was added, and the mixture was added dropwise, and the mixture was allowed to react to room temperature for 1 hour, and the reaction was completely monitored by TLC. The solvent was evaporated under reduced pressure, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Methyl chloride: acetone = 50:1), obtained as a white powdery solid, 2.50 g, yield 93.9%. ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 13.02 (s, 1H), 8.56 (d, J = 8.96Hz, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.97 (d , J = 2.44 Hz, 1H), 7.66 (dd, J = 2.44, 8.92 Hz, 1H), 4.30 (q, J = 7.12 Hz, 2H), 1.31 (t, J = 7.12 Hz, 3H).

f) 2.50 g (9.24 mmol) of 2-(2-carboxamido-4-chloro-phenyl)aminoglycolate (I-7) was dissolved in 28 mL of ethanol and slowly stirred at 0 ° C to the solution. 7.60 mL (11.1 mmol) of a 10% sodium ethoxide ethanol solution was added dropwise, and the reaction was continued for 3 h, and the reaction was completely monitored by TLC. The pH was adjusted to 3-4 with 1N hydrochloric acid, a white solid was precipitated, filtered, and washed with water (10 mL×3). The filter cake was dried to constant weight and purified by silica gel column chromatography (dichloromethane: acetone = 100:1). White powdery solid 2.00 g, yield 85.8%. ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 12.83 (s, 1H), 8.10 (d, J = 2.36Hz, 1H), 7.92 (dd, J = 2.46,8.68Hz, 1H), 7.85 (d , J = 8.68 Hz, 1H), 4.39 (q, J = 7.12 Hz, 2H), 1.35 (t, J = 7.12 Hz, 3H).

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

h) 0.23 g (1.00 mmol) of 6-chloro-4-oxo-3H,4H-quinazoline-2-carboxylic acid (I-9) was dissolved in 5 mL of chloroform, and 0.87 mL was added to the solution ( 12.0 mmol) of thionyl chloride and a drop of N,N-dimethylformamide were heated to reflux for 0.5 h, and the reaction was monitored by TLC. The temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure to give Intermediate (I-6).

i) The intermediate (I-10) was dissolved in 5 mL of dry dichloromethane, and stirring was carried out at -35 ° C, and 0.42 mL (3.00 mmol) of triethylamine and 185 mg (1.00 mmol) of N- were slowly added dropwise to the solution. Boc-piperazine, the reaction was continued for 0.5 h, and the reaction was monitored by TLC. After quenching with water, add 30 mL of dichloromethane, wash with water (10 mL×3), wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, and evaporate the solvent and purify on silica gel column (dichloromethane:methanol = 50:1), 0.40 g of a yellow powdery solid was obtained, yield 48.7%. ^{1 H-NMR (400MHz, CDCl} 3) δ: 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) 0.20 g (0.49 mmol) of 4,6-dichloro-2-[1-(4-N-tert-butoxycarbonyl)piperazinyl]formylquinazoline (I-11), 79 mg (0.49 mmol) 1-cyclopropyl-1H-imidazol-4-amine hydrochloride (I-4) and 0.18 mL (1.08 mmol) of N,N-diisopropylethylamine dissolved in 4 mL of DMF and warmed to 65 ° C. 12h. The temperature was lowered to room temperature, poured into water, and filtered, and the filter cake was purified by silica gel chromatography (dichloromethane:methanol = 20:1, 0.5% triethylamine).

k) The above solid (I-12) was dissolved in 2 mL of hydrochloric acid / ethyl acetate, and the mixture was reacted for 6 hr under stirring at room temperature to precipitate a yellow solid, which was filtered with suction, and the filter cake was dried to constant weight to obtain a yellow powdery solid. 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

Following the procedure of Example 51, the starting material cyclopropylamine in step b) was replaced with trifluoroethylamine, and 1-cyclopropyl-1H-imidazol-4-amine hydrochloride in step j) was replaced with 1-trifluoroethyl. Example-1 was obtained via Step ak. 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

Following the procedure of Example 50, the starting material methyl iodide in step 1) was replaced with cyclopropylmethyl bromide, the solvent was changed to DMF, and the 1-methyl-1H-imidazol-4-amine hydrochloride in step i) was replaced with 1-cyclopropanyl-1H-imidazol-4-amine hydrochloride, Example 53 was obtained via step aj. 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

Following the procedure of Example 50, the starting material methyl iodide in step 1) was replaced with isopropyl bromide, the solvent was changed to DMF, and the 1-methyl-1H-imidazol-4-amine hydrochloride in step i) was replaced with 1 -Isopropyl-1H-imidazol-4-amine hydrochloride, Example 54 was obtained via step aj. 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

Following the procedure of Example 51, the starting material cyclopropylamine in step 1) was replaced with 3-chloroaniline, and 1-methyl-1H-imidazol-4-amine hydrochloride in step j) was replaced with 1-(3-chloro). Phenyl)-1H-imidazol-4-amine hydrochloride, Example 57 was obtained via step ak. ESI-MS m/z: 468.5 [M+H]+.

Example 56: In vitro Enzyme Inhibitory Activity of Partial Products of the Invention

Experimental Materials:

F500酶标仪。 Tecan

F500 microplate reader.

KinEASE ^TM-STK试剂盒(包含生物素化的多肽底物S2，Eu3+标记的只针对特异性磷酸化位点的单抗，Sa-XL665标记的链霉亲和素，KinEASE酶反应缓冲液)，384浅孔板，PAK4全长蛋白。PAK4蛋白浓度0.0256ng/μl，MgCl ₂，乙二胺四乙酸(EDTA)，二硫苏糖醇(DL-Dithiothreitol，DTT)，DMSO。

KinEASE ^TM -STK kit (containing a biotinylated peptide substrate S2, Eu3 + labeled monoclonal antibody only against specific phosphorylation sites, Sa-XL665 labeled streptavidin, avidin, KinEASE enzyme reaction buffer), 384 shallow well plates, full length protein of PAK4. PAK4 protein concentration 0.0256 ng/μl, MgCl ₂ , ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DTT), DMSO.

experimental method:

The first step: the kinase reaction. The compound sample was first formulated into a 20 mM solution in DMSO, and then diluted to a concentration of 100 μM, 10 μM, 1 μM, etc., using a kinase reaction buffer solution according to the test. Then, PAK4 kinase (concentration: 0.0256 ng/μl), ATP (4 μM), biotin-labeled polypeptide substrate S2 (1 μM) and compound sample (4 μl) were added to 10 μl of kinase reaction buffer solution (containing MgCl _{2 )} In 5 mM and DTT 1 mM), the kinase incubated the substrate S2 for 40 minutes at room temperature. Then, 10 μl of a detection reagent containing EDTA was added to detect the phosphorylated product.

The second step: detection of phosphorylated products. The rare earth element cerium (Eu ³⁺ ) labeled antibody recognizes the phosphorylated substrate and the XL665 labeled streptavidin binds to biotin on the substrate. Eu ³⁺ is a fluorescent donor and XL665 is a fluorescent acceptor. When Eu ³⁺ is close to XL665, Eu ³⁺ energy is transferred to XL665, producing an HTRF signal.

Results Evaluation Method: The fluorescence signal was generated from the 620 nm fluorescence absorption signal of Eu ³⁺ and 665665 of XL665. Therefore, the ratio of the HTRF signal (665/620) of each well plate reaction is calculated.

Table 2 Percentage of PAK4 inhibitory activity of some example compounds in vitro at a concentration of 1 μM and 0.1 μM

Compound 1μM 0.1μM Compound 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% twenty two% Example 44 99% 92% Example 24 62% twenty four% 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 above table, some of the compounds of the formula (I) of the present invention have a marked inhibitory effect on PAK4 kinase activity.

Example 57: In vitro selectivity test of PAK4/PAK1 for some products of the invention

Experimental materials: EnVision multi-label microplate detector, PAK4 full-length protein and PAK1 full-length protein, peptide substrate, buffer solution Hepes, MgCl2 solution, EGTA, EDTA, Brij-35, DTT and other buffer components.

Experimental Method: Z'-LYTE ^TM kinase assay ^{(Z'-LYTE TM Kinase Assay)} , the kit according to the standard test conditions. The test method is divided into a kinase reaction step, a transformation reaction step and a detection step.

The specific steps of the reaction step are as follows:

1. Determine the experimental conditions for the Ki assay based on the results of the enzyme titration and ATP Km experiments. Among them, PAK1 Km=180000nM, PAK4Km=3000nM.

2. Compound solution formulation: The compound DMSO solution was diluted from 10 mM to 1 mM. The solution was serially diluted three times using a Agilent automated pipetting station (Bravo) for a total of 11 concentrations.

3. Enzyme reactions: PAK1 (kinase domain) and PAK4 (kinase domain) proteins, oxachacol ketone (fluorescent donor) and fluorescein (fluorescent receptor) labeled polypeptide substrate (Ser/thr19, Ser/thr20) ATP (Km) and test compounds were incubated in a kinase 22 ° C reaction. The 10 μL reaction solution contained 50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA, 2 μM FRET polypeptide substrate, and PAK enzyme (20 pM PAK1 KD; 80 pM PAK 4 KD).

4.60 minutes after the addition of 5μL of Z'-LYTE ^TM kinase reaction conversion agent (Development Reagent) to terminate the reaction, non-linear curve fitting equation to calculate the Ki. The experimental results are as follows:

Table 3 Part of the example compounds Ki for PAK4 and Ki for PAK1

As shown in the above table, some of the compounds of the formula (I) of the present invention have significant inhibitory activity against PAK4 and PAK4/PAK1 selectivity, which is superior to the typical PAK4 inhibitor PF3758309 and staurosporine, and has significant technical progress and advantages.

Example 58: In vitro Enzyme Inhibitory Activity of Partial Products of the Invention

The compound of the formula (I) in the present invention may be administered alone, but usually it is administered in a mixture with a pharmaceutically acceptable carrier which is selected according to the desired route of administration and standard pharmaceutical practice, each of which is separately used below. The preparation of a pharmaceutical dosage form, such as a tablet, a capsule, an injection, an aerosol, a suppository, a film, a pill, a topical tincture and an ointment, illustrates its new application in the pharmaceutical field.

Example 59: Tablet

10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 34) was mixed according to the general tableting method and 20 g of the adjuvant, and then compressed into 100 pieces each weighing 300 mg.

Example 60: Capsule

Using 10 g of the compound of claim 1 (exemplified by the compound of Example 34), 20 g of the excipients were mixed according to the requirements of the pharmacy capsule, and then filled into hollow capsules each weighing 300 mg.

Example 61: Injection

Using the compound containing the compound of claim 1 (exemplified by the compound of Example 34) 10g, according to the conventional method of pharmacy, the activated carbon is adsorbed, filtered through a 0.65 μm microporous membrane, and filled into a nitrogen tank to prepare a water needle preparation. Only 2mL is installed, and a total of 100 bottles are filled.

Example 62: Aerosol

After 10 g of the compound of claim 1 (exemplified by the compound of Example 34) was dissolved in an appropriate amount of propylene glycol, distilled water and other pellets were added to prepare a 500 mL clear solution.

Example 63: Suppository

Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 34), the amount of glycerin was added to the finely divided amount, and the melted glycerin gelatin was added thereto, uniformly ground, and poured into a model of the lubricant. , 50 suppositories were prepared.

Example 64: Membrane

Using 10 g of the compound of claim 1 (exemplified by the compound of Example 34), polyvinyl alcohol, medicinal glycerin, water, etc. were stirred and expanded, heated and dissolved, filtered through an 80 mesh screen, and the compound of Example 18 was added thereto. The filtrate was stirred and dissolved, and 100 film-coated membranes were applied.

Example 65: Pills

10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 34) was heated and melted with 50 g of a substrate such as gelatin, and then dropped into a low-temperature liquid paraffin to prepare a pellet of 1000 pills.

Example 66: Topical tincture

10 g of the compound of claim 1 (exemplified by the compound of Example 34) was mixed with 2.5 g of an auxiliary agent such as an emulsifier according to a conventional pharmaceutical method, and distilled water was added to 200 mL.

Example 67: Ointment

10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 34) was ground and then kneaded with 500 g of an oily base such as petrolatum.

Although the invention has been described in terms of specific embodiments, modifications and equivalents are obvious to those skilled in the art and are included in the scope of the invention.

Claims (10)

An amide/thioamide derivative of the formula (I), and geometric isomers thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;

Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₆ alkyl, halo-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen substituted cycloalkyl C ₃ -C ₆ -alkyl, C ₁ a C ₄ alkoxy group, a six membered aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted by 1 to 6 R _x ; The B ring is selected from the group consisting of a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocyclic ring, a 5-7 membered saturated aliphatic ring, and a 5-7 membered unsaturated aliphatic ring, and the B ring may be further substituted with 1-4 R ₂ ; R _{2 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halo C ₁ -C ₆ alkyl; In general formula (I)

a portion of Z is selected from O or S; The C ring is a 4-7 membered heterocyclic group, a 5-7 membered unsaturated heterocyclic group, and a 4-7 membered bicyclic heterocyclic group, and the above ring contains at least one nitrogen atom, and the nitrogen atom and the acyl group or the thioacyl moiety

Forming an amide bond, the ring further comprising another 0-2 N, O, or S hetero atom, and the ring may be further substituted by 1-4 Rx, and the chiral carbon atom formed by R _x substitution is an R configuration , S configuration or racemic form; R _x is -H, hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxy, amino or halo(C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, singly or di(C ₁ -C ₆ alkane Substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylsulfinyl, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl acyl, carbamoyl, mono- or di-(C) _1- C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy. An amide/thioamide derivative of the formula (I) according to claim 1, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, Wherein, the B ring is selected from the group consisting of a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocyclic ring, and the B ring may be further substituted with 1-4 R ₂ ; R _{2 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen-substituted C ₁ -C ₄ alkyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, Methyl, ethyl, methoxy, ethoxy, hydroxy, trifluoromethyl. An amide/thioamide derivative of the formula (I) according to claim 1 or 2, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein Wherein the A ring portion is selected from

R ₁ is selected hydrogen, C ₁ -C ₃ alkyl, halo substituted C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, halogen substituted cycloalkyl C ₃ -C ₅ -alkyl, C ₁ -C ₃ alkoxy, phenyl, benzyl, wherein the phenyl, benzyl group may be further substituted with from 1 to 6 R _x . An amide/thioamide derivative of the formula (I) according to any one of claims 1 to 3, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or pharmaceutically acceptable salt thereof medicine, Wherein the C ring is a 6-membered heterocyclic group, the ring contains at least one nitrogen atom, and the nitrogen atom and the acyl or thioacyl moiety

Forming an amide bond, the ring further comprises 0-1 heteroatoms of N, O or S, the ring may be further substituted by 1-4 R _x , and the chiral carbon atom formed by substitution of R _x is R configuration, S Configuration or racemic form; R _x is -H, hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxy, amino or halo(C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, singly or di(C ₁ -C ₆ alkane Substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylsulfinyl, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl acyl, carbamoyl, mono- or di-(C) _1- C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy. An amide/thioamide derivative of the formula (I) according to any one of claims 1 to 4, and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof ,among them Wherein, the B ring is a benzene ring, the benzopyrimidine ring composed of the benzene ring and the adjacent ring is further substituted by 1-4 R ₂ , and R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, Methoxy, hydroxy, trifluoromethyl. An amide/thioamide derivative of the formula (I) according to any one of claims 1 to 5, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof ,among them C ring is piperazine ring

Ring and acyl or thioacyl moiety

Forming an amide bond, the ring may be further substituted by 1-2 Rx, Rx is selected from hydrogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ a cycloalkyl group, a halogenated (C ₃ -C ₆ )cycloalkyl group, wherein the chiral carbon atom formed after the substitution of Rx is in the R configuration, the S configuration or the racemic form, and the C ring is preferably:

a derivative, and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug 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-cyclopropyl)pyrazolyl]aminoquinazoline hydrochloride

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

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

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

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

6-Chloro-2-[3-oxopipazinyl]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-hydroxy-4-methylpiperidinyl]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-[3-aminomonoheterobutyl]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-aminopiperidinyl]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 salt

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

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

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

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

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 salt

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

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

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

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

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

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

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

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

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

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

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

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

6-Chloro-2-[1-piperazinyl]formyl-4-[1-methyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

6-Chloro-2-[1-piperazinyl]formyl-4-[1-cyclopropyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

6-Chloro-2-[1-piperazinyl]formyl-4-[1-trifluoroethyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

6-Chloro-2-[1-piperazinyl]formyl-4-[1-cyclopropylmethyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

6-Chloro-2-[1-piperazinyl]formyl-4-[1-isopropyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

6-Chloro-2-[1-piperazinyl]formyl-4-[1-isopropyl-1H-imidazol-4-yl]aminoquinazoline hydrochloride

A pharmaceutical composition comprising the derivative according to any one of claims 1 to 7 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient. The derivative according to any one of claims 1 to 7 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or the pharmaceutical composition according to claim 8 for the preparation of a prophylactic or therapeutic agent against PAK4 kinase The use of drugs for the expression or activity-related diseases. The derivative according to any one of claims 1 to 7, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for preventing or treating an antitumor Applications.