WO2011120327A1 - Anti-tumor medicament of structure of diarylurea or thiourea kind based on indazole or aza-indazole - Google Patents

Abstract

An anti-tumor medicament, especially an anti-tumor medicament of structure of diarylurea or thiourea kind based on indazole or aza-indazole is disclosed in the present invention. The structure of the medicament is shown as formula (Ia) or (Ib): wherein, Z is N atom or C atom; W is O, S, NH, NOH, NCN and so on; M is O, S, N, CH and so on; n is 1 or 2; Y and R are halogen atom, H, R¹, CF₃, OCF₃, OH, OR², OCOR³, NH₂, NHR⁴, NR⁵ ₂, NHCOR⁶, carboxyl, ester, cyano, thiol, alkylthio, sulfonyl, sulfoxide group, sulfonic group, sulfonate group, sulphonylamino, keto, aldehyde group, nitro group, nitroso group. The medicament can be used for treating lung cancer, renal carcinoma, colon cancer, liver cancer, stomach cancer and breast cancer in human.

Description

 Biaryl urea or thiourea-based antitumor drug based on carbazole or azacarbazole

 The present invention belongs to the field of medicine, and relates to an antitumor drug, and more particularly to an antitumor drug based on a bisazole or a carbazole structure of a bisazole or a thiourea. Pharmacological experiments have shown that these drugs have good anti-tumor effects on human lung cancer, 'human kidney cancer, human colon cancer, human liver cancer, human gastric cancer, and human breast cancer.

Background technique:

 According to WHO statistics, there were as many as 12 million newly diagnosed cancer patients in the world in 2007, and more than 7 million patients died of cancer every year in the world in the past few years. This number is very close to the number of people who died of acute cardiovascular disease. Cancer is about to become the most deadly disease in the world.

 Renal cell carcinoma (RCC), a form of kidney cancer caused by tubular cells. Renal cell carcinoma accounts for 90-95% of kidney tumors, with the highest incidence being clear cell carcinoma (about 75% of all renal cell carcinomas) and about 2% in adult malignancies. Renal cell carcinoma is the sixth leading cause of cancer deaths, with an estimated 95,000 deaths worldwide each year. Advanced renal cell carcinoma is characterized by easy metastasis, locally advanced and/or unresectable, with an average survival time of 6-12 months; patients with migratory renal cell carcinoma have a 2-20% probability of surviving 2 years, 5 years The survival rate is only 5%.

 Cytokine therapy is currently the treatment of patients with advanced renal cell carcinoma, but a variety of cytokines including medroxyprogesterone (MPA), interferon (IFN), IL or IFN + IL treatment for advanced kidney The efficacy of cancer patients is not ideal, and does not help to improve the quality of life of patients.

The occurrence and development of renal cell carcinoma cannot be separated from the participation of genes that directly or indirectly promote tumor cell proliferation. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and Ras (GTP-binding protein)/Raf signaling pathway is an important pathway for tumor cell proliferation and angiogenesis [Strumberg D. Drugs Today, 2005, 41 (12): 773-784]; Raf is a serine/threonine (Ser/Thr) protein kinase, a downstream effector of Ras, which, once activated, activates the mitogen-activated proteins MEK1 and MEK2 kinase, MEK1 In addition, MEK2 phosphorylates and activates the extracellular signal-regulated kinases ERK1 and ERK2, and translocates to the nucleus, stimulating transcriptional initiation and translational activation pathways, leading to cell proliferation. This signaling pathway directly regulates the formation and development of tumors in various tumor tissues of the human body [Beeratn M, Patnaik A, Ro insky EK. Clin Adv Hematol Oncol, 2003, 1 (8): 476-481] ₀ Sorafenib (Soraf enib, WO00/42012), trade name Nexavar NEXAVAR, chemical name 4- {4- [3_ (4-chloro-3-trifluoromethylphenyl) acyl urea] phenoxy}pyridine-2- Amide) is a novel bisaryl urea oral multi-kinase inhibitor, which is used clinically as a tosylate salt. It has a dual anti-tumor effect, which directly inhibits tumor growth by downstream inhibition of the above Raf/MEK/ERK signaling pathway; on the other hand, it inhibits several tyrosine kinase receptors involved in neovascularization and tumor development upstream. Activity, including vascular endothelial growth factor receptor-2 (VEGFR-2), VEGFR-3, platelet-derived growth factor receptor-beta (PDGFR-Ρ) and c-KIT proto-oncogene, blocks tumor angiogenesis, Indirectly inhibits the growth of tumor cells, thereby playing an anti-tumor effect. The molecular structure of sorafenib is -

The relative bioavailability of oral sorafenib tablets was 38% to 49% _{; the} high-fat diet reduced the bioavailability of sorafenib by 29%. The sirfinib peak time is about 3 hours, the average elimination half-life is about 25 to 48 hours, and the plasma protein binding rate is 99.5%. Sorafenib is mainly oxidatively metabolized by the liver metabolic enzyme CYP3A4, and is subjected to glucuronidation metabolism by UGT1A9.

 The TARGET of the Renal Cancer Treatment Global Trial (TARGET) showed that the median disease progression-free survival time (PFS) of the patients in the sorafenib group and the placebo group was 24 weeks and 12 weeks, respectively (HR=0.44, P <0. 000001). After 6 months of randomization, the clinical benefit (including complete response, partial response, or stable disease) in the sorafenib and placebo groups was 84% and 55%, respectively, and the rate of disease progression occurred. They are 12% and 37% respectively. The investigators measured the size of the tumor before and after treatment, and found that 76% and 25% of patients in the sorafenib and placebo groups had tumor shrinkage, respectively. Due to the high selectivity of sorafenib, its adverse reactions are mild compared with cytokine therapy and other targeted therapies, which is beneficial for long-term use. Because it can significantly prolong the patient's disease-free survival and good safety, it was quickly approved by the FDA for the treatment of advanced renal cell carcinoma on December 20, 2005. It was listed in China on November 30, 2006.

 Liver cancer is one of the major health problems of humans today. It is the fifth most common cancer in the world and the third leading cause of cancer-related deaths worldwide. According to the latest survey data, there are 62.60 million new cases of liver cancer in the world each year, of which about 55% are Chinese patients. The main causes of HCC include chronic HBV infection (the main cause of Asia), HCV infection (the main cause of Europe), and alcoholic cirrhosis. Liver cancer is usually hidden, and many patients have progressed to the advanced stage of the disease when they are diagnosed, losing the best time for surgery. There has been a lack of effective therapeutic drugs for a long time. Doxorubicin is reported to be the most widely used drug, but only one randomized controlled trial involving 60 patients supports its use. Doxorubicin can cause as much as 25% of fatal complications. Mitoxantrone is an approved treatment for hepatocellular carcinoma, but it is not considered to be a specific drug for the treatment of hepatocellular carcinoma.

The results of the Sorafenib Hepatocellular Carcinoma Evaluation Program (SHARP) clinical trial were presented at the 43rd Annual Meeting of Clinical Oncology in 2007; Sorafenib significantly prolonged overall survival (OS) compared with placebo, with a median OS of 10 At 7 months and 7.9 months (P=0. 0006), the inhibitor of this agent against multiple kinases increased the survival rate of liver cancer by 44%; the median disease progression time (TTP) in the Sorafenib group It was also significantly longer than the placebo group. The median TTP was 5.5 months and 2. 8 months (P=0. 000007), and the drug delayed the onset of symptoms by 73%. The results of the 0RIENTAL Phase III clinical trial of NEXA in the treatment of advanced HCC in the Asia-Pacific region are highly consistent with the results of the SHARP study, suggesting that NEXAVAR has clinical benefit in HCC patients of different races and regions. In light of the results of the above two studies, the 2008 National Cancer Integrated Network (NCCN) HCC guidelines have identified Nexavar as a first-line standard systemic treatment for patients with advanced HCC. In China, following the formal approval of kidney cancer indications for less than two years, Solafenib (Nexaco) has been approved by the China Food and Drug Administration (SFM) for rapid treatment or inaccessibility. Metastatic hepatocellular carcinoma (HCC).

 However, as long-term high-dose use of taxane injections has caused patient resistance and reduced efficacy. There is growing evidence that resistance can limit the efficacy of sorafenib. Therefore, the development of a new generation of anticancer drugs, especially in the treatment of liver cancer and kidney cancer, is of great significance.

 Recently, based on the structure of sorafenib, Kim et al. synthesized a series of pyrrolopyridines.

(pyrrolo [3, 2- b] pyridine ) and pyrrolo [2, 3-d] pyrimidine compounds are used to inhibit melanoma growth (Kim, H., et al., Bioorg. Med) Chem. Lett, 2010, 20,

413-417; Kim, H., et al., Bioorg. Med. Chem. Lett, 2009, 19, 6538-6543). patent

US2008/0119466 or WO2005/080330 synthesize a series of similar compounds such as pyrrolo[2,3-b] pyridine, imidazo [4, 5~b] pyridine and purin. Treatment includes diseases such as cancer. Patent W02003/032989 also reports the synthesis of a series of pyrrolo[2,3-b]pyridines, imidazo [4, 5-b] pyridine, purin and pyrazolopyrimidine. ) and the like are used to treat diseases such as inflammation, but the aromatic rings to which they are linked are naphthalene rings. In addition, patents W02009/065596 and W02006/066937 report the synthesis of a series of pyrazolopyrimidine analog compounds for treatment.

Alzheimer disease. However, no patents or other literature reports based on carbazole (benzopyrazole) or pyrazolopyridine (La and lb) compounds have been found so far.

Summary of the invention:

 The object of the present invention is to provide an anti-tumor drug and a pharmaceutically acceptable salt of a bis-zolyl or thiourea-based structure based on carbazole or azacarbazole for the deficiencies of the prior art: it may be inorganic or organic Any salt derived from an acid. The acid can be selected from any medically acceptable acid.

 Another object of the present invention is to provide a method for preparing an antitumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, including their synthetic preparation methods and screening methods, especially for treating various cancers. Research on ingredients and methods related to related diseases.

 Another object of the present invention is to provide an antitumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, in particular for the preparation of a human lung cancer, human kidney cancer, human colon cancer, Human liver cancer, human gastric cancer, human breast cancer drugs.

The present invention provides an anti-tumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, which has the structural formula shown by formula (la) or (lb):

( la) (lb)

In the formula:

Z is an N or C atom;

The total number of germanium atoms in the ring is 1 to 5; wherein the total number of germanium atoms in the 6-membered ring is 0 to 3, and the total number of germanium atoms in the 5-membered ring is 1 to 2.

 W is an atom or group such as 0, S, NH, N0H, NCN;

 M is 0, S, N or CH;

 n is 1 or 2;

Y is a halogen atom, H, R', CF ₃ , 0CF ₃ , 0H, 0R ² , 0C0R ³ , NH ₂ , NHR ⁴ , NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group, cyano group, fluorenyl group, sulfonium group , sulfone group, sulfoxide group, sulfonate group, sulfonate group, sulfonamide group, ketone group, aldehyde group, nitro group, nitroso group, wherein R', R ² , R ³ , R ⁴ , R ⁵ , a hydrocarbon group of R ⁶ ;

R is a halogen atom, H, R\CF ₃ , 0CF ₃ , 0H, 0R ² , 0C0R ³ , NH ₂ , leg ⁴ , NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group, cyano group, fluorenyl group, thiol group, Sulfone, sulfoxide, sulfonate, sulfonate, sulfonamide, keto, aldehyde, nitro, nitroso, wherein R ¹ R ² , R ³ , RRR ^e are d- ₁₂ ;

 The halogen atom includes F, Cl, Br or I, and the hydrocarbon group includes a saturated or unsaturated open-chain hydrocarbon group, a saturated or unsaturated cyclic hydrocarbon group.

 Y may be at any position chemically permissible on the fused ring, and the fused ring may have no substituent or one or more substituents.

 The antitumor drug is a compound of the formula (la) or (lb) structure and a pharmaceutically acceptable salt, or a mixture of the structural compound of the formula (la) and (lb) and a pharmaceutically acceptable salt. The compound of the formula (la) or (lb) structure and the pharmaceutically acceptable salt have antitumor activity by mixing alone or in any ratio.

Preferably, formula (la) and (lb)

From any of the following structures -

More preferably

, Equations (la) and (lb) are derived from any of the following structures:

In the above structure, various substituents may be present on the two rings of the fused ring, such as a hydrocarbon group (saturated or unsaturated, open chain or cyclic), a substituted hydrocarbon group, CF ₃ , 0CF ₃ , a hydroxyl group, a decyloxy group, an amino group ( Substituted amino group, amide group, substituted amide group, halogen atom, carboxyl group, ester group, cyano group, decyl group, alkylthio group, sulfone group, sulfoxide group, sulfonic acid group, sulfonate group, sulfonamide group, ketone a group such as a aldehyde group, an aldehyde group, a nitro group, a nitroso group, a heterocyclic group, a substituted heterocyclic group or the like. The position of the substituent on the ring can be any position that is chemically permissible. There may also be no substituents on the ring.

 Preferably, M is CH; n = 2 o

 The present invention also provides a method for preparing an antitumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, and the synthetic route is as shown in the following equation:

Lib lb Y

In the formula: Z is N or C; the total number of N atoms in the fused ring ^l f is 1 to 5.

Y and R are a halogen atom (F, Cl, Br, 1), H, R', CF ₃ , 0CF ₃ , 0H, OR ² . 0C0R ³ , NH ₂ , NHR NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group , cyano, fluorenyl, sulfonyl, sulfone, sulfoxide, sulfonate, sulfonate, sulfonamide, keto, aldehyde, nitro, nitroso, wherein R', R ² , RR ⁴ , R ⁵ and R ⁶ are hydrocarbyl groups of ς- ₁₂ ; Υ may be at any position which is chemically permissible for the fused ring, and one or more substituents may be absent or present on the fused ring.

 A method for preparing an antitumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, comprising the following steps:

 The compound of the formula (Ila) or (lib) is reacted with a compound of the formula (ΙΠ) in an organic solvent at a temperature of from 10 ° C to 100 ° C for from 1 to 36 hours to form a ruthenium based on the formula (la) or (lb). a bisazole urea or thiourea-based tumor drug of azole or azacarbazole; the structure of the compound of the formula (Ila), (lib) is -

The structure of the compound of formula (III) is:

 (III)

 W is an atom or group such as 0, S, NH, N0H, NCN;

 M is 0, S, N, CH, etc.:

 n is 1 or 2.

The compound of the formula (Ila) or (lib) is reacted with a compound of the formula (ΙΠ) in an organic solvent in the above manner to give a carbazole- or azacarbazole-based double represented by the formula (la) or (lb). A mixture of anti-tumor drugs of aryl urea or thiourea structure. Preferably, formula (III)

Further, it also includes a cyclic isocyanate or isothiocyanate having the following structure, wherein M is CH, N, 0, S, etc., and if it is a hetero atom, the hetero atom may be chemically allowed at any position in the ring, There can be more than one or / and one hetero atom. Preferably, the formula (ΙΠ)

From any of the following structures:

The ring may have no substituents and may have one or more substituents; the substituent may be at any position chemically permissible on the ring. More preferably, formula (III)

From any of the following structures:

More preferably, the formula (ΙΠ)

Specific compounds of formula (III) are selected from the group consisting of -phenyl isocyanate, halogenated (fluorine, chlorine, bromine, iodine) phenyl isocyanate, hydrocarbyl (d- ₁₂ ) phenyl isocyanate, alkoxy (C, - ₁₂ ) phenyl isocyanate , trifluoromethylphenyl isocyanate, trifluoromethoxyphenyl isocyanate, ketophenyl isocyanate, ester phenyl isocyanate, nitrophenyl isocyanate, nitrosophenyl isocyanate, sulfophenyl isocyanate, sub a sulfophenyl phenyl isocyanate, an amido phenyl isocyanate, an N-substituted amido phenyl isocyanate, a sulfonylamino phenyl isocyanate; a trifluoromethylphenyl isocyanate containing the above various substituents, and a plurality of the same or Different substituents of phenyl isocyanate.

 Preferably, the compound of formula (ΙΠ) is selected from the group consisting of: trifluoromethylphenylisocyanate, chlorotrifluoromethylphenylisocyanate, fluorotrifluoromethylphenylisocyanate, iodotrifluoromethylphenylisocyanate, hydrazine (Cw) trifluoromethylphenyl isocyanate, decyloxytrifluoromethylphenylisocyanate, ruthenium (C) oxycarbonyltrifluoromethylphenylisocyanate, fluorophenyl isocyanate, chlorophenyl isocyanate, alkyl ( C, J fluorophenyl isocyanate, alkane (C) oxycarbonyl fluorophenyl isocyanate, trifluoromethoxyphenyl isocyanate, carbamoyl fluorophenyl isocyanate, N-substituted carbamoyl fluorophenyl isocyanate, sulfonic acid Ethyl fluorophenyl isocyanate.

 More preferably, the compound of formula (III) is selected from the group consisting of: trifluoromethylphenylisocyanate, chlorotrifluoromethylphenylisocyanate, fluorotrifluoromethylphenylisocyanate, methoxytrifluoromethylphenylisocyanate , ethoxytrifluoromethylphenyl isocyanate, dimethylphenyl isocyanate.

In addition to the above isocyanates having various substituents on the benzene ring, isocyanates having various substituents described above on the pyridine ring, the furan ring, the thiophene ring, and the N-substituted pyrrole ring are also included in the patent. Preferably, the compound of formula (III) is selected from the group consisting of: fluoropyridyl isocyanate, chloropyridyl isocyanate, methoxycarbonylfluoropyridyl isocyanate, ethoxylated fluoropyridyl isocyanate, trifluoromethylpyridyl isocyanate, chlorotrifluoro Methyl pyridyl isocyanate, fluorotrifluoromethyl pyridyl isocyanate, methoxy trifluoromethyl pyridyl isocyanate, ethoxy trifluoromethyl pyridyl isocyanate;

 The compound of the formula (III) is selected from the group consisting of fluorofuranyl isocyanate, chlorofuranyl isocyanate, methoxyfurfuryl fluorofuranyl isocyanate, and ethoxycarbonyl fluorofuranyl isocyanate. Trifluoromethylfuranyl isocyanate, chlorotrifluoromethylfuranyl isocyanate, fluorotrifluoromethylfuranyl isocyanate, methoxytrifluoromethylfuranyl isocyanate, ethoxytrifluoromethylfuranyl isocyanate.

 The compound of formula (III) is further selected from the group consisting of: fluorothienyl isocyanate, chlorothienyl isocyanate, methoxycarbonyl fluorothienyl isocyanate, ethoxycarbonyl fluorothienyl isocyanate, trifluoromethylthienyl isocyanate, chlorotrifluoromethylthiophene Isocyanate, fluorotrifluoromethylthienyl isocyanate, methoxytrifluoromethylthienyl isocyanate, ethoxytrifluoromethylthienyl isocyanate.

The compound of formula (III) is further selected from the group consisting of: N-fluorenyl (d- ₆ ) pyrrolyl isocyanate, N-fluorenyl (C _1→i ) fluoropyrrolyl isocyanate, N-formyl (C _M ) trifluoromethyl Pyrrolyl isocyanate, N-sulfonylpyrrole isocyanate, N-sulfonyl (C _M ) fluoropyrrole isocyanate, N-sulfonyl (C _M )trifluoromethylpyrrole isocyanate.

 Specifically, the isothiocyanate is the same as the specific isocyanate described above.

Preferably, a solution of the compound of the formula (Ila) or (lib) is slowly added dropwise to the solution of the compound of the formula (III) at a reaction temperature of -10 ° C to 50 ° C _{; the} reaction temperature is 0 ° after the addition. C ~ 100 ° C. Preferably, the reaction is carried out under the protection of an inert gas selected from nitrogen or argon.

 Synthesis of compounds of formula (Ila) and (lib):

 In the synthesis of the compounds (Ila) and (lib), the corresponding nitro group can be reduced to an amino group. The main methods for reducing nitro groups to amino groups are: hydrogen reduction by metal catalysts such as Pa-C, nickel, ruthenium and osmium, and metal reduction methods (iron, zinc, tin, aluminum, bismuth, indium, titanium, nickel, Or a salt or a compound thereof, a sulfide reduction method (sodium sulfide, sodium hydrosulfide, ammonium sulfide, etc.), a hydride reduction method, a hydrazine reduction method, or the like. The compounds (Ila) and (lib) may also be synthesized by other methods, such as reduction of the corresponding hydrazine, reduction of the carbonitrile, reduction of the amide, reduction of the azide compound, reduction of the azo compound, reductive amination of the carbonyl compound, Amide hydrolysis of halides, Hofmann rearrangement of amides, Curtius rearrangement of acyl azides, Lossen rearrangement of hydroxydecanoic acid, Schmidt reaction of carboxylic acid and hydrazoic acid, and the like.

 Synthesis of a compound of the formula (ΠΙ) (isocyanate or isothiocyanate):

There are many synthetic methods for the intermediate compound isocyanate (III), such as phosgene method, carbonylation method, thermal decomposition method of carbamate or imide compound, cyanidation method, rearrangement of azide or acylhydroxylamine compound. Law and so on. The current main preparation method is still the phosgene method. The phosgene method can use a gas phosgene, a liquid diphosgene or a solid triphosgene. The solid triphosgene method has obvious advantages: (1) It is safe and harmless; (2) Convenient, generally does not require the use of complex absorption and protection facilities; (3) The reaction is easy to measure, because it is solid, it can be accurately called (4), mild reaction conditions; (5), products Good quality and high yield.

The main synthetic methods of the intermediate compound isothiocyanate are: halogenated product and thiocyanate reaction method, phosphinimine ylide and carbon disulfide reaction method, amine and carbon disulfide reaction and then chloroformate reaction method, amine and sulfur The phosgene reaction method, the substituted thiourea thermal decomposition method, the reaction between the amine and the carbon disulfide, and the heavy metal salt decomposition method. In recent years, the reaction of an amine, carbon disulfide and triphosgene with triethylenediamine as a catalyst gives an aryl group having a nitro group, a trifluoromethyl group, two or more halogen atoms and other substituents attached to the aromatic ring.

 The compounds (la) and (lb) are structurally belonging to ureas and thioureas, respectively. This type of compound can be synthesized by various methods, such as reaction of an isocyanate or isothiocyanate with an amine, reaction of an amine with carbonyldiimidazole or thiocarbonyldiimidazole, reaction of an amine with phosgene or thiophosgene, Hydrocarbylation reaction of urea or thiourea, and the like.

 The molar ratio of the compound of the formula (Ila) or (lib) to the compound of the formula (III) is 1. 0: 0. 8~2. 5, preferably, the molar ratio is 1. 0: 1. 0~1. The present invention employs the reaction of an isocyanate or a thiocyanate (ΠΓ) (a compound of the formula (III)) with an amine (a compound of the formula ((Ila) and (lib)) to synthesize the two types of compounds. Formula (Ila) or The compound (Ila) or the molar ratio is 1. 0: 1. 0~ compound (Ila) or (lib) The reaction with the compound (ΠΙ) or (ΠΓ) is carried out in an organic solvent. The solvent which can be selected is an organic solvent which is inert to isocyanate or isothiocyanate (ΠΓ), mainly carboxylic acid esters. Halogenated hydrocarbons, benzene and its homologues, halogenated benzenes, ethers, cyclic ethers, dimethylacetamide, dimethylformamide, petroleum ethers, alcohols, etc. Preferably, the organic solvent is selected from the group consisting of ethyl acetate and acetic acid. Ester, chloroform, methylene chloride, benzene, toluene, ethylbenzene, xylene, chlorobenzene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, dimethylformamide, dimethyl Acetamide, petroleum ether, or a combination of two or more of them. Various petroleum ethers such as ~60 ° C, 60 to 90 ° C, 90 to 120 ° C.

 The feed temperature is from -10 ° C to room temperature or above room temperature, preferably, the feed temperature is from 0 ° C to 3 (TC. The reaction temperature after the addition is from 0 ° C to 10 (TC, preferably, the reaction temperature is from room temperature to 80 ° 'C, more preferably, the reaction temperature is from room temperature to 60 °C.

 After the addition is completed, the reaction time is from 1 hour to 36 hours. Preferably, it is 6 to 24 hours at room temperature; when the reaction temperature is high, the reaction time can be appropriately shortened.

 The invention also provides an anti-tumor drug based on a bisazole or a carbazole-based bisaryl urea or a thiourea structure, which is used for preparing human lung cancer, human kidney cancer, human colon cancer, human liver cancer, human gastric cancer, Human breast cancer drugs.

 The invention has the beneficial effects of providing an antitumor drug based on carbazole or azacarbazole bisaryl urea or thiourea structure and a preparation method thereof for overcoming the resistance of sorafenib and developing a new generation Anticancer drugs for the treatment of human lung cancer, human kidney cancer, human colon cancer, human liver cancer, human gastric cancer, human breast cancer drugs. Especially in the treatment of liver cancer and kidney cancer, it is of great significance.

detailed description: The following examples are further illustrative of the invention, but the invention is not limited thereto.

Example 1: Ν-{4-[1-(5-Azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (1):

5-Azacarbazole (0.96 g, 8.0 mmol), p-fluoronitrobenzene (1.13 g, 8.0 s), cesium carbonate (5.2 g, 16.0 mmol), dissolved in DMF (20 ml) The reaction solution was poured into water and filtered, and the filter cake was washed with water to obtain the desired product. The product was used in the next reaction without purification.

7.5 g (32.0 mmol) of SnCl ₂ was dissolved in 70 mL of concentrated hydrochloric acid, and 1.9 g (8.0 mmol) of nitrophenyl-5-azacarbazole obtained in the above procedure was added, and the mixture was stirred at room temperature overnight. It was adjusted to pH 9, dichloromethane with a saturated sodium bicarbonate solution. The organic layer was dried with anhydrous sodium sulfate and evaporated. Purification by column chromatography (ethyl acetate: petroleum ether = 2: 1) afforded 1-(4-aminophenyl)-5-azacarbazole 1.0 g as a white solid.

0.15 g (0.73 mmol) of the above 1-(4-aminophenyl)-5-azacarbazole was dissolved in 20 mL of dichloromethane, argon-protected, and slowly added dropwise at 0 °C under stirring. Phenyl 3-trifluoromethyl isocyanate 161 mg (0.73 mmol) A solution in 10 mL of dichloromethane. After the addition, the reaction was carried out at room temperature overnight. Filtration, washing the cake with dichloromethane, methanol to give {4-[1-(5-azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl] Urea (1) White solid 250 mg, yield 80%. HPLC: 97.8%, LC-MS (C 2 .H, 3 C1F 3 N 5 0, MW = 431): M + l = 432. See Table _1 for the spectral data.

Example 2: N-{4-[1-(5-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (2):

4-chloro-3-(trifluoromethyl)aniline 6.4g (33 ol), triethylenediamine 11.2 g (100 mmol) was dissolved in 40 mL of toluene, then cooled to 0 ° C, and CS ₂ was slowly added dropwise. 7.6 g (100 mmol), stir the reaction at room temperature for 10 h, filter, and filter cake washed with toluene. The filter cake was dissolved in 40 mL of CHCl ₃ , then added with triphosgene (BTC) 3.3 g (11.0 mmol) in 15 ml of CHC1 ₃ solution, stirred at room temperature for 1 h, and refluxed for 1 h. Cool to room temperature and filter. The filtrate was concentrated, and purified by column chromatography (DCM: EtOAc: 1:1) to yield: 4-chloro-3-trifluoromethylphenyl isothiocyanate as a yellow oily liquid, yield: 38.5%. 1-(4-Aminophenyl)-5-azacarbazole. The above 1-(4-aminophenyl)-5-azacarbazole 100 mg (0.49 mmol) was dissolved in 20 mL of dichloromethane, argon-protected, and slowly added dropwise at 0 °C under stirring. -Chloro-3-trifluoromethylisothiocyanate 116 mg (0.49 mmol) A solution in 10 mL of dichloromethane. After the addition, the reaction was carried out at room temperature overnight. Filtration, filter cake washed with dichloromethane, methanol to give {-{4-[1-(5-azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylbenzene Thiourea (2) 165 mg, yield 76% LC (UV254) purity 100% LC-MS

(C ₂₁ H ₁₄ C1F ₃ N, S, MW = 446.8, m/z 447 [M + H] ⁺ . See Table 1 for spectral data.

Example 3: Ν-{[4-[1-(6-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (3):

 Referring to the method in Example 1, 9.6 mg (40.0 mmol) of p-nitrophenyl-6-azacarbazole was substituted for p-nitrophenyl-5-azacarbazole, and the other raw materials were mixed and operated in the same manner. , 1-(4-aminophenyl)-6-azacarbazole 5.4 g yield 70%.

Referring to the method in Example 1, 1-(4-aminophenyl)-6-azaindazole (100 mg, 0.49 mmol) was used instead of 1-(4-aminophenyl)-5-azacarbazole. The other raw materials were mixed and operated in the same manner to obtain N-{[4-[1-(6-azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (3) 170 mg, yield 81% HPLC: 100%, LC-MS (C ₂₀ H ₁₃ C1F ₃ N _S 0, 丽 = 431): M+l = 432; See Table - 1 for spectral data

Example 4: N-{[4-[1-(6-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (4):

Referring to the synthesis method of Example 2, 1-(4-aminophenyl)-6-azaindazole 100 mg (0.49 mmol) was used instead of 1-(4-aminophenyl)-5-azacarbazole, and the others. The ratio of raw materials and the operation method are unchanged, and Ν-{[4-[1-(6-azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]sulfide Urea (4) 170 mg, yield 78% HPLC: 97.9%, LC-MS (C ₂ „H _]3 C1F ₃ N ₅ S, MW=446.9): M+l=448, see Table-1 for spectral data. Example 5: N-{[4-[1_(7-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (5): Reference Example In the method of 1, the p-nitrophenyl = 7 azacarbazole 0.96 g (4.0 mmol), instead of p-nitrophenyl 5-azacarbazole, the other raw materials ratio and operation method are the same, get 1- (4-Aminophenyl)-7-azaindazole 660 mg, yield 70%. Referring to the method in Example 1, 1-(4-aminophenyl)-7-azacarbazole (206 mg, 1.0 mmol) was used instead of 1-(4-aminophenyl)-5-azaindole, others The ratio of raw materials and the operation method are the same, and Ν-{[4-[1-(7-azacarbazole)]phenyl}N'-[4-chloro-3-trifluoromethylphenyl]urea (5) 340 mg, yield 79% HPLC: 100%, LC-MS (C ₂ „H ₁₃ C1F ₃ N ₅ 0, 丽=431): M+l=432, M+Na=454; - 1

Example 6: N-{[4-[1-(7-Azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (6):

Referring to the synthesis method of Example 2, 1-(4-aminophenyl)-7-azaindazole (100 mg, 0.49 mmol) was used instead of 1-(4-aminophenyl)-5-azacarbazole. Other raw materials ratio and operation method are unchanged, and Ν-{[4-[1-(7-azacarbazole)]phenyl}-Ν'-[4-chloro-3-trifluoromethylphenyl] Thiourea (6) 150 mg, yield 70% HPLC: 96.0%, LC-MS (C ₂ H ₁₃ C1F ₃ N ₅ S, s. = 446.9): M+l=448, M+Na=470. See Table-1 for spectral data.

Example 7: N-{[4-[1-(4-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (7):

Referring to the method of Example 1, 1-(4-aminophenyl)-5-azacarbazole was replaced by I-(4-aminophenyl)-4-azaindazole (206 mg, 1.0 mmol). The other raw materials were mixed and operated in the same manner to give 1^-{[4-[1-(4-azacarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl] Urea (7) 300 mg, yield 70% HPLC: 100%, LC-MS (C ₂₀ H ₁₃ C1F ₃ N ₅ 0, MW=431): M+l=432

Example 8: N {[4-[1-(4-Azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (8):

Referring to the synthesis method of Example 2, 1-(4-aminophenyl)-4-azaindazole (100 mg, 0.49 mmol) was used instead of 1-(4-aminophenyl)-5-azacarbazole. Other raw materials ratio and operation method are unchanged, and N-{[4-[1-(4-Azaindazole)]phenyl}-Ν'-[4-chloro-3-trifluoromethylphenyl] is obtained. Thiourea (8) 175 mg, yield 80% HPLC: 96.0%, LC-MS (C ₂ H ₁₃ C1F ₃ N ₅ S, 丽 = 446.9): M+ 1 = 448, M+Na=470

Example 9: N- {4- [1-(4-bromocarbazole)]phenyl }- N' _[4-chloro-3-trifluoromethylphenyl]urea (9):

Referring to the method of Example 1, 1-(4-aminophenyl)-4-bromocarbazole (153 mg, 0.53 mmol) was dissolved in dichloromethane, 0 Ό, 4 chloro-3-trifluoro was added dropwise. A solution of methyl isocyanate (117 mg, 0.53 ol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 9. Purification by column chromatography (silica gel G, n-hexane: ethyl acetate = 4: 1) afforded the title compound 9 LC (UV254) purity 99% LC-MS m/z 531 [M+Na] + 533 [M+ Na] ⁺ (Molecular formula C ₂₁ H, ₃ BrClP 0, molecular weight 508, 510. See Table-1 for spectral data.

Example 10: N-{4 [1-(4-bromocarbazole)]phenyl} N'-[4-chloro-3-trifluoromethylphenyl]thiourea (10):

Referring to the method in Example 2, 1-(4-aminophenyl)-4-bromocarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane, 0 ° C, 4-chloro-3 was added dropwise. A solution of trifluoromethyl isothiocyanate (159.49 mg, 0.67 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid to give the title compound 10 (60 mg) o LC (UV254) purity 98% LC-MS m/z 547 [M + Na] + 549 [M + Na] ⁺ (Molecular formula C ₂₁ H ₁₃ BrClF S, Molecular weight 524, 526).

Example 11: N - {4-[1-(4trifluoromethylcarbazole)]phenyl}-N'[4-chloro-3-trifluoromethylphenyl]urea (11): Referring to the method in Example 1, 1-(4-aminophenyl)-4-trifluoromethylcarbazole (100 mg, 0.36 mraol) was dissolved in dichloromethane at 0 ° C, and 4 chloro 3 was added dropwise. A solution of trifluoromethyl isocyanate (80 rag, 0.36 mmol) in dichloromethane was added and stirred at room temperature overnight. The solid was washed with isopropyl ether to give the title compound 11. Column chromatography and purification (silica gel G, n-hexane: ethyl acetate = 4:1) afforded the title compound 11, 80 mg, yield 45%. HPLC: 99.6%, LC-MS (C 22 H 13 C1F 6 N 4 0, gall = 498): M + 1 = 499, M + Na = 521. See Table-1 for the spectral data.

Example 12: N-{4-[1(4-Trifluoromethylcarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (12): Reference The method of Example 2 was dissolved in dichloromethane with 1-(4-aminophenyl)-4-trifluoromethylcarbazole (193 mg, 0.67 mmol), 0 Ό, 4-chloro-3- A solution of trifluoromethyl isothiocyanate (159, 5 mg, 0.67 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 12, 45 mg, 24.5% yield. HPLC: 100%; LC-MS (C 22 H 13 C] .F 6 N, S, MW = 514): M + l-5.15, M + Na = 537. See Table-1 for the spectral data.

Example 13: N-{4-[1-(4-carbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (13):

Referring to the method in Example 1, 1-(4-aminophenyl)carbazole (100 mg, 0.48 mmol) was dissolved in dichloromethane at 0 ° C, and 4-chloro-3-trifluoromethyl isocyanate was added dropwise. (106 mg, 0.36 mmol) of methylene chloride solution was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 13. Column chromatography and purification (silica gel G, n-hexane: ethyl acetate = 4:1) afforded the title compound 13, 100 mg, 49% yield. HPLC: 99, 7%, LC- MS (C 22 H C1F 3 N 4 0, MW = 430): M + l = 431, M + Na = 453. See Table-1 for the spectral data.

Example 14: N-{4-[1-(carbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (14):

 Referring to the method in Example 2, 1-(4-aminophenyl)carbazole (193 mg, 0.67 ramol) was dissolved in dichloromethane at 0 ° C, and 4-chloro-3-trifluoromethyl was added dropwise. A solution of isothiocyanate (159.49 mg, 0.67 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 14 40 mg, 18.7% yield. HPLC:

97.2%; LC-MS (C ₂₁ H _I4 C1F ₃ N ₄ S, should be =446): M+l=447 M+Na=469.

Example 15: N-{4-[1-(4-methylcarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (15):

Referring to the method in Example 1, 1-(4-aminophenyl)-4-(methylcarbazole) (100 mg, 0.45 mmol) was dissolved in dichloromethane at 0 ° C, and 4-chlorochloride was added dropwise. A solution of -3-trifluoromethyl isocyanate (99 mg, 0.45 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 15. Separation and purification by column chromatography (silica gel, n-hexane: ethyl acetate = 4:1) afforded the desired compound 15, 100 mg, 50% yield. HPLC: 100%, LC-MS (C 22 H 16 C1F 3 N 4 0, li = 444): M + l = 445, M + Na = 467. See Table-1 for the spectral data.

Example 16: N-{4-[1-(4-methylcarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (16):

 Referring to the method of Example 2, 1-(4-aminophenyl)-4-methylcarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane, 0 ° C, 4-chloro- A solution of 3-trifluoromethyl isothiocyanate (159 mg, 0.67 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 16 40 mg, 19.3% yield. HPLC:

100%; LC-MS (C ₂₂ H ₁₆ C1F with S, medical = 460): M+l=461, M+Na=483. Example 17: Ν-{4-[1-(4-chlorocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (17): Reference Example 1 In the above method, 7.5 g (32.0 mmol) of SnC12 was dissolved in 70 mL of concentrated hydrochloric acid, and nitrophenyl-4-chlorocarbazole 1.9 g (8.0 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was adjusted to pH 9 with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate (500 ml×3). The extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The side plate was used to detect the ratio of the two isomers. When the ratio of product to impurity was about 1:1, the addition of p-toluenesulfonic acid was stopped, stirred for 30 minutes, filtered, and the filter cake was washed with ethyl acetate. In water, adjust to weakly basic with solid sodium carbonate, extract with ethyl acetate, dry, and distill under reduced pressure to give pure 1-(4-aminophenyl)-4-(chlorocarbazole) (Ila), Rfa= 0.30 (ethyl acetate: petroleum ether = 1:10). The yield is about 45%, LC-MS^Hwd should be = 243): M+l=244, M+Na=266; lH-NMR (600MHz, DMSO) (ppm): 8.30 (1H, s), 7.57 ( 1H, d), 7.41 (1H, t), 7.3K3H, dd), 6.74 (2H, d), 5.43 (2H, s); Ethyl acetate layer was evaporated to dryness and recrystallized from isopropyl alcohol to give 2- 4-aminophenyl)-4-(chlorocarbazole) (lib), yield is about 10%, Rfb=0.25 (ethyl acetate: petroleum ether = 1:10), 1H-匪R (600 丽z, DMSO) (ppm): 8.94 (1H, s), 7.76 (2H, d), 7.65 (1H, d), 7.26 (1H, t), 7.15 (1H, d), 6.70 (2H, d), 5.51 ( 2H, s;).

Referring to the method in Example 1, 1-(4-aminophenyl)-4-(chlorocarbazole) (300 mg, 1.23 mmol) was dissolved in dichloromethane, 0 ° C, and 4-chloro was added dropwise. A solution of 3-trifluoromethyl isocyanate (70 mg, 1.23 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 17. Separation and purification by column chromatography (silica gel G, n-hexane: ethyl acetate = 4:1) afforded the desired compound 17, 190 rag, 33% yield. HPLC: 98.5%, IX-MS (C ₂₂ H ₁₃ C1 ₂ F ₃ N ₄ 0, s=464): M+l=465, M+Na=487. See Table-1 for the spectral data.

Example 18: N-{4-[1-(4-Chlorocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (18):

 Referring to the method of Example 2, 1-(4-aminophenyl)-4-chlorocarbazole (193 mg, 0.67 诵ol) was dissolved in dichloromethane, 0 ° C, 4-chloro- A solution of 3-trifluoromethyl isothiocyanate (159 mg, 0.67 leg ol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 18, 100 mg, 25.6% yield.

HPLC: 100% LC-MS (C ₂₁ H _I3 C1 ₂ F ₃ N ₄ S, s = 480): M + l = 481, M + Na = 503. See Table _1 for spectral data. Example 19: N-[1-(4-Fluorocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (19):

Referring to the method in Example 1, 1- (4-aminophenyl) -4- (fluoro-indazole) (100 mg, 0.44 mmol) was dissolved in dichloromethane, 0 ° C _S solution of 4-chloro - A solution of 3-trifluoromethylisocyanate (97 mg, 0.44 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 19. Separation and purification by column chromatography (silica gel, n-hexane: ethyl acetate = 4:1) gave the objective compound 19, 70 mg, 36% yield. HPLC: 99.8%, LC-MS (C ₂₁ H ₁₃ C1F ₄ N ₄ 0 ₎ MW = 448): M+l=449, M+Na=471.

Example 20: Ν-{4-[1-(4-Fluorocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (20):

Referring to the method of Example 2, 1-(4-aminophenyl)-4-fluorocarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane, 0 ° C, and 4-chloro-3 was added dropwise. A solution of trifluoromethyl isothiocyanate (159 mg, 0.67 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 20, 40 mg, 19.6% yield. HPLC: 98.5%; I-MS (C ₂₁ H ₁₃ Cl F^S, lans 464): M+l=465, M+Na=487. Example 21: N-{4-[1-(4-Methylaminocarbazole)]phenyl} N'-[4-chloro-3-trifluoromethylphenyl]urea (21): Reference Example Method 1 in which 1 (4 aminophenyl 4 (methylamino carbazole) (153 mg, 0.53 ol) is dissolved in dichloromethane, 0 ° C, 4-chloro-3-trifluoromethylene is added dropwise A solution of methyl isocyanate (117 mg, 0.53 诵ol) in methylene chloride was added, and the mixture was stirred at room temperature overnight. The solid was filtered to give the title compound 21, 30 mg, 48.0% yield. HPLC: 94.8 %; MS (C ₂₂ H ₁₇ C1F ₃ N ₅ 0, 丽 = 459): M+l=459.

Example 22: N-{4-[1-(4-Methylaminocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (22): Reference The method of Example 2 was dissolved in dichloromethane in the form of 1-(4-aminophenyl)-4-methylaminocarbazole (193 mg, 0.67 mmol) at 0 ° C. A solution of 3-trifluoromethyl isothiocyanate (159 rag, 0, 67 mmol) in dichloromethane was added and stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 22. HPLC: 94%; LC-MS (C 22 H 17 C1.F 3 N 5 S, MW-475): M + l = 476.

Example 23: Ν-{4-[1-(4-methoxycarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (23):

Referring to the method in Example 1, 1-(4-aminophenyl)-4-(methoxycarbazole) (153 m _g , 0.53 mmol) was dissolved in dichloromethane, 0 ° C, dropwise A solution of 4-chloro-3-trifluoromethylisocyanate (117 rag, 0.53 mmol) in dichloromethane was added and then stirred at room temperature overnight. Filtration and washing of the solid gave the desired compound 23. Column chromatography and purification (silica gel G, n-hexane: ethyl acetate = 4: 1) gave the title compound 23, 100 mg, 51.8% yield. HPLC (UV254) purity _{100%; LC MS (C 22} H 16 C1F 3 N 4 0 2, MW = 460); M + l = 461, M + Na = 483.

Example 24: N - {4-[l-(4-Methoxycarbazole)]phenyl}- N' _[4-chloro-3-trifluoromethylphenyl] 'thiourea (24): Referring to the method of Example 2, 1-(4-aminophenyl)-4-methoxycarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane at 0 ° C, and 4-chloro- A solution of 3-trifluoromethyl isothiocyanate (159 mg, 0.67 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 24, 20 mg, 10.0% yield. HPLC (UV254) _{Purity: 98.2% LC- MS (C 22} H 16 C1F having 0S, significantly = 476):. M + l = 477, M + Na = 499.

Example 25: N {4 [1-(4-methoxycarbazole)]phenyl }- N' [2, 5 dimethylphenyl]urea (25)

Referring to the method in Example 1, 1-(4-aminophenyl)-4-(methoxycarbazole) (153 mg, 0.53 mmol) was dissolved in dichloromethane, 0 ° C, dropwise 2 , 5-dimethylisocyanate (117 mg, 0.53 mmol) in chloromethane. After the addition, the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 25. Separation and purification by column chromatography (silica gel G, n-hexane: ethyl acetate = 4:1) to give the title compound 25, 70 mg, 43.2% yield. HPLC: 99.6 %; LC-MS (C ₂₃ H ₂₂ N ₄ 0 ₂ , </RTI> = 386): M+l=386, M+Na= 408.

Example 26: N - {4-[1-(4-Trifluoromethylcarbazole)]phenyl}-N'-[4-trifluoromethylphenyl]urea (26)

Referring to the method in Example 1, 1-(4-aminophenyl)-4-trifluoromethylcarbazole (100 mg, 0.36 mmol) was dissolved in dichloromethane, 0T:, 4-3- a solution of fluoromethyl isocyanate (80 mg, 0.36 mmol) in dichloromethane, After the addition was completed, the mixture was stirred at room temperature overnight. Filtration, isopropyl ether solid to give the title compound 26. Separation and purification by column chromatography (silica gel G, n-hexane: ethyl acetate = 4:1) gave the title compound 26, 40 mg, yield 24%. IiPLC: 100% LC-MS ( C 22 H 14 F 6 N 4 0, MW = 464): M + l = 464, M + Na = 486.

Example 27: N-{4-[1-(4-Trifluoromethylcarbazole)]phenyl}-N'-[4-trifluoromethylphenyl]thiourea (27):

Referring to the method of Example 2, 1-(4-aminophenyl)-4-trifluoromethylcarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane, 0 V, 4-chloro- A solution of 3-trifluoromethyl isothiocyanate (159 mg, 0.67 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 27, 100 mg, 50.0% yield. HPLC (UV254) purity: 99% . LC-MS (C ₂₂ H _i4 F ₆ N ₄ S, MW-480): M+l=48i. See Table-1 for spectral data.

Example 28: N-{4-[1-(4-Chloroxazole)]phenyl}-N'-[4-trifluoromethylphenyl]urea (28) _:

Referring to the method of Example 1, 1-(4-aminophenyl)-4-chlorocarbazole (100 mg, 0.36 mmol) was dissolved in dichloromethane at 0 ° C, and 4-trifluoromethyl was added dropwise. A solution of isocyanate (80 mg, 0.36 mmol) in dichloromethane was added and stirred at room temperature overnight. The solid was washed with isopropyl ether to give the title compound. Column chromatography and purification (silica gel G, n-hexane: ethyl acetate = 4:1) gave the title compound 28, 12411. 1^0 : 100% IX-MS (C ₂₁ H ₁₄ C1F. 'MW=430): M+l=431, M+Na=453. See Table-1 for the spectral data. - Example 29: N {4- [1-(4-chlorocarbazole)]phenyl}- N'-[4-trifluoromethylphenyl]thiourea (29):

Referring to the synthesis method of Example 2, 1-(4-aminophenyl)-4-chlorocarbazole was substituted for p-aminophenyl-5-azacarbazole, and the other raw materials ratio and operation method were unchanged, Ν-{ 4-[1-(4-Chlorocarbazole)]phenyl}-N'-[4-trifluoromethylphenyl]thiourea (29): 30 mg, yield 14.6%. LC (UV254) purity 100%. LC-MS (C ₂₁ H, ₄ C1F ₃ N ₄ S, s=446.9), m/z 447 [M + H] ⁺ M+Na=469. See Table _1 for spectral data.

Example 30: 4-{4-[3-(4-Chloro-3-trifluoromethylphenyl) thiourea]phenoxy }pyridine-2-carboxamide (30)

4-Chloro-3-trifluoromethylphenyl isothiocyanate was synthesized by the method of Example 2. The compound 4-{4-aminophenoxy}pyridine-2-carboxamide (200 mg, 0.8 mmol) was slowly added dropwise (TC) to 4-chloro-3-trifluoromethyl isothiocyanate Phenyl ester 190 mg (0.8 mmol) in 2 mL of dichloromethane. After the addition, the reaction was carried out at room temperature for 1 h, and allowed to react to room temperature overnight. After filtration, the filter cake was washed with dichloromethane and methanol to give compound 32. LC-MS: [M+Na] ⁺ 502.9, [M+H] + 480.9 (Formula C ₂₁ H ₁₆ C1F ₃ N ₄ 0 ₂ S, 480). See Table-1 for spectral data.

Example 31: N-{4-[2-(4-Chlorocarbazole)]phenyl }- N' _[4-chloro-3-trifluoromethylphenyl]urea (31):

Referring to the method in Example 1, 2-(4-aminophenyl)-4-(chlorocarbazole) (300 mg, 1.23 mmol) was dissolved in dichloromethane, 0 ° C, and 4-chloro was added dropwise. A solution of -3-trifluoromethyl isocyanate (70 mg, 1.23 诵ol) in dichloromethane was added and stirred at room temperature overnight. Filtration, washing of the dough, to obtain the target compound 31. Column chromatography and purification (silica gel G, n-hexane: ethyl acetate = 4: 1) gave the title compound 31, 180 mg, 31.2% yield. HPLC: 100%, LC-MS (C ₂₂ H ₁₃ C1 ₂ F ₃ N ₄ 0, lite = 464): M+l = 465. See Table-1 for spectral data.

Example 32: N-{4-[2-(4-Chlorocarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (32):

Referring to the method in Example 2, 2-(4-aminophenyl)-4-chlorocarbazole (193 mg, 0.67 ramol) was dissolved in dichloro In a formazan, a solution of 4-chloro-3-trifluoromethyl isothiocyanate (159 mg, 0.67 mmol) in dichloromethane was added dropwise at 0 ° C, and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 32, 59 mg, 15.2% yield. HPLC:

99% LC-S (C ₂₁ H _j3 Cl ₂ F ₃ N ₄ S, MW=480): M+l=481, M+Na=503. See Table 1 for spectral data.

Example 33: N-{4-[2-(4-Trifluoromethylcarbazole)]phenylphenyl N'-[4-chloro-3-trifluoro(phenyl)phenyl]urea (33): Refer to The method in Example 1 was dissolved in dichloromethane with 2-(4-aminophenyl)-4-trifluoromethylcarbazole (100 mg, 0.36 mmol), 0 Ό, 4-chloro-3- 3- A solution of fluoromethyl isocyanate (80 mg, 0.36 ol) in dichloromethane was added and stirred at room temperature overnight. The solid was washed with isopropyl ether to give the title compound 33. Column chromatography on avian purification (silica gel G, n-hexane: ethyl acetate = 4:1) gave the title compound 33, 129 rag, yield 72.6% HPLC: 99%, LC-MS (C ₂₂ H ₁₃ C1F ₆ N ₄ 0, earn = 498): M+l=499, M+Na=521.

Example 34: N-{4-[2-(4-Trifluoromethylcarbazole)]phenyl}- N' _[4-chloro-3-trifluoromethylphenyl]thiourea (34): Referring to the method of Example 2, 2-(4-aminophenyl)-4-trifluoromethylcarbazole (193 mg, 0.67 mmol) was dissolved in dichloromethane, 0 Ό, 4-chloro- A solution of 3-trifluoromethyl isothiocyanate (159.5 mg, 0.67 mmol) in dichloromethane was added and the mixture was stirred at room temperature overnight. Filtration and washing of the solid gave the title compound 34 40 mg, 21.6% yield. HPLC: .100%; IC-MS (C ₂₂ H ₁₃ Cl F _e N, S, = 514): M+l=5]5, M+Na=537.

Example 35: [\1-{4-[1-(4-Chlorocarbazole)]phenyl}--[4-chloro-3-trifluoromethylphenyl]ureatoluenesulfonate (35): Ν-{4-[1-(4-Chlorocarbazole)]phenyl}- N'-[4-chloro-3-trifluoromethylphenyl]urea (1.0 mmol) and p-toluenesulfonic acid (210) Mg, 1.1 mmol) dissolved in ethyl acetate (20 ml), refluxed for 15 min, cooled to room temperature, filtered, filtered, washed with ethyl acetate and dried to give N-{4-[4-(4-chlorocarbazole). Phenyl}_N'-[4-chloro-3-trifluoromethylphenyl]ureatoluenesulfonate 200 mg, yield 78.5 ° /. . Ή-NMR (600MHz, DMSO) (ppra): 9.28 (1H, s), 9.16 (1H, s), 8.42 (1H, s), 8.14 (1H, d) , 7.75 (1H, d) , 7.71 (5H , m), 7.63 (1H, d), 7.48 (3H, dd), 7.35 (1H, d), 7.11 (2H, d), 2.29 (3H, s).

 NMR indicated the formation of a 1:1 tosylate salt.

Example 36: Ν-{4-[1-(4-Trifluoromethylcarbazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]ureatoluenesulfonate

(36):

 N-{4-[1_(4-Trifluoromethylcarbazole)]phenyl}- N' _[4-chloro-3-trifluoromethylphenyl]urea (1.0 mmol) and p-toluenesulfonic acid (210 mg, 1.1 mmol) dissolved in ethyl acetate (20 ml), refluxed for 15 min, cooled to room temperature, filtered, filtered, washed with ethyl acetate and dried to give N-{4-[1-(4_3 Fluoromethyl carbazole)]phenyl}- N'-[4-chloro-3-trifluoromethylphenyl]ureatoluene sulfonate 200mg, yield 78.5° / - NMR (600MHz, DMSO) (ppra) 9,29 (1H, s 9.19 (ΙΗ' s), 8.47 (1H, s 8.15 (1H, d) , 8.08 (1H, d), 7.69 (8H, m) 7.48 (2H, d) , 7.12 (2H d 2.29 (3H, s).

 NMR indicated the formation of a 1:1 tosylate salt.

Example 37: N-[4-(5-Azaindole)phenyl]-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (37):

Referring to the synthesis method of Example 2, p-aminophenyl-5-azaindole was substituted for p-aminophenyl-5-azacarbazole. The other raw materials ratio and operation method were unchanged, and N-[4-( 5-azaindole)phenyl]-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (37) 360 mg, yield 80%. LC (UV254) purity 100%. IX-MS (C ₂₁ H ₁₄ C1F ₃ N ₄ S, MW=446.9), m/z

447[M + H] ⁺ . See Table-1 for the spectral data.

Example ³⁸ _: N-[ ⁴ -( ⁶ -azaindole)phenyl] - N' - [ ⁴ -chloro- ³ -trifluoromethylbenzene ^3⁄4 ]sulfur | (38): Referring to the synthesis method of Example 2, p-aminophenyl-6-azaindole was substituted for p-aminophenyl-5-azacarbazole, and the other raw materials ratio and operation method were unchanged, and N-[4-( 6-azaindole)phenyl]-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (38) 365 mg, yield 81%. LC (UV254) purity 99%. _{LC-MS (C 21 H H} C1F 3 N 4 S, hide = 446.9), m / z 447 [M + H] +. See the table for the spectral data - 1.

 Example 39: N-[4-(6-Azaindole)phenyl]-N'-[4-chloro-3-trifluoromethylphenyl]urea cyanide (39)

The compound of Example 38 (223 mg, 0.5 mmol) was suspended in 20 mL dichloromethane. The monocyanamide (210 mg) was dissolved in 5 mL of THF, added to the reaction mixture, and stirred at room temperature over the weekend. Column chromatography (silica gel G, methylene chloride: methanol = 30: 1) gave the title compound 39, 80 mg, and LC (UV254) purity 97%. LC-MS m/z 455 [M + H] +. (Molecular formula C ₂₂ H ₁₄ ClF ₃ N _e , molecular weight 454). See the table for the spectral data - 1.

510).

HPLC: 100%; LC-MS

N-{4-[l-(4 (C ₂₂ H ₁₆ C1F ₃ N ₄ S, MW=460)

- methyl 吲M+l=461,

 Oxazole)]phenyl}-

No.16

 N ' -[4-chlorine

 -3-trifluoromethyl

 Phenyl] sulfur

 Urea

 HPLC: 98.5%, LC-MS

(C ₂₂ H ₁₃ C1 ₂ F 0, MW=464):

Ν-{4-[1-(4 M+l=465, M+Na=487. 'H-NMR-chlorocarbazole)] (600MHz, DMS0) (ppm): 9.26

 (1H, s) , 9.14 (1H, s) , 8.42

No.17 phenyl }- N'

 (1H, s) 8.14 (1H, d) , 7.75 - [4-Chloro-3-(1H, d) 7.70 (5H, m), 7.64 trifluoromethylbenzene (1H, d) 7.48 (1H, in) , 7.35

 (1H, d)

 Urea

HPLC: 100%; LC-MS

(C ₂₁ H, ₃ C1 ₂ FS, MW=480): M+l=481, M+Na=503. - NMR

Ν-{4-[1-(4

 (600MHz, DMSO) (ppm): 10.32 -chlorocarbazole)] (1H, s), 10.21 (1H, s), 8.46

No.18 Phenyl }- N' (1H, s), 8.11 (1H, d) 7.84

 (1H, dd), 7.80 (1 d) 7.77 -[4-Chloro-3-(1H, s), 7.76 (1H, s) 7.70 Trifluoromethylbenzene (3H, m), 7.50 (1H, t) 7.37 base] thiourea (1H, d).

HPLC: 99.8%, LC-MS

(C ₂₁ H,, C1F ₄ N ₄ 0, MW=448)

 N- {4-[1- (4

 M+l-449, M+Na=471.

 -fluoxazole)]

 No.19 phenyl }- N'

 -[4-chloro-3-trifluoromethylbenzene

Urea

HPLC (UV254) 98.2% . LC-MS

(C ₂₂ H ₁₆ C1F

 N- {4- [1- (4 with OS, MW=476):

 M+l=477, M+Na=499.

 -methoxy oxime

 Oxazole)]phenyl}

No.24

 N ' -[4 -chlorine

 - 3 - Trifluoro

 Phenyl] sulfur

 Urea

HPLC: 99.6 %: LC-MS (C ₂ , H ₂₂ N ₄ 0 _2; MW = 386): M+l=386, M+Na= 408.

Ν-{4-[1-(4

 -methoxy oxime

 No.25 azole)]phenyl} - N ' - [2,5-dimethylbenzene

 Urea

HPLC: 100% LC-MS ( C 22 H, 4 F 6 N 4 0, ■ = 464): M + l = 464, M + Na = 486.

Ν-{4-[1-(4

 -trifluoromethyl

 No.26 oxazole)] benzene

 Base }- N '

 - [4-Trifluoro

 Phenyl phenyl

HPLC (UV254) 99%. LC-MS (C ₂₂ H"F6N ₄ S, MW=480.4): m/z

N- {4- [1- (4- 481 [M + H]+ Ή-NMR (600MHz,

 DMS0) (ppm): 10.29 (2H, s), trifluoromethyl hydrazine

 9.24 (1H, s), 8.17 (2H, d), o. 27 azole)]phenyl}- N 8.06 (1H, d) , 7.74 (6H, m),

'- [4-Trifluoromethyl 7.58 (1H, d), 7.48 (1H, t). Phenylthiourea

LC-MS (C ₂ , H, ₃ C1 ₂ F ₃ N ₄ S, MW=480):

N-{4-[2-(4

 M+l=481, M+Na=503; 'H-NMR-chlorocarbazole)] (600MHz, DMSO) (ppm): 10.30 Phenyl N' (2H, d), 9.22 (1H, s), 8.13

No.32

 -[4-chloro-3-(3H, m), 7.83 (1H, m) , 7.70

 (4H, m), 7.32 (1H, m), 7.21 trifluoromethylbenzene (1H, d).

 Thiourea

N-{4-[2-(4 HPLC: 100%, LC-MS (C ₂₂ H ₁₃ C1F ₆ N ₄ 0: -trifluoromethyl MW=498): M+l=499, M+Na=521 Carbazole)] benzene

 No.33 base }- N '

-[4-chloro-3-trifluoromethylbenzene

 Urea

N- {4- [2 -(4 HPLC: 99%; LC-MS (C ₂₂ H ₁₃ C1F ₆ N ₄ S _:

Read =514) : M+l-515, M+Na=537 ₀ -trifluoromethyl

 Benzazole)] benzene

 No.34 - base }- N '

-[4-chloro-3-

 Trifluoromethylbenzene

 Thiourea

 Ν-{4-[1-(4 H-NMR (600MHz, DMSO) (ppm)

 9.28 (1H, s), 9.16 (1H, s), -chlorocarbazole)] 8.42 (1H, s), 8.14 (1H, d) , phenyl}- Ν' 7.75 (1H, d), 7.71 (5H , m) ,

No.35 - [4-Chloro-3- 7.63 (1H, d), 7.48 (3H, dd),

 7.35 (1H, d) , , 7.11 (2H, d), trifluoromethylbenzene

 2.29 (3H, s) „

 Urea toluene

 Sulfonate

 N- {4- [1- (4 'H-NMR (600MHz, DMSO) (ppm):

 9.29 (1H, s), 9.19 (1H, s), -trifluoromethyl 8.47 (1H, s), 8.15 (1H, d), carbazole)] Benzene 8.08 (1H, d), 7.69 (8H, m ) 7.48 Kib N ' (2H, d) , 7.12 (2H, d), 2.29

No.36 (3H, s).

 -[4-chloro-3-trifluoromethylbenzene

 Urea toluene

Sulfonate

Cell analysis method:

 Compounds were tested for different tumor cells by MTT assay.

Material

1) Cell line: NCI-H460, A549, OS-RC-2, L0V0, HT-29, MDA-MB-231, SGC7901, HepG2 or BEL-7402 cell line, using 10% fetal bovine serum (Hyclone) D-MEM cell culture medium, routine The initial cell concentration in culture was about 3*10 ⁵ /ml, and it was passaged once every 2 to 3 days 1:3. On the day before the experiment, 1: 2 passage, the cell concentration during the experiment was between ^ 10 * 10 Vml.

2) Dissolution and dilution of the compound: Calculate the number of moles based on the molecular weight and mass of each drug, and uniformly set the highest applied mother liquor concentration to 64 μΜ. Drug dissolution, dilution: First add a certain volume of DMSO (SIGMA company, DMS0 final concentration does not exceed 10%) Dissolve the drug (the highest concentration of the drug is unified to 20 mM, then add a certain volume of culture solution to dilute, the diluted drug is stored at -20 ° C The concentration of the drug mother liquor is 64, 32, 16, 8, 4, 2, 1 μΜ ₀

 3) D-MEM or RPMI 1640 cell culture medium, Gibco; fetal bovine serum, Hyclone; cell digestive juice, 0. 25% Trypsin + 0. 02% EDTA

 4) MTT solution, MTT dry powder (Sigma), fully dissolved in PBS to prepare 5 mg/ml, 0.22 μπι microporous membrane filter, and then stored at - 20 °C.

 5) PBS buffer; 10% acidified SDS, 0. 01N HC1

 6) Centrifuge tubes, straws, etc. (BD company), 96-well plate (Costar)

 Steps:

1) Cell seeding: The cells were cultured 24 hours after passage and grew well. The cells were routinely harvested, and the cell concentration was adjusted to 2-4 x ^{10 5} / _m ]. (adherent cells) with fresh medium. The cells were inoculated with 100 μ]./well, cultured in a 37 ° C, 5% CO ₂ incubator for 24 h, and the old culture solution was discarded, and fresh culture solution was added at 95 μM/well. Suspension cells were inoculated directly to 95 μΐ/well.

 2) Drug treatment: Set 9 concentration gradients for each drug, set 3 replicate wells for each concentration, and set 5 replicate wells for the drug blank control group. Each test was done at the same time as a control. Sorafenib was used as a positive control. The concentration of the drug added was 64, 32, 16, 8, 4, 2, 1 μΜ, 50 μl per well, and the final concentration was 32, 16, 8, 4, 2, 1, 0. 5 μΜ, 50 μM medium was added to the control group.

3) Cell culture and detection: After adding the drug, incubate in 37 ° C, 5% CO ₂ incubator for 72 h, then add MTT 10 μ]. to each well, continue to culture for 4 h, add 100 μΐ 10% SDS per well ( 0. 01N HC1 ) was dissolved. After 24 h, the absorbance (A) of each well was measured with a Bio- rad 680 ELISA reader with a detection wavelength of 570 nm and a reference wavelength of 630 nm. Calculation: First, the absorbance of each replicate well is averaged (to remove overly disparate data), and the inhibition rate (IR) for each drug concentration of each cell is calculated. IR (%) = (1- UA„) X 100%, A _n The average absorbance of the experimental wells, A. is the average absorbance of the drug blanks. Using the EXCEL software, plot the drug concentration effect curve and select a reasonable calculation method to calculate the drug concentration of 50% cell survival (IC ₅ ).

 Table 2 The efficacy of the compound on nine human cell lines IC50 (μΜ)

 0S-RC Bel SGC-790 MDA-MB-23 No. H460 A549 HT29 L0V0 HEPG2

 -2 7402 1 1

NO. 1 1. 4 3. 4 >32 10. 5 8 4 2. 7 22. 6 16

NO. 2 4 5. 3 〉32 32 6. 5 >32 4 >32 26. 1 -οε-

≤9£000/llOZN3/X3d ζ.ζεοζι/ποζ θΛν

/ OlnoiAV /.z:/s/l£i0n0s S9

a: not tested

 Sor is sorafenib, as a control

NCI-H460 is a human lung cancer cell line A549 is a human lung cancer cell line

0S-RC-2 is a human kidney cancer cell line HT29 is a human colon cancer cell line L0V0 is a human colon cancer cell line HepG2 is a human liver cancer cell line Bel7402 is a human liver cancer cell line SGC7901 is a Human gastric cancer cell line MDA-MB-231 is a human breast cancer cell line

Claims

Rights request

 An anti-tumor drug based on a bisazole or azacarbazole-based bisarylurea or thiourea structure, which has the structural formula shown by formula (la) or (lb);

 ( la) (lb)

In the formula:

Z is an N or C atom;

The total number of N atoms in the range is 1 to 5; wherein the total number of N atoms in the 6-membered ring is 0 to 3, and the total number of N atoms in the 5-membered ring is 1 to 2;

 W is selected from 0, S, NH, NOH or NCN;

 M is 0, S, N, CH, etc.;

 n is 1 or 2;

Y is a halogen atom, H, R CF ₃ , 0CF _{: i} , 0H, OR ² , 0C0R ^{: i} , NH ₂ , NHR ⁴ , NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group, cyano group, fluorenyl group, sulfonium group , sulfone group, sulfoxide group, sulfonate group, sulfonate group, sulfonamide group, keto group, aldehyde group, nitro group, nitroso group, wherein R', R ² , R'\ RR\ R ⁶ are ( a hydrocarbon group of ₁₂ ;

R is a halogen atom, H, R', CF ₃ , 0CF ₃ , 0H, 0R ² , 0C0R'\ NH ₂ , NHR ⁴ , NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group, cyano group, mercapto group, alkylthio group , sulfone group, sulfoxide group, sulfonate group, sulfonate group, sulfonamide group, keto group, aldehyde group, nitro group, nitroso group, wherein RR ² , R ³ , RR ⁵ , R ⁶ are C ^ Hydrocarbyl group;

 The halogen atom includes F, Cl, Br or I, and the hydrocarbon group includes a saturated or unsaturated open-chain hydrocarbon group, a saturated or unsaturated cyclic hydrocarbon group;

 The antitumor drug is a compound of the formula (la) or (lb) structure and a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt includes a mineral acid or/and an organic acid derived salt.

 2. The carbazole or azacarbazole-based bisaryl urea or thiourea-based antitumor drug according to claim 1, wherein

The sign is, (la) and (lb)

From any of the following structures:

And the above fused ring compound having a substituent selected from the group consisting of: a hydrocarbon group, a substituted hydrocarbon group, CF ₃ , 0CF ₃ , a hydroxyl group, an alkoxy group, an amino group, a substituted amino group, an amide group, a substituted amide group, a halogen atom, a carboxyl group, Ester, cyano, decyl, sulfonyl, sulfone, sulfoxide, sulfonate, sulfonate, sulfonamide, keto, aldehyde, nitro, nitroso, heterocyclic or substituted Heterocyclic group.

3. The carbazole or azacarbazole-based bisaryl urea or thiourea-based antitumor drug according to claim 1, wherein The fused ring compound z' in the formulas (la) and (lb) is derived from any of the following structures:

And the above fused ring compound having a substituent selected from the group consisting of: a hydrocarbon group, a substituted hydrocarbon group, CF ₃ , 0CF ₃ , a hydroxyl group, a decyloxy group, an amino group, a substituted amino group, an amide group, a substituted amide group, a halogen atom, a carboxyl group, Ester, cyano, decyl, alkylthio, sulfone, sulfoxide, sulfonate, sulfonate, sulfonamide, keto, aldehyde, nitro, nitroso, heterocyclic or substituted Heterocyclic group.

The antitumor drug according to claim 1, wherein M is CH _; n = 2o

 The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisarylurea or thiourea structure according to claim 1, comprising the steps of:

 The compound of the formula (Ila) or (lib) is reacted with a compound of the formula (ΙΠ) in an organic solvent at a temperature of from 10 ° C to 100 ° C for from 1 to 36 hours to form a ruthenium based on the formula (la) or (lb). An anti-tumor drug of bisazole urea or thiourea structure of azole or azacarbazole; said formula (Ila), (l

 (Ila) (lib)

The structure of the compound of formula (III) is:

(III)

 W is an atom or group such as 0, S, NH, N0H, NCN;

 M is 0, S, N, CH, etc.;

 n is 1 or 2;

R is a halogen atom, H, R ¹ . CF ₃ , 0CF ₃ , 0H, 0R ² , 0C0R ³ , NH ₂ , NHR ⁴ , NR ⁵ ₂ , NHCOR ⁶ , carboxyl group, ester group, cyano group, fluorenyl group, sulfonium group , sulfone group, sulfoxide group, sulfonate group, sulfonate group, sulfonamide group, keto group, aldehyde group, nitro group, nitroso group, wherein R', R\R ³ , R\ R ⁵ , R ^e a hydrocarbon group of (^ _-12 );

 The halogen atom includes F, Cl, Br or I, and the hydrocarbon group includes a saturated or unsaturated open-chain hydrocarbon group, a saturated or unsaturated cyclic hydrocarbon group.

 The carbazole or azacarbazole-based bisaryl urea or thiourea-based antitumor drug according to claim 5

 ― a 3⁄4T(CH)n

The preparation method is characterized in that the compound ^W_e_N Μ of the formula (III) includes not only phenyl isocyanate, phenyl isothiocyanate, but also a cyclic isocyanate or a cyclic isothiocyanate, wherein η is 1 Or 2, Μ is CH, Ν, 0 or S. R is a halogen atom, H, R', CF ₃ , 0CF ₃ , 0H, 0R ² , 0C0R ³ , N , NHR ⁴ , NR ⁵ ₂ , NHCOR ⁶ , a carboxyl group, an ester group, a cyano group, a decyl group, a thiol group, Sulfhydryl, sulfoxide, sulfonate, sulfonate, sulfonamide, keto, aldehyde, nitro, nitroso, wherein R', RRR ⁴ , R ⁵ , R ⁶ are Cw ₂ ;

 The halogen atom includes F, Cl, Br or I, and the hydrocarbon group includes a saturated or unsaturated open-chain hydrocarbon group, a saturated or unsaturated cyclic hydrocarbon group.

 The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisaryl urea or thiourea structure according to claim 5, wherein the compound of the formula (III) is selected from the group consisting of:

Phenyl isocyanate, halogenated (fluorine, chlorine, bromine, iodine) phenyl isocyanate, hydrocarbyl (C _W2 ) phenyl isocyanate, alkoxy (d-, 2) phenyl isocyanate, trifluoromethyl phenyl isocyanate, three Fluoromethoxyphenyl isocyanate, ketophenyl isocyanate, ester phenyl isocyanate, nitrophenyl isocyanate, nitrosophenyl isocyanate, sulfophenyl isocyanate, sulfoxide phenyl isocyanate, amido phenyl Isocyanate, N-substituted amidophenyl isocyanate, sulfonylaminophenyl isocyanate; trifluoromethylphenyl isocyanate containing various substituents described above, and phenyl isocyanate containing the plurality of the same or different substituents described above;

Preferably, the compound of formula (III) is selected from the group consisting of: trifluoromethylphenylisocyanate, chlorotrifluoromethylphenylisocyanate, fluorotrifluoromethylphenylisocyanate, iodotrifluoromethylphenylisocyanate, alkane (C, J-trifluoromethylphenyl isocyanate, alkane (C, H oxy trifluoromethyl phenyl isocyanate, alkane (C _M ) oxycarbonyl trifluoromethyl phenyl isocyanate, fluorophenyl isocyanate, chlorobenzene Isocyanate, mercaptofluorophenyl isocyanate, decyl (d- ₆ ) oxycarbonyl fluorophenyl isocyanate, trifluoromethoxyphenyl isocyanate, carbamoyl fluorophenyl isocyanate, N-substituted carbamoyl fluorophenyl Isocyanate, sulfonate fluorophenyl isocyanate;

More preferably, the compound of formula (III) is selected from the group consisting of: trifluoromethylphenylisocyanate, chlorotrifluoromethylphenylisocyanate, fluorotrifluoromethylphenylisocyanate, methoxytrifluoromethylphenylisocyanate Ethoxytrifluoromethylphenylisocyanide Acid ester, dimethylphenyl isocyanate;

 The compound of the formula (ΠΙ) is further selected from the group consisting of: fluoropyridyl isocyanate, chloropyridyl isocyanate, methoxycarbonylfluoropyridyl isocyanate, ethoxylated fluoropyridyl isocyanate, trifluoromethylpyridyl isocyanate, chlorinated three Fluoromethylpyridinium isocyanate, fluorotrifluoromethylpyridyl isocyanate, methoxytrifluoromethylpyridyl isocyanate, ethoxytrifluoromethylpyridyl isocyanate;

 The compound of the formula (ΠΙ) is further selected from the group consisting of fluorofuranyl isocyanate, chlorofuranyl isocyanate, methoxycarbonylfluorofuranyl isocyanate, ethoxycarbonylfluorofuranyl isocyanate. Trifluoromethylfuranyl isocyanate, chlorotrifluoromethylfuranyl isocyanate, fluorotrifluoromethylfuranyl isocyanate, methoxytrifluoromethylfuranyl isocyanate, ethoxytrifluoromethylfuranyl isocyanate;

 The compound of the formula (ΙΠ) is further selected from the group consisting of: fluorothienyl isocyanate, chlorothienyl isocyanate, methoxycarbonyl fluorothienyl isocyanate, ethoxycarbonyl fluorothienyl isocyanate, trifluoromethylthienyl isocyanate, chlorotrifluoro Methylthienyl isocyanate, fluorotrifluoromethylthienyl isocyanate, methoxytrifluoromethylthienyl isocyanate, ethoxytrifluoromethylthienyl isocyanate;

The compound of the formula (ΙΠ) is further selected from the group consisting of: N-alkyl (d- ₆ ) pyrrolyl isocyanate, N-alkyl (C _1→i ) fluoropyrrolyl isocyanate, N-mercaptotrifluoromethylpyrrole Isocyanate, N-sulfonyl (C _M ) pyrrole isocyanate, N-sulfonyl fluoropyrrole isocyanate, N-sulfonyl (C, -.)trifluoromethylpyrrole isocyanate.

 The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisaryl urea or thiourea structure according to claim 6, wherein:

 _3⁄4^(CH)n

In the compound of formula (in), ιντ ^{1 is} derived from any of the following structures:

 Preferably,

 R , ^^- Λ(CH)n

Formula (ΠΙ) The compound is derived from any of the following structures -

More preferably, formula (ΠΙ)

From phenyl or substituted phenyl.

The carbazole or azacarbazole-based bisaryl urea or thiourea-based antitumor drug according to claim 5 The preparation method is characterized in that a solution of the compound of the formula (Ila) or (lib) is slowly added dropwise to the solution of the compound of the formula (ΠΙ) at the beginning of the reaction, and the feeding temperature is at -10 ° C and 50 ° C; The temperature is between 01 and 100 ° C;

 Preferably, the feeding temperature is between 0 ° C and 30 ° C; the reaction temperature after the addition is from room temperature to 80 ° C;

 More preferably, the reaction temperature is from room temperature to 60 Torr;

More preferably, the reaction is carried out at room temperature, and the reaction time is 6 to 24 h _;

 More preferably, the addition is completed and the reaction time is from 1 hour to 36 hours.

 10. The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisarylurea or thiourea structure according to claim 5, wherein the reaction is carried out under inert gas protection, said inertness The gas is selected from nitrogen or argon.

 The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisaryl urea or thiourea structure according to claim 5, wherein the compound of the formula (Ila) or (lib) is 0。 1. The ratio of the molar ratio is 1. 0: 1. 0~1.

 The method for preparing an anti-tumor drug based on a carbazole or azacarbazole-based bisaryl urea or thiourea structure according to claim 5, wherein the organic solvent is selected from the group consisting of a carboxylic acid ester, a halogenated hydrocarbon, benzene and its homologues, halogenated benzene, ether, cyclic ether, dimethylacetamide, dimethylformamide, petroleum ether, alcohol; preferably the organic solvent is selected from the group consisting of ethyl acetate, methyl acetate, Chloroform, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, dimethylformamide, dimethyl An amide, a petroleum ether, or a combination of two or more thereof; wherein the petroleum ether comprises 30 to 60 ° C, 60 to 90 ° C, and 90 to 120 Ό petroleum ether.

 13. The use of a carbazole or azacarbazole-based bisarylurea or thiourea-based antitumor drug according to claim 1, for the preparation of a human lung cancer, human kidney cancer, human colon cancer, human body Liver cancer, human gastric cancer, and human breast cancer drugs.