WO2010051664A1 - 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine derivations and the use thereof - Google Patents

Abstract

The invention provides 7H-imidazo[1,20-a]pyrano[2,3-c]pyridine derivations of formula I and salts, hydrates, solvates thereof, wherein R¹, R² and A are groups which defined in description. The invention further provides the use of compounds of formula I in preparing the drug with the effect of treating or preventing cancer or other proliferative diseases.

Description

 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives and applications thereof

 The present invention relates to novel 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives, and optically active or racemic or pharmaceutically acceptable salts, hydrates thereof Or solvates, methods for their preparation, and pharmaceutical compositions containing the compounds. The present invention also relates to 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives for use in the preparation of therapeutic and

/ or use in drugs to prevent cancer and other proliferative diseases. technical background

 Malignant tumors are diseases that seriously endanger human life and health. With the changes of external factors such as environmental pollution, the number of cancers in the world is increasing year by year. According to the World Health Organization (WHO), about 10 million are diagnosed every year in the world. In cancer patients, 7 million people die from diseases caused by tumors, so malignant tumors have become the second largest killer of humans after cardiovascular disease.

At present, most of the clinical cancer treatment drugs kill tumor cells by acting on different stages of the cell cycle, mainly in the S phase of DNA synthesis and the M phase of mitosis, such as cytarabine and 6-mercaptopurine. Antitumor drugs, vincristine, and paclitaxel are M-phase specific anti-tumor drugs. However, many slow-growing tumors (such as colon cancer) mainly exist in the resting period, that is, the G _Q phase, and some rapidly proliferating tissues such as bone marrow, blood cells, hair, etc. are mainly present in the S or M phase, so these drugs are likely to cause serious Toxic side effects, but not effective for slow-growing tumors. Targeted anti-tumor drugs have better selectivity and lower toxic side effects, and have become a hot research field for anti-tumor drugs.

 Malignant carcinogenesis is generally thought to be caused by uncontrolled cell division and proliferation due to the loss of spontaneous apoptosis. Therefore, the most effective anti-tumor drug should be able to eliminate the need or seriousness by activating the cell death process in the body. Impaired cells, apoptosis will open up new avenues for cancer treatment.

Programmed cell death regulatory genes are present in all multicellular organisms that have evolved Highly conservative. Studies have shown that in addition to multicellular organisms, some bacteria maintain a stable internal cell environment through a similar process. In the process of apoptosis, the most important gene expression product is caspase. The original form of the gene expression product of Caspases in cells is its zymogen form (Procaspase), including the N-terminal domain.

(Prodomain), the large subunit in the middle and the small subunit in the C-terminus. The original domain is cleaved, and the peptide bond between the large subunit and the small subunit is cleaved to form an enzymatically active tetramer (Graf Dirk, Bode Johannes G., Haussinger Dieter. Caspases and receptor cleavage. Archives of Biochemistry and Biophysics , 2007, 462(2): 162-170. ). Activation of caspase is mediated by two pathways, one is activated by the initiation of caspase (including caspase-8 and caspase-9) in response to apoptotic signals; the second is by effect caspase (including caspase-3 and caspase) -7, etc.) to enhance various apoptotic signal activities. After caspase activation, a cascade reaction occurs, resulting in DNA fragmentation, cytoskeleton, actin, laminin and other degradation, which ultimately leads to apoptosis. Although cancer cells contain caspase, the lack of a molecular mechanism that activates the caspase cascade makes cancer cells lose their ability to commit suicide, causing cells to die without malignant proliferation. Some of the anticancer drugs currently being studied can trigger cancer cell death by activating the resting caspase cascade to achieve the purpose of clearing tumor cells. Studies have shown that there are points in the process of apoptosis that control the activation of the caspase cascade. These control points include the CED-9-BCL and CED-3-ICE gene family products, which are the cell's own intrinsic proteins that regulate apoptosis. process. It is reported in the literature that 4H-benzopyrans (II) have the effect of inducing apoptosis, and the 4-position R group is a phenyl or aryl or cyclohexyl group containing different substituents (Kemnitzer William, Drewe John, Jiang Songchun , et al. Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-based High-Throughput Screening Assay. 1. Structure-Activity Relationship of the 4-Aryl Group. Journal of Medicinal Chemistry, 2004, 47(25): 6299-6310).

WO 01/34591公开了一系列取代的 4H-色烯及其类似物， 该类化合物能够激活半胱 天冬酶 （Caspases) 的活性， 并且能够诱导细胞凋亡。 该类化合物可抑制恶性增殖细胞 的生长， 还能阻断异常细胞的扩散。 其中 B环选自苯环、 萘环、 喹啉环和异喹啉环。

WO 01/34591 discloses a series of substituted 4H-chromenes and analogs thereof which are capable of activating the activity of caspases and are capable of inducing apoptosis. These compounds inhibit the growth of malignant proliferating cells and block the spread of abnormal cells. Wherein the B ring is selected from the group consisting of a benzene ring, a naphthalene ring, a quinoline ring and an isoquinoline ring.

 Based on the reference literature, the present inventors designed and synthesized a series of imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives, and inhibited tumor cells in vitro against various tumor cell lines. Activity screening, the results indicate anti-tumor activity. Summary of the invention:

 The present invention relates to 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives of the formula I, and optically active or racemic forms thereof, or pharmaceutically acceptable thereof Salt, hydrate or solvate,

R ¹ is H, dC ₆ alkyl; R ² is H, dC ₆ alkyl;

A is aryl, aryl CC ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl CC ₄ alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl dC _{a 4} alkyl group, a 5-10 membered saturated or partially saturated heterocyclic group, a 5-10 membered saturated or partially saturated heterocyclic group dC ₄ alkyl group, said heteroaryl group and heterocyclic group having 1-3 selected from 0, N and S heteroatoms, and A optionally 1-3 R ³ substituted;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) alkyl, amino (CC ₄ ) alkyl, allyl, (2-methyl)allyl , (CC ₄ )alkylamido, (CC ₄ )alkyl Sulfonyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC ₄ )decylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonyl, anthracene, fluorenyl-di(dC ₄ )alkylaminosulfonyl, (dC ₃ )alkylene Dioxyl,

Or R ³ is an NR ⁴ R ⁵ ;

R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, which may be optionally substituted by 1-3 identical or different, or with R ₅ and The linked nitrogen atoms together form a 5-10 membered saturated heterocyclic group which may contain from 1 to 3 heteroatoms selected from 0, N and S in addition to the nitrogen atom to which R ⁴ and R ^{5 are} attached. , optionally substituted by 1 to 3 identical or different R ⁶ ;

R ⁶ is. . ₄焼 base.

 The present invention preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

Wherein R ¹ is H, dC ₄ alkyl; R ² is H, dC ₄ alkyl;

A is an aryl group, an aryl CC ₄ alkyl group, a 5-10 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and A optionally 1-3 R ³ substitution;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(dC ₄ )alkyl, allyl, (2- Methyl)allyl, (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4 Alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonate Acyl, hydrazine, fluorenyl-di(CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy,

Or R ³ is an NR ⁴ R ⁵ ;

R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl, C ₃ -C ₆ cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R ⁶ , or R ⁴ and R ⁵ Together with the nitrogen atom to which they are attached, a 5-10 membered saturated heterocyclic group is formed, which may contain, in addition to the nitrogen atom to which R ⁴ and R ^{5 are} attached, 1-3 selected from 0, N and a hetero atom of S, optionally substituted by 1 to 3 identical or different R ⁶ ;

R ⁶ is a C1-C4 alkyl group.

 The present invention preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

 among them

A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R ³ substituted;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-C ₄ )alkenyl , (Ci-C ₄ ) alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(Ci-Ca)alkyl, amino(dC ₄ )alkyl, allyl, ( 2-methyl)allyl, (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d -C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N,N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )fluorenyl Aminosulfonyl, indole, fluorenyl-di(CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy).

 The present invention also preferably relates to a derivative of the formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

 among them

R ¹ is H, Ci-. 4 burning base 5

R ² is H;

A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R ³ substituted;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) Alkyl, amino (CC ₄ ) alkyl, allyl, (2-methyl)allyl, (CC ₄ )alkylamido, (CC ₄ )alkylsulfinyl, (C C4)alkyl Sulfonyl, (d-C4) alkoxymethyl, (d-C4)alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(dC ₄ ) fluorenyl Carboyl, sulfamoyl, N-(dC ₄ )nonylaminosulfonyl, anthracene, fluorenyl-di(dC ₄ )alkylaminosulfonyl, (dC ₃ )alkylenedioxy,

Or R ³ is an NR ⁴ R ⁵ ;

R ⁴ and R ^{5 are the} same or different, and each independently is selected from a C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, which may be optionally substituted by 1 to 3 identical or different R ⁶ or R ⁴ and R ⁵ Together with the nitrogen atom to which they are attached, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl;

 The present invention particularly preferably defines a compound of formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

 among them,

R ¹ is H, -CH ₃ ; R ² is H;

A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, trinitrogen Azolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally 1-3 R ³ substituted;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(CC ₄ )alkyl, allyl, (2- Methyl)allyl, (CC ₄ )alkylamido, (CC ₄ )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4 Alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonate Acyl, anthracene, fluorenyl-di(dC ₄ )alkylaminosulfonyl, (dC ₃ )alkylenedioxy,

Or R ³ is an NR ⁴ R ⁵ ;

R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl, C ₃ -C ₆ cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R ⁶ or R ⁴ and R ⁵ Forming morpholinyl, pyrrolidine together with the nitrogen atom to which they are attached Base, piperazinyl, 4-methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl;

 Also particularly preferred in the invention are compounds of formula I, and optically active or racemic forms thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof,

 among them,

R ¹ is H, -CH ₃ ; R ² is H;

A is phenyl, and A is optionally substituted with 1-3 R ³ ;

R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (C C4)alkyl, (C C4)alkenyl, (C C4) alkynyl, (C C4)alkoxy, (C C4)alkylthio, hydroxy (C C4) alkyl, amino (dC ₄ )alkyl, allyl, (2-methyl)allyl , (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (dC ₄ )alkylsulfonyl, (d-C4)alkoxymethyl, (dC ₄ )alkylacyl,aminocarbyl Acyl, N-id-C) alkylcarbamoyl, N, N-di(dC ₄ )nonylcarbamoyl, aminosulfonyl, N-(dC ₄ )nonylaminosulfonyl, hydrazine, hydrazine (CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy,

Or R ³ is an NR ⁴ R ⁵ ;

 The compound of the formula I of the present invention, and its optically active or racemic form or a pharmaceutically acceptable salt, hydrate or solvate thereof are preferably the following compounds, but these compounds are not meant to limit the invention:

 9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-amino-8-cyano-7-(3-propylpropyl-4-carbo-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2] ,3-c]pyridine

2-methyl-9-amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine 9-Amino-8-cyano-7-(3-allyl-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3- c]pyridine

 2-methyl-9-amino-8-cyano-7-[[3-(2-methyl)allyl]-4-methyl-5-methoxyphenyl]-7H-imidazo[ 1,2-a] pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(4-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3,4-difluorophenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 2-methyl-9-amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(2-hydroxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 2-methyl-9-amino-8-cyano-7-(2-methoxy-3-allylphenyl)-7H-imidazo[1,2-a]pyrano[2,3 -c]pyridine

 2-methyl-9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[ 2,3-c] pyridine

 9-Amino-8-cyano-7-(4-pyridyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-[4-(4-methylpiperazin-1-yl)phenyl]-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 2-methyl-9-amino-8-cyano-7-[3-methoxy-4-methyl-5-(2-methylallyl)phenyl]-7H-imidazo[ 1,2-a] pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3,5-diisopropyl-4-hydroxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine The following compounds are particularly preferred in the present invention:

 9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 9-Amino-8-cyano-7-(3-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-amino-8-cyano-7-(3-dallow-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3- c]pyridine

 Moreover, according to some common methods in the art to which the present invention pertains, the 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives of the above formula I of the present invention can be used in the formation of pharmaceutically active acids. Acceptable salt. 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.

 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) Converted to the corresponding biologically active form.

 In the present invention, "halogen" means fluorine, chlorine, bromine or iodo; "alkyl" means a straight or branched alkyl group; "alkylene" means a straight or branched alkylene group; "Cycloalkyl" means a substituted or unsubstituted cycloalkyl group; "aryl" means a phenyl group having no substituent or a substituent; "heteroaryl" means having one or more selected from N, 0 a monocyclic or polycyclic ring system of S heteroatoms, the cyclic system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4) - triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolinyl, benzimidazolyl, benzo "oxazolyl" or the like; "saturated or partially saturated heterocyclic group" means a monocyclic or polycyclic ring system containing one or more hetero atoms selected from N, 0, S, such as pyrrolidinyl, morpholine Base, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl and thiazolinyl and the like.

 The present invention may contain a 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivative of the above formula I, and a pharmaceutically acceptable salt, hydrate or solvate thereof as an activity The composition is prepared into a composition by mixing with a pharmaceutically acceptable carrier or excipient, and is prepared into a clinically acceptable dosage form, and the above pharmaceutically acceptable excipient means any diluent and auxiliary which can be used in the pharmaceutical field. And/or carrier. 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 composition of the present invention can be formulated into several dosage forms, which contain some commonly used forms in the field of medicine. Agent. 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 tanning agent, an ointment or the like.

 Carriers for use in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, non-pigmenting, flavoring agents , 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.

 Through the in vitro antitumor activity test, we have found that the compound of the present invention has antitumor activity, and thus the compound of the present invention can be used for the preparation of a medicament for treating and/or preventing various cancers such as breast, lung, liver, kidney, colon, rectum, stomach. , prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophageal cancer and leukemia, neuroblastoma, etc. It is especially useful for the preparation of a medicament for the treatment and/or prevention of lung cancer and liver cancer.

 The active compound of the present invention or a pharmaceutically acceptable salt thereof and a solvate thereof can be used alone as the sole antitumor drug, or can be combined with an antitumor drug which has been marketed (for example, the platinum drug cisplatin, the camptothecin drug irinotene). Kang, vinca alkaloids noviben, deoxycytidine drugs gemcitabine, etoposide, paclitaxel, etc.). Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

 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 following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all of which are prepared by the methods described in these schematics, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final derivatives of the present invention are prepared by the methods described in these schematics or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All of the variable factors applied in these schematics are as defined below or as defined in the claims. A -CHO + NC

、CN

, CN

 III. Derivatives of formula I according to the invention may be prepared by condensation of compounds IV and II according to the method of Scheme 1; wherein 2-amino-3-hydroxypyridine is cyclized with a compound of formula V to give compound IV, Dimerization of dinitrile to give compound II;

Wherein substituent II of formula II, hydrazine, and substituent RR ² of formula IV and formula V are as defined for the compound of formula I. The compounds of formula ΠΙ and formula V can be prepared by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. Detailed ways:

The examples are intended to illustrate and not to limit the scope of the invention. The nuclear magnetic resonance spectrum of the derivative was measured by Bruker ARX-600, and the mass spectrum was measured by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.

 Example 1: 9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c] Preparation of pyridine step A 8-hydroxyimidazo[1,2-a]pyridine

 5 g (45 mmol) of 2-amino-3-carbopyridine was added to 50 mL of ethanol, and 7.7 mL (47 mmol) of a 40% aqueous solution of chloroacetaldehyde was slowly added dropwise at room temperature, and the mixture was refluxed for 12 hours. After the reaction was completed, the pH of the solution was adjusted to neutral with a 20% aqueous NaOH solution. The solid was precipitated, suction filtered, dried and weighed 5.4 g. The water was recrystallized and dried to give a pale yellow solid product (yield: 71%).

Step B Preparation of 2-[(3,4,5-trimethoxy)phenyl]methylenemalononitrile 3,4,5-trimethoxybenzaldehyde 10 g (51 mmol) and malononitrile 3.4 g (51 mmol) were added to 50 mL of ethanol, 1 drop of piperidine was added dropwise, and stirred at room temperature for 3 hours to precipitate a solid. The filter cake was filtered, washed with ethanol and dried to give 9.7 g (yield: 78%).

 Step C 9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine Preparation

 4.3 g (32 mmol) of 8-hydroxyimidazo[1,2-a]pyridine, 7.8 g (32 mmol) of 2-[(3,4,5-trimethoxy)phenyl] Methylmalononitrile and 1.4 g (16 mmol) of piperidine were added to reflux for 8 hours, and the solid was precipitated. The reaction mixture was cooled, filtered, filtered, and filtered, and dried to give 12.1 g (yield: 84%). ).

MS [MH ⁺ ] (m/z): 378.8; 1H NMR (DMSO-d ₆ ): δ 3.62 (s, 3 H), 3.72 (s, 6 H), 4.71 (s, 1 H), 6.51 (d , 1 H), 6.58 (s, 2 H), 7.17 (s, 2 H), 7.54 (s, 1 H), 7.93 (s, 1 H), 8.20 (d, 1 H).

 Following the method of Example 1, the 8-hydroxyimidazo[1,2-a]pyridine derivative was prepared by first reacting 2-amino-3-light pyridine with a suitable α-chloroaldehyde (ketone); Further, a suitable aldehyde is reacted with malononitrile to prepare a 2-substituted methylenemalononitrile; an 8-hydroxyimidazo[1,2-a]pyridine derivative obtained by the above method and a 2-substituted sub Methylmalononitrile was subjected to a condensation reaction to obtain the compounds of Examples 2-26:

 Example 2: 2-Methyl-9-amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2 ,3-c]pyridine

MS [MH ⁺ ] (m/z): 393.1; 1H NMR (DMSO-d ₆ ): δ 2.32 (s, 3 H), 3.60 (s, 3 H), 3.72 (s, 6 H), 4.70 (s , 1 H), 6.44 (d, 1 H), 6.56 (s, 2 H), 7.16 (s, 2 H), 7.66 (s, 1 H), 8.12 (d, 1 H).

 Example 3: 9-Amino-8-cyano-7-(3-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

MS [MH+] (m/z): 357.1.

 Example 4: 9-Amino-8-cyano-7-(4-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

MS [MH ⁺ ] (m/z): 372.9; 1H NMR (DMSO-d ₆ ): δ 4.87 (s, 1 H), 6.47 (d, 1 H), 7.25 (s, 2 H), 7.33 (d , 2 H), 7.40 (d, 2 H), 7.58 (s, 1 H), 7.97 (s, 1 H), 8.24 (d, 1 H).

 Example 5: 9-Amino-8-cyano-7-(3,4-difluorophenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

MS [MH+] (m/z): 325.1; 1H NMR (DMSO-d ₆ ): δ 4.90 (s, 1 H), 6.58 (d, 1 H), 7.16 (d, 1 H), 7.26 (s, 2 H), 7.40 (m, 2 H), 7.70 (s, 1 H), 8.04 (s, 1 H), 8.30 (d, 1 H). Example 6: 9-Amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 MS [MH+] (m/z): 295.0.

 Example 7: 2-Methyl-9-amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine MS [MH+] (m/z): 331.1.

 Example 8: 9-Amino-8-cyano-7-(4-bromo-2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine MS [ MH+] (m/z): 374.2.

 Example 9: 9-Amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c] Pyridine

MS [MH ⁺ ] (m/z): 333.1; 1H NMR (DMSO-d ₆ ): δ 4.70 (s, 1 H), 5.97 (d, 2 H), 6.48 (d, 1 H), 6.85 (d , 1 H), 7.15 (s, 2 H), 7.18 (d, 1 H), 7.52 (s, 1 H), 7.58 (s, 1 H), 7.96 (s, 1 H), 8.22 (4 1 H ).

 Example 10: 2-Methyl-9-amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2 ,3-c]pyridine

MS [MH+] (m/z): 347.1; 1H NMR (DMSO-d ₆ ): δ 2.43 (s, 3 H), 4.76 (s, 1 H), 5.98 (d, 2 H), 6.65 (d, 1 H), 6.78 (t, 2 H), 6.80 (d, 1 H), 7.12 (s, 2 H), 7.83 (s, 1 H), 8.26 (d, 1 H).

 Example 11: 9-Amino-8-cyano-7-(2-lightylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

MS [MH ⁺ ] (m/z): 304.8.

Example 12: 9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3 -c] pyridine step D Preparation of 3-bromo-4-hydroxy-5-methoxybenzaldehyde 5 g (33 mmol) 4-light 3-methoxybenzaldehyde was dissolved in 50 mL of glacial acetic acid at room temperature 2.5 ml (36 mmol) of liquid bromine was added dropwise, and the mixture was added dropwise, and the mixture was reacted at room temperature for 18 hours. After the completion of the reaction, the mixture was filtered, and then filtered, and then filtered to afford white solid, which was obtained as a white solid (yield: 92%). Step E Preparation of 3-bromo-4,5-dimethoxybenzaldehyde 3-bromo-4-hydroxy-5-methoxybenzaldehyde 5 g (21 mmol), potassium carbonate 8.6 g (62 mmol) In 50 mL of acetone, 2.3 mL (24 mmol) of dimethyl sulfate was added dropwise at room temperature, and the mixture was heated under reflux for 6 hours. The reaction is completed, The organic layer was concentrated under reduced pressure. The solvent was evaporated to dryness under reduced pressure to give a crude oily product. The yield was 82%. The compound of Example 12 was prepared according to the method of Example 1.

MS [MH+] (m/z): 426.7; 1H NMR (DMSO-d ₆ ): δ 3.71 (s, 3 H), 3.82 (s, 3 H), 4.92 (s, 1 H), 6.87 (d, 1 H), 7.06 (s, 1 H), 7.08 (s, 1 H), 7.21 (s, 2 H), 7.92 (s, 1 H), 8.20 (s, 1 H), 8.41 (4 1 H) .

 Example 13: 2-Methyl-9-amino-8-cyano-7-benzyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine MS [MH+] (m/z): 317.1.

 Example 14: 9-Amino-8-cyano-7-(2-furyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 MS [MH+] (m/z): 279.0.

 Example 15: 2-Methyl-9-amino-8-cyano-7-cyclopentyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine MS [MH+] (m/z): 294.9

Example 16: 9-Amino-8-cyano-7-(3-dallow-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[ Preparation of 2,3-c]pyridine step F 3-methoxy-4-(dipropoxy)benzaldehyde 3 g (20 mmol) 4-hydroxy-3-methoxybenzaldehyde, 3.29 g (24 Methyl carbonate and 2.4 g (16 mmol) of sodium iodide were dissolved in 30 mL of DMF. 3 mL (23.6 mmol) of 3-bromopropene was added dropwise at room temperature, and the reaction was completed at room temperature for 6 hours. After completion of the reaction, 50 mL of water, 80 mL of dichloromethane were added and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3.4 g (yield: 90%). Step G 3-Allyl-4-hydroxy-5-methoxybenzaldehyde Preparation 4 g (20.8 mmol) of 3-methoxy-4-(dipropoxy)benzaldehyde was placed in an eggplant bottle , without solvent, heat to 240 ° C, reaction for 14 hours. After completion of the reaction, the mixture was cooled to room temperature, and a 20% aqueous NaOH solution was added to the reaction mixture, and the pH was adjusted to 8, washed with 80 mL of dichloromethane, and the aqueous layer was combined, adjusted to pH 3 with 30% hydrochloric acid, and suction filtered. Drying gave a pale yellow solid product 2.5 g (yield: 63%). The compound of Example 16 was obtained according to the procedure of Example 1. MS [MH+] (m/z): 374.8; 1H NMR (DMSO-d ₆ ): δ 3.25 (d, 2 H), 3.75 (s, 3 H), 4.62 (s, 1 H), 4.95 (m, 2 H), 5.87 (m, 1 H), 6.44 (d, 1 H), 6.56 (s, 1 H), 6.74 (s, 1 H), 7.10 (s, 2 H), 7.53 (s, 1 H ), 7.92 (s, 1 H), 8.19 (d, 1 H).

 The compound of Example 17 was obtained according to the method of Example 16.

 Example 17: 2-methyl-9-amino-8-cyano-7-(3-allyl-4-hydroxy-5-methoxyphenyl)-7H-imidazole

[1,2-a]pyrano[2,3-c]pyridine

 MS [MH+] (m/z): 388.9.

 Example 18: 2-Methyl-9-amino-8-cyano-7-(2-methoxy-3-allylphenyl)-7H-imidazo[1,2-a]pyran [2,3-c]pyridine

 According to the method of steps 1\G and E, the allyloxybenzaldehyde derivative is prepared by reacting with a suitable hydroxybenzaldehyde and 3-bromopropene, and then subjected to a rearrangement reaction to obtain a hydroxyl group-containing and allyl-substituted group. The benzaldehyde derivative was finally methylated with dimethyl sulfate to prepare the appropriate aldehyde for use in the synthesis of the compound of Example 18-21.

MS [MH ⁺ ] (m/z): 359.2; 1H NMR (DMSO-d ₆ ): δ 2.32 (s, 3 H), 3.41 (d, 2 H), 3.71 (s, 3 H), 5.02 (s , 1 H), 5.10 (m, 2 H), 5.97 (m, 1 H), 6.29 (d, 1 H), 7.02 (m, 3 H), 7.16 (s, 2 H), 7.66 (s, 1 H), 8.08 (d, 1 H).

 Example 19: 2-Isopropyl-3-methyl-9-amino-8-cyano-7-(2-methoxy-3-allylphenyl)-7H-imidazo[1,2 -a]pyrano[2,3-c]pyridine

 Step Preparation of H 2-Chloro-4-methyl-3-pentanone

 Add 5 g (50 mmol) of 2-methyl-3-pentanone and 40 mL of carbon tetrachloride to a 100 mL dry three-necked flask, add sulfonyl chloride 7.3 g (55 mmol), and react at room temperature for 20 hours. After completion, 40 mL of water and 50 mL of dichloromethane were added to the reaction mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, aqueous sodium chloride and water, and dried. The organic solvent was distilled off under normal pressure, and the mixture was evaporated under reduced pressure. The fraction obtained at 60 ° C under O.l MPa was collected to obtain 3.8 g (yield: 57%).

 The compound of Example 19 was obtained according to the procedure of Example 1.

MS [MH ⁺ ] (m/z): 414.8. Example 20: 9-Amino-8-cyano-7-(3-propylpropyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyran

[2,3-c]pyridine

 MS [MH+] (m/z): 389.1.

 Example 21: 2-Methyl-9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a] Pyrano[2,3-c]pyridine

MS [MH ⁺ ] (m/z): 375.0; 1H NMR (DMSO-d ₆ ): δ 2.34 (s, 3 H), 3.28 (d, 2 H), 3.67 (s, 3 H), 3.76 (s , 3 H), 4.71 (s, 1 H), 4.99 (m, 2 H), 5.87 (m, 1 H), 6.49 (d, 1 H), 6.62 (d, 1 H), 6.84 (d, 1 H), 7.14 (s, 2 H), 7.71 (s, 1 H), 8.15 (d, 1 H).

 Example 22: 9-Amino-8-cyano-7-(5-methyl-3-isoxazolyl)-7H-imidazo[1,2-a]pyrano[2,3-c] Pyridine

 MS [MH+] (m/z): 294.1.

 Example 23: 9-Amino-8-cyano-7-(4-pyridyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

 MS [MH+] (m/z): 289.8.

 Example 24: 9-Amino-8-cyano-7-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine

MS [MH+] (m/z): 288.9; 1H NMR (DMSO-d ₆ ): δ 4.76 (s, 1 H), 6.44 (d, 1 H), 7.19 (s, 2 H), 7.26 (m, 3 H), 7.34 (m, 2 H), 7.56 (s, 1 H), 7.94 (s, 1 H), 8.21 (d, 1 H).

 Example 25: 2-Methyl-9-amino-8-cyano-7-(4-dimethylaminophenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine

MS [MH ⁺ ] (m/z): 345.8.

 Example 26: 9-Amino-8-cyano-7-(4-methanesulfonylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine MS [MH+ ] (m/z): 367.2.

 Example 27: 9-Amino-8-cyano-7-[4-(4-methylpiperazin-1-yl)phenyl]-7H-imidazo[1,2-a]pyran

[2,3-c]pyridine

 MS [MH+] (m/z): 386.9.

 Example 28: 2-Methyl-9-amino-8-cyano-7-[3-methoxy-4-methyl-5-(2-methylallyl)phenyl]-7H-imidazole And [1,2-a]pyrano[2,3-c]pyridine

MS [MH+] (m/z): 400.8. Example 29: 9-Amino-8-cyano-7-(3,5-diisopropyl-4-hydroxyphenyl)-7H-imidazo[1,2-a]pyran

[2,3-c]pyridine

 MS [MH+] (m/z): 416.9.

 Antitumor activity of the product of the invention

 Inhibition of human breast cancer cell MDA-MB-23 human lung cancer cells in vitro by 7H-imidazo[1,2-a]pyrano[2,3-c]pyridine derivatives of the above formula I according to the present invention H226, human lung cancer cell A549 and human hepatoma cell Bel7402 activity screening, control product 2-amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-吲哚[4 , 5-b]pyran (C) was prepared according to the method described in WO 01/34591.

(1) After the cells were resuscitated and passaged for 2-3 times, they were digested from the bottom of the culture flask with trypsin solution (0.25%). After the cell digest is poured into a centrifuge tube, the culture solution is then added to terminate the digestion. Centrifuge the tube at 800r/min for 10min, discard the supernatant, add 5mL of the culture solution, mix and mix the cells, and pipette 10 μL of the cell suspension into the cell counting plate to adjust the cell concentration to 10 ⁴ / hole. In the 96-well plate, except for the A1 well, which was blank, no cells were added, and the rest were added with 100 μΐ: cell suspension. The 96-well plate was placed in an incubator for 24 h.

 (2) Dissolve the test sample with 50 μΐ: dimethyl sulfoxide, then add the appropriate amount of the culture solution to dissolve the sample into 2 mg/mL solution, and then dilute the sample to 20, 4, 0.8 in a 24-well plate. , 0.16, 0.032 g/mL.

 Each concentration was added to 3 wells, and the growth of the surrounding two rows and two columns was greatly affected by the environment, and only used for blank cell wells. The 96-well plate was placed in an incubator for 72 h.

(3) Discard the drug-containing medium in the 96-well plate, rinse the cells twice with phosphate buffer solution (PBS), and add MTT (tetrazole) (0.5 mg/mL) to each well 100 μΐ: After 4 h in the incubator, the MTT solution was discarded and dimethyl sulfoxide 100 μΐ was added. Oscillating on a magnetic oscillator fully dissolved the viable cells and the hydrazine reaction product formazan, and placed the results in a microplate reader. The drug IC ₅ o value can be determined by the Bliss method.

The results of inhibiting the activity of the compound in human breast cancer MDA-MB-231 cells, human lung cancer H226 cells, human liver cancer Bel7402 cells and human lung cancer A549 cells are shown in Table 1. IC ₅₀

 Example (μg/mL

 Serial number MDA-MB-231 H226 Bel7402 A549

 Breast cancer cells lung cancer cells liver cancer cells lung cancer cells

 Example 1 2.3 0.2 0.4 0.5 Example 2 5 1.3 2.9 1.5 Example 3 44 0.1 0.3 0.4 Example 4 6.4 49 - - Example 5 11 2 1.5 5.3 Example 6 66 7.8 15.2 23.1 Example 7 10 1.2 1.8 0.9 Implementation Example 9 6 1.2 2.8 4.6 Example 10 31 5.2 4.7 8.3

 Example 11 6.7 1.9 599 45

 Example 12 6 0.00001 0.00001 0.00001 Example 16 6 0.00001 0.00001 0.0005 Example 17 16 5.2 6.7 6.3

 Example 18 22 1.2 1.7 2.9

 Example 20 30 0.009 0.8 0.5

 Example 21 15 3.5 288 - Example 23 5.8 19 25 16

 Example 24 10 6.4 1.9 3.8

Example 27 86 4.8 - - Compound C 4.1 5.3 7.2 6.1 It is clear from the above test results that the compound of the formula I to be protected by the present invention has good antitumor activity in vitro, and some compounds and the compound c reported in the literature. The activity is comparable or superior to compound c. The compounds of formula I in the present invention may be administered alone, but are usually administered as a mixture of pharmaceutically acceptable carriers which are selected according to the desired route of administration and standard pharmaceutical practice. The preparation of dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, pills, topical tinctures and ointments, illustrates their new applications in the pharmaceutical field. Example 30: Tablet 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 12) was mixed according to the general tableting method and 20 g of the adjuvant, and then compressed into 100 tablets each weighing 300 mg.

 Example 31: Capsule

 Using a compound containing the compound of claim 1 (exemplified by the compound of Example 16) 10 g, 20 g of the adjuvant was mixed as required by the pharmacy capsule, and then filled into hollow capsules each weighing 300 mg.

 Example 32: Injection

 Using a compound containing the compound of claim 1 (taking the compound of Example 1 as an example) 10 g, according to a conventional method of pharmacy, adsorption of activated carbon, filtration through a 0.65 μηι microporous membrane, and filling with a nitrogen tank to prepare a water needle preparation , each 2 mL, a total of 100 bottles.

 Example 33: Aerosol

 Using a compound containing the compound of claim 1 (taking the compound of Example 2 as an example) 10 g, dissolved in an appropriate amount of propylene glycol, and then adding distilled water and other pellets, a 500 mL clear solution was obtained.

 Example 34: Suppository

 Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 9), add it to the appropriate amount of glycerin, grind it, add the melted glycerin gelatin, grind it evenly, and pour into the model of the coated lubricant. In the process, 50 suppositories were prepared.

 Example 35: Membrane

 Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 18), polyvinyl alcohol, medicinal glycerin, water, etc. are stirred and expanded, heated and dissolved, filtered through an 80 mesh screen, and the compound of Example 18 is further used. It was added to the filtrate and stirred to dissolve, and 100 film-coated membranes were applied.

 Example 36: Pills

 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 7) was heated and melted with 50 g of a gelatin or the like, and then dropped into a low-temperature liquid paraffin to prepare a pellet of 1000 pills.

Example 37: Topical tincture Using a compound containing the compound of claim 1 (exemplified by the compound of Example 21) 10 g, it is prepared by mixing and grinding with 2.5 g of an auxiliary agent such as an emulsifier according to a conventional pharmaceutical method, and adding distilled water to 200 mL.

 Example 38: Ointment

 Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 17), it was finely ground and then prepared by culturing 500 g of an oily substrate such as petroleum jelly.

 Although the present 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

Claim A compound of formula I, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

 I  among them R ¹ is H, dC ₆ alkyl; R ² is H, dC ₆ alkyl; A is aryl, aryl dC ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl dC ₄ alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl^ _{a 4} alkyl group, a 5-10 membered saturated or partially saturated heterocyclic group, a 5-10 membered saturated or partially saturated heterocyclic group _{4 4} alkyl group, said heteroaryl group and heterocyclic group having 1-3 selected from 0, N and S heteroatoms, and A optionally 1-3 R ³ substituted; R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(dC ₄ )alkyl, allyl, (2- Methyl)allyl, (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (dC ₄ )alkylsulfonyl, (d-C4)alkoxymethyl, (dC ₄ ) Alkyl acyl, carbamoyl, N-id-C ) alkylcarbamoyl, N, N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonyl , Ν, Ν-di(CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy, Or R ³ is an NR ⁴ R ⁵ ; R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl, C ₃ -C ₆ cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R ⁶ , or R ⁴ and R ⁵ Together with the nitrogen atom to which they are attached, a 5-10 membered saturated heterocyclic group is formed, which may contain, in addition to the nitrogen atom to which R ⁴ and R ^{5 are} attached, 1-3 selected from 0, N and a hetero atom of S, optionally substituted by 1 to 3 identical or different R ⁶ ; R is a Ci-C ₄ fluorenyl group.  2. A compound of formula I according to claim 1, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R ¹ is H, dC ₄ alkyl; R ² is H, dC ₄ alkyl; A is an aryl group, an aryl CC ₄ alkyl group, a 5-10 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and A optionally 1-3 R ³ substitution; R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(dC ₄ )alkyl, allyl, (2- Methyl)allyl, (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (dC ₄ )alkylsulfonyl, (d-C4)alkoxymethyl, (dC ₄ ) Alkyl acyl, carbamoyl, N-id-C ) alkylcarbamoyl, N, N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonyl , Ν, Ν-di(CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy, Or R ³ is an NR ⁴ R ⁵ ; R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl, C ₃ -C ₆ cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R ⁶ , or R ⁴ and R ⁵ Together with the nitrogen atom to which they are attached, a 5-10 membered saturated heterocyclic group is formed, which may contain, in addition to the nitrogen atom to which R ⁴ and R ^{5 are} attached, 1-3 selected from 0, N and a hetero atom of S, optionally substituted by 1 to 3 identical or different R ⁶ ; R ⁶ is a C1-C4 alkyl group.  3. A compound of formula I according to claim 2, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R ¹ is H, dC ₄ alkyl; R ² is H; A is phenyl, pyridyl, thienyl, furyl, pyrrolyl, naphthyl, quinolyl, isoquinolinyl, imidazolyl, Pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, phenethyl, and optionally A - 3 R ³ substitutions; R ³ is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, azido, nitro, cyano, fluorenyl, (d-Ca)alkyl, (Ci-Ca)alkenyl, (d-Ca)alkynyl, (d-Ca)alkoxy, (d-Ca)alkylthio, hydroxy(d-C4)alkyl, amino(dC ₄ )alkyl, allyl, (2- Methyl)allyl, (dC ₄ )alkylamido, (dC ₄ )alkylsulfinyl, (C C4)alkylsulfonyl, (d-C4)alkoxymethyl, (d-C4 Alkyl acyl, carbamoyl, N-id-C) alkylcarbamoyl, N, N-di(CC ₄ )nonylcarbamoyl, aminosulfonyl, N-(CC ₄ )nonylaminosulfonate Acyl, hydrazine, fluorenyl-di(CC ₄ )alkylaminosulfonyl, (dQ alkylenedioxy, Or R ³ is an NR ⁴ R ⁵ ; R ⁴ and R ^{5 are the} same or different, and each independently selects dC ₆ alkyl, C ₃ -C ₆ cycloalkyl, which may be optionally substituted by 1 to 3 identical or different R ⁶ or R ⁴ and R ⁵ Together with the nitrogen atom to which they are attached, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl;  4. A compound of formula I according to claim 3, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R ¹ is H, -CH ₃ ; R ² is H;  5. A compound of formula I according to claim 4, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A is phenyl, and A is optionally substituted with 1-3 R ³ ;  6. A derivative of the formula I according to claim 1 and an optically active or racemic or a pharmaceutically acceptable salt, hydrate or solvate thereof:  9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine 9-Amino-8-cyano-7-(3-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine 9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-amino-8-cyano-7-(3-propylpropyl-4-carbo-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2] ,3-c]pyridine  2-methyl-9-amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-Amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3-allyl-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3- c]pyridine  2-methyl-9-amino-8-cyano-7-[[3-(2-methyl)allyl]-4-methyl-5-methoxyphenyl]-7H-imidazo[ 1,2-a] pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(4-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3,4-difluorophenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  2-methyl-9-amino-8-cyano-7-(2-thienyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3,4-methylenedioxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(2-hydroxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  2-methyl-9-amino-8-cyano-7-(2-methoxy-3-allylphenyl)-7H-imidazo[1,2-a]pyrano[2,3 -c]pyridine  2-methyl-9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[ 2,3-c] pyridine  9-Amino-8-cyano-7-(4-pyridyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-[4-(4-methylpiperazin-1-yl)phenyl]-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 2-methyl-9-amino-8-cyano-7-[3-methoxy-4-methyl-5-(2-methylallyl)phenyl]-7H-imidazo[ 1,2-a] pyrano[2,3-c]pyridine 9-Amino-8-cyano-7-(3,5-diisopropyl-4-hydroxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine 7. The derivative of the following formula I according to claim 1, and an optically active or racemic thereof or a pharmaceutically acceptable salt, hydrate or solvate thereof:  9-Amino-8-cyano-7-(3,4,5-trimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-Amino-8-cyano-7-(3-bromo-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine 9-Amino-8-cyano-7-(3-trifluoromethylphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c]pyridine  9-amino-8-cyano-7-(3-allyl-4,5-dimethoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3-c Pyridine 9-amino-8-cyano-7-(3-dallow-4-hydroxy-5-methoxyphenyl)-7H-imidazo[1,2-a]pyrano[2,3- c]pyridine  A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, an optically active substance or a racemate thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable composition An acceptable excipient.  9. A compound according to any one of claims 1 to 7, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the treatment and/or prevention of various cell growth disorders and The application of drugs for abnormal cell proliferation diseases.  10. A compound according to any one of claims 1 to 7, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of various cancer diseases Application in .  11. A compound according to any one of claims 1 to 7, and an optically active or racemic thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for the treatment and/or prevention of lung cancer or liver cancer Applications.