KR20130013264A - Imidazopyridine derivatives, pi3k and/or mtor inhibiting composition and composition used in diseases linked to pi3k and/or mtor comprising the same - Google Patents

Abstract

PURPOSE: An imidazopyridine derivative and a pharmaceutical composition containing the same for suppressing PI3k and/or mTOR inhibitor are provided to treat diseases caused by abnormal cell growth or function. CONSTITUTION: An imidazopyridine compound or a pharmaceutically acceptable salt thereof is denoted by chemical formula 1. The salt includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulphonic acid, benzene sulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid, gluconic acid, lactic acid, benzoic acid, salicylic acid, citric acid, or propionic acid. A composition which suppresses PI3K and/or mTOR kinase contains the compound of chemical formula 1 and a pharmaceutically acceptable carrier or diluent.

Description

Imidazopyridine derivatives, PI3K and / or mTOR inhibiting composition and composition used in diseases linked to PI3K and a pharmaceutical composition for pi3k and / or mTOR inhibitors comprising the same, and a pharmaceutical composition for treating diseases associated with pi3x and / or mTOR / or mTOR comprising the same}

The present invention relates to an imidazopyridine derivative, a pharmaceutical composition for phosphatidylinositol 3-kinase and / or a serine and threonine kinase inhibitor comprising the same, and a disease associated with phosphatidylinositol 3-kinase and / or serine and threonine kinase. It relates to a therapeutic pharmaceutical composition.

Phosphatidyl inositol (abbreviated herein as "PI") is one of the many phospholipids found in cell membranes. Recently, it has become clear that PI plays an important role in intracellular signal transduction. In the late 1980s, phosphatidylinositol 3-kinase (hereinafter referred to as 'PI3K') was found to be an enzyme that phosphorylates position 3 of the inositol ring of phosphatidylinositol (D. Whitman et al, 1988, Nature, 332, 664).

PI3K was originally considered to be a single enzyme, but now it has become apparent that there are numerous subtypes of PI3K. Each subtype has its own mechanism for regulating activity. Three major classes of PI3Ks were classified based on their in vivo substrate specificity. (B. Vanhaesebroeck, 1997, Trend in Biol. Sci, 22, 267) Substrates of class IPI3Ks are PI, PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI (4,5) P ₂ ). . Class I PI3Ks are further divided into two groups, Class Ia and Class Ib, in terms of their active mechanism. Class Ia PI3Ks include the PI3K p110α, p110β and p110δ subtypes that carry signals from tyrosine kinase coupled receptors. Class IbPI3K contains a p110r subtype activated with G protein coupled receptors. PI and PI (4) P are known as substrates for class II PI3Ks. Class II PI3Ks include the PI3K C2α, C2β and C2r subtypes, which feature a C2 domain at the C terminus. The substrate for class III PI3Ks is PI alone. In the PI3K subtype, the Class Ia subtype has been investigated to be the most widely used.

Three subtypes of class Ia are the heterodimer of the catalyst 110 kDa subunit and the control subunit of 85 kDa or 55 kDa. The control subunit contains an SH2 domain and binds to tyrosine residues phosphorylated by growth factor receptors or oncogene products with tyrosine kinase activity, inducing PI3K activity of the p110 catalytic subunit, which performs phosphorylation of lipid substrates. . Thus, type Ia subtypes are believed to be associated with cell proliferation and carcinogenesis.

Class II enzymes are based on PI, PI (4) P, and include PI3K C2α, C2β, C2γ subtypes. Regulatory subunits with C2 domains at the C terminus and recognized as Class I enzymes have not been found to date.

It is reported that class III enzymes use only PI as a substrate and human Vps34, p150, a human homolog of Vps34 isolated from yeast, is involved in the control of membrane transport.

Analysis of these PI3K knockout mice shows that p110δ of Class Ia is different from T-cell and B-cell differentiation and function, and that p110γ of Class Ib is neutrophils, mast cells, platelets and cardiomyocytes. Involvement has been reported. (Phosphoinositide 3-kinase signaling-which way to target Trends in Pharmacological Science, 24 (7), 366-376 (2003))

By targeting p110δ and p110γ of class I based on these results, usefulness against autoimmune diseases, inflammation, asthma, heart disease and the like is expected.

Recently, in many carcinomas (particularly, ovarian cancer, colorectal cancer, breast cancer, etc.), amplification of p110α encoding gene PIK3CA, constant activation by mutations, and thus high expression of p110α at protein levels have been reported. It is known that the suppression of apoptosis by the constant activation of survival signals plays a part of the mechanism of cancerization. High frequency of mutations of the PIK3CA gene in human cancers. Science, 304, 554, (2004))

In addition, deletion and mutation of PTEN, a phospholipid phosphatase based on PI (3,4,5) P ₃ , one of the products of PI3K, have been reported in cancer. Since PTEN functions as a suppressor of PI3K by using PI (3,4,5) P ₃ as a substrate, deletion and mutation of PTEN are known to be linked to activation of PI3K in the PI3K signal.

For this reason, it is expected that useful anticancer action is obtained in cancers with enhanced PI3K activity, in particular by inhibiting the activity of p110α.

As such, PI3K inhibitors, which are expected to have high utility in immune disease, anti-inflammatory and anti-cancer areas, are LY294002 (H Yano et al., J. Biol. Chem., 268, 25846, 1993) having the following structural formula as specific inhibitors. ), Wortmannin (WO 9105784) and the like are known.

[LY294002] [Wartmannin]

Recently, a number of other compounds having a PI3K inhibitory activity have been reported, but until now, there is no drug provided in clinical trials such as an anticancer agent as a drug, and the anticancer action based on the PI3K inhibitory action is experimental. There is a need for early development of anticancer drugs having clinically usable PI3K inhibitory effects.

Another area of interest is serine and threonine kinases and one serene and threonine kinase of particular interest is mTOR.

Serine and threonine kinases (hereinafter referred to as mTOR) are 289 kDa serine and threonine kinases and are PI3K-like kinases that associate mitogen stimulation and nutritional status with cell growth and division. mTOR was found in a study conducted to understand the mechanism of rapamycin's activity. In the process of introduction into the cell, rapamycin binds to its intracellular target FKBP12 and this complex then binds to and inhibits mTOR. Thus, mTOR is also referred to as FKBP-RAP related protein (FRAP), RAPFKBP12 target (RAFT1) and RAP target (RAPT1). Cells involved in organ rejection stop growth by the action of rapamycin, which inhibits the signal of anabolic activity regulated by mTOR. Since inhibition of cell growth is an effective method for treating cancer, it would be therapeutically valuable to design new drugs that inhibit mTOR.

In humans, mTOR regulates signals of assimilation from two sources, such as nutrients and activated growth factor receptors introduced into cells. It exists as at least two distinct complexes: rapamycin-sensitive complexes, called mTOR complex 1 (mTORC1), defined by interaction with a secondary protein raptor (regulatory related protein of mTOR). Since mTORC1 phosphorylates and activates the translational regulator eukaryotic initialization factors, 4-E binding protein 1 and ribosomal p70 S6 kinase, normal activation of mTOR results in increased protein translation. Thus, by inhibiting mTOR, rapamycin results in a decrease in phosphorylation of such effectors and reduces the synthesis of proteins, effectively blocking the post-growth activity of mTOR.

The second complex, mTOR complex 2 (mTORC2), is rapamycin insensitive and is defined by interaction with rictor (rapamycin insensitive analog of mTOR). mTORC2 is involved in regulating this by phosphorylating epigenetic kinase Akt and / or PKB on S473. Along with phosphorylation of T308 by PDK1, S473 phosphorylation is required for the full activity of Akt. Recent literature describes that long-term treatment with rapamycin against certain cells also inhibits Akt by inhibiting the combination and function of TORC2, and that the properties of rapamycin affect the anti-apoptotic effect of drugs. . mTOR is also one of the major downstream effectors in phosphatidylinositol 3-kinase (PI3K) and / or Akt, and thus inhibition of mTOR at least partially provides an opportunity to inhibit the PI3K and / or Akt pathway.

Additional pathways affected by mTOR, which are known to be particularly important in renal cell carcinoma, include factors that cause hypoxia (HIF). With the loss of the Von Hippel-Lindau (VHL) gene function commonly seen in cell renal cell carcinoma, there is an accumulation of oxygen sensitive transcription factors HIF-1 and HIF-2. Accumulation of such factors results in increased growth factors induced in vascular endothelial growth factor (VEGF) platelets, and stimulation for converting growth factors. This effect is increased by the stimulation of mTOR, which stimulates both protein stabilization and protein translation, and increases HIF-1 activity.

In addition, nodular sclerosis complex genes, TSC1 and TSC2, are known to work together to inhibit downstream signal transduction regulated by mTOR. Mutations in these genes occur in nodular sclerosis, and their loss of function leads to another pathway leading to increased mTOR activity and induction of VEGF production. TSC2 also regulates HIF. Thus, studies evaluating the effects of TSC1 and TSC2 mutations show a correlation between increased VEGF and activated mTOR and angiogenesis. To date, four mTOR inhibitors have been tested in clinical trials: prototype rapamycin and three rapamycin derivatives, CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. Rapamycin, also called Sirolimus, is a natural antibiotic produced by Streptomyces hygroscopicus. It was initially developed as an antifungal agent applied to Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. Lapamycin was then developed as an immunosuppressive agent, and this study has helped to understand the mechanism of action of these inhibitors. As an anticancer agent, rapamycin has been shown to inhibit the growth of mouse and human cancer cell lines in a concentration dependent manner both in tissue culture and xenograft models. In 60 tumor cells investigated at the US National Cancer Center, the general sensitivity to rapamycin was seen in doses below 2000 ng / ml, more evident in leukemia, ovarian cancer, breast cancer, central nervous system cancer, and small cell lung cancer cell lines. It was. Moreover, rapamycin inhibited tumor turnover of human cells induced by PI3K or Akt and showed growth inhibition and angiogenesis inhibitory effects of metastatic tumors in an in vivo mouse model.

Based on the results of these preclinical studies, clinical trials of rapamycin as anticancer agents were performed, and rapamycin analogs having more desirable pharmaceutical properties were developed. The more soluble ester derivative of rapamycin, CCI-779, has been identified by investigators at Wyeth Ayerst as a cell nontoxic agent that delays tumor cell proliferation. In several non-toxic doses, CCI-779 is alone or toxic in various types of human cancer models such as primitive neuroectoderm tumors such as glioma, rhabdomyosarcoma, medulloblastoma, brain, neck, prostate, pancreatic and breast cancer cells. In combination with the drug showed antitumor activity. Treatment of mice with CCI-779 inhibits the activity of p70S6K and reduces tumor proliferation. As in rapamycin, PTEN-deficient human tumors are more sensitive to CCI-779 regulatory growth inhibition than PTEN expressing cells. Specifically, in vitro studies of eight human breast cancer cell lines showed that six of the eight cancer cell lines studied were inhibited by CCI-779 with an IC ₅₀ in the low concentration (nanomolar) range. However, two lines were not suppressed at IC ₅₀ > 1 μM. Sensitive cell lines were estrogen receptor positive or overexpressing HER-2 and / or Neu, or lost tumor suppressor gene product PTEN. The main toxicity of CCI-779 included toxicity to the skin and mild myelosuppression (mainly hyperplateletemia).

RADOO1, a 4O-O- (2-hydroxyethyl) -rapamycin, is another analog of rapamycin that can be administered orally. Its anti-neoplastic activity was assessed to have IC ₅₀ values ranging from 5-1800 nM in different ex vivo human cancer cell lines and in vivo xenograftmodels. p70S6K inhibition and anti-neoplastic effects are optimal at 2.5 mg / kg / day in melanoma, lung carcinoma, pancreas carcinoma and colon carcinoma In these models. Similarly, RAD001 demonstrated concentration dependent anticancer activity in a syngenic rat pancreas carcinoma model according to an intermittent dosing schedule. RAD001 also exhibits antiangiogenic activity and inhibits human vascular endothelial cell (HUVEC) proliferation. Toxicity reported for RAD001 includes hypercholesterolemia, hypertriglyceridemia, positive leukocytosis and thrombocytopenia. In clinical I trials conducted on advanced cancer patients, RAD001 exhibited an excellent stability profile with mild to moderate skin and mucosal toxicity of up to about 30 mg weekly. Preliminary efficacy results showed an objective response in patients with non-small cell lung cancer.

AP23573 is the most recently reported rapamycin analog in clinical development. The compound is a phosphorus-containing compound synthesized with the aid of computer modeling studies. AP23537, alone or in combination with cytotoxic or target substances, has been found to be stable in organic solvents, aqueous solvents, and plasma and whole blood with varying pH both in vitro and in vivo, and in nude mice As a transplanted xenograft and in vitro, it has shown potential inhibition of various human cancer cell lines. Therefore, there are many studies demonstrating that mTOR inhibitors can improve cancer patient survival. However, rapamycin and analogs thereof did not exhibit universal anticancer activity in early clinical trials. Response rates vary from up to 10% in patients with glioblastomas and advanced renal-cell cancer to as high as about 40% in patients with mantle cell lymphoma. Knowledge of the state of PTEN and PI3K and / or Akt and / or mTOR linkage pathways will aid in the selection of tumor types that respond to mTOR inhibitors. Furthermore, since many tumor types still do not respond to single drug treatment of rapamycin derivatives, it is important to continue investigating factors predicted to be resistant or sensitive to mTOR inhibitors. Molecules that directly inhibit mTOR kinase activity are of particular interest, and such molecules will inhibit both mTORC1 and mTORC2. Such inhibitors may be useful for treating tumors with enhanced Akt phosphorylation and may reduce the growth, proliferation and survival effects associated with Akt activation. If mTOR-rictor is an important activator of the Akt dependent survival process, such a drug would promote apoptosis of tumor cells in compliance with Akt's dependent regulatory mechanisms.

Furthermore, mTOR inhibitors have been shown to be highly effective in preventing tissue rejection following transplantation through their effects on immune responses, demonstrating the potential for treatment of cancer as well as autoimmune and inflammatory diseases.

In addition to angiogenic cytokines, as a major component of downstream signaling pathways of angiogenic growth factors such as VEGF, FGF and PDGF, through the role of the PI3K isoform and in the regulation of vascular endothelial growth factor (VEGF) Due to the role of mTOR, PI3K and mTOR inhibitors also have the potential to treat diseases supported by pathological neovascularization. This includes inflammatory diseases such as tumorigenesis, rheumatoid arthritis, and ocular neovascular diseases such as age-related macular degeneration (AMD), Retinal vascular diseases (vein occlusion and diabetic retinopathy) and other possible proliferative vascular diseases.

mTOR and PI3K have been identified as protein kinases involved in numerous disorders, and compounds in which one or more targets of such kinases show useful biological activity. Thus, compounds that inhibit mTOR and / or PI3K-mTOR and / or PI3K are useful and improved in the treatment of diffuse disorders such as cancer, immune, and inflammatory diseases caused by excessive neovascularization and organ transplant rejection. It is expected to provide more biologically active compounds that are expected to have pharmaceutical properties.

Since compounds that inhibit both mTOR and PI3K simultaneously act at multiple points in the PI3K and / or Akt and / or mTOR pathways, these compounds are expected to play a role in potent diffusion inhibition and angiogenesis inhibition. Numerous inhibitors of this kind are currently being investigated for the first time in clinical settings (eg BEZ235, XL765, GDC0941, PX866, SF1126).

As described above, it is urgent to study drugs that can simultaneously inhibit PI3K and mTOR.

Accordingly, the first problem to be solved by the present invention is to provide an imidazopyridine compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof.

The second problem to be solved by the present invention relates to a pharmaceutical composition for PI3K and / or mTOR inhibitor containing a compound according to the formula [1] as an active ingredient with a pharmaceutically acceptable carrier or diluent and PI3K and / or mTOR It is to provide a pharmaceutical composition for the treatment of diseases.

The present invention provides an imidazopyridine compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof in order to achieve the first object.

[Formula 1]

Wherein X is carbon or nitrogen, R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, an acetyl group, a pyrazole group, a morpholine group, an ester group, a cyano group, a tetrazole group, an oxadiazole group, a substitution or It is selected from an unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, R ₂ is selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

According to an embodiment of the present invention, R ₁ and R ₂ may each independently be a substituted or unsubstituted aryl group having 6 to 12 carbon atoms or a substituted or unsubstituted heteroaryl group having 5 to 24 carbon atoms.

According to an embodiment of the present invention, R ₁ may be hydrogen, an acetyl group, a pyrazole group, a morpholine group, an ester group, a cyano group, a tetrazole group, or an oxadiazole group. When R ₁ is an oxadiazole group, it may be optionally substituted, and the substituent may be an alkyl group. In addition, when R ₁ is an aryl group or heteroaryl group may be optionally substituted, the substituent may be a cyano group.

According to one embodiment of the present invention, the aryl group or heteroaryl group of R ₂ may be optionally substituted, the substituent may be one or more selected from the group consisting of amine group, arylsulfonamide group and morpholinosulfonyl group. . In the arylsulfonamide group, aryl may be preferably substituted or unsubstituted benzene, and the substituent may be one or more selected from the group consisting of halogen or alkyl groups.

According to a preferred embodiment of the present invention, R ₁ may be any one selected from the group represented by the following [Formula 1], and R ₂ may be any one selected from the group represented by the following [Formula 2]. Can be.

[Structural formula 1]

[Formula 2]

According to a preferred embodiment of the present invention, the compound of [Formula 1] according to the present invention may be specifically any one of the following compounds.

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulphone amides

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3-morpholininoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3-acetylimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide

5- (3-morpholinioimidazo [1,2- a ] pyridin-6-yl) -3- (morpholinosulfonyl) pyridin-2-amine

3,5-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide

2,4-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide

N- (5- (3- (3-cyanophenyl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3- (pyridin-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3- (pyridin-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

3- (imidazo [1,2- a ] pyridin-6-yl) aniline

5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine

N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

Ethyl 6- (5- (phenylsulfonamido) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carboxylate

6- (6-amino-5- (morpholinosulfonyl) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carbonitrile

N- (5- (3- ( 1H -pyrazol-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulfonamide

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulphone amides

N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide

N- (5- (imidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide

Ethyl 6- (5- (2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate

The imidazopyridine compound according to the present invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like, and tartaric acid, formic acid. Organic acids such as citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, maleic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, and methane Acid addition salts formed by sulfonic acids, such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like, may be included, and include free carboxyl substituents. The imidazopyridine compound represented may include the above acid addition salts and salts of sodium, calcium and ammonium.

In addition, alkali or alkaline earth metal salts formed by pharmaceutically acceptable base addition salts such as lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, and dicyclohexylamine Organic salts such as N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethyl amine and the like.

The imidazopyridine compound of [Formula 1] according to the present invention can be converted to its salt by a conventional method, and the preparation of the salt can be easily made by those skilled in the art based on the structure of [Formula 1] without further explanation. Can be performed.

Unless otherwise stated below, the imidazopyridine compound of Formula 1 includes pharmaceutically acceptable salts thereof, all of which are to be construed as being included in the scope of the present invention. For convenience of description, these are simply expressed as compounds of [Formula 1].

In order to achieve the second object, the present invention provides a pharmaceutical composition for PI3K and / or mTOR inhibitor and PI3K and / or containing an imidazopyridine compound of Formula 1 as an active ingredient together with the pharmaceutically acceptable carrier or diluent. Or it provides a composition for treating mTOR-related diseases.

In addition, a composition containing a compound according to the above Formula 1 as an active ingredient together with a pharmaceutically acceptable carrier or diluent may be used for proliferative diseases, immune diseases, cardiovascular diseases, neurological diseases, which are associated with PI3K and / or mTOR kinase, Provided are compositions for treating inflammatory diseases, endocrine diseases, metabolic diseases and viral infectious diseases.

The proliferative disease is cancer, the cancer is leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon cancer, peritoneal cancer, peritoneal metastasis cancer and Pancreatic cancer, angina pectoris, myocardial infarction may be any one selected from the group consisting of.

The immune disease may be any one selected from the group consisting of leukemia.

The cardiovascular disease may be any one selected from the group consisting of angina pectoris, hypertension and myocardial infarction.

The neurological disease may be any one selected from the group consisting of nervous gastritis and irritable bowel syndrome.

The inflammatory disease may be any one selected from the group consisting of arthritis.

The endocrine disease may be any one selected from the group consisting of diabetes.

The metabolic disease may be any one selected from the group consisting of obesity, hereditary metabolic diseases.

The viral infection disease may be any one selected from the group consisting of AIDS, viral pneumonia.

In the definition of the substituent and terminology of the imidazopyridine compound of [Formula 1] according to the present invention, the term “alkoxy” refers to alkyloxy having 1 to 10 carbon atoms, and preferably 1 to 3 unless otherwise defined. It may be an alkoxy group having two carbon atoms.

The term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be “saturated alkyl” that does not include alkenyl or alkynyl moieties, or “unsaturated alkyl” that includes at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group containing at least one carbon-carbon double bond, and "alkynyl" refers to a group containing at least one carbon-carbon triple bond. Alkyl may be branched or straight chain, respectively, when used alone or in combination, such as alkoxy.

The alkyl group may be lower alkyl having 1 to 6 carbon atoms, and preferably an alkyl group having 1 to 3 carbon atoms, unless otherwise defined.

Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, C ₁ -C ₄ -alkyl has 1 to 4 carbon atoms in the alkyl chain and consists of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Is selected from the group.

The term 'aryl' includes at least one ring having a shared pi electron field and includes, for example, a monocyclic or fused polycyclic (ie, rings that divide adjacent pairs of carbon atoms) groups. . That is, aryl in the present specification may include aryl, phenyl, naphthyl and the like unless otherwise defined.

The term “heteroaryl” may be heteroaryl containing one to four heteroatoms selected from the group consisting of N, O and S, preferably including one or more N, unless otherwise defined. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadia Sol, pyridine, pyridazine, pyrimidine, pyrazine and similar groups, but is not limited thereto. Examples of bicyclic heteroaryl include indole, indolin, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furypyridine and similar groups, but are not limited to these.

The term 'acetyl group' is an atomic group represented by -COCH ₃ , and includes a methyl group linked to a carbonyl group by a single bond, and the term 'cyano group' can be represented by -CN, and is an atomic group in which carbon and nitrogen are bonded by one atom It has a triple bond, and other atoms or functional groups may be bonded to carbon atoms to be hydrogen cyanide, metal cyanide or nitrile.

The term 'sulfonyl' refers to a SO ₂ -R group, where R can be hydrogen, aryl, heteroaryl, alkyl, alkylamino, heteroarylamino, morpholino group, and the like, thus, 'morpholinosulfonyl group', It may be, but is not limited to, an alkylsulfonamino group and a heteroarylsulfonamino group.

As a specific example of a morpholino group, a morpholino group, 2-methyl morpholino group, 3-methyl morpholino group, 4-methyl morpholino group, 2-ethyl morpholino group, 4-n-propyl morpholino group, 3-n -Butyl morpholino group, 2,4-dimethylmorpholino group, 2,6-dimethylmorpholino group, and 4-phenylmorpholino group, and the like, but are not limited thereto.

In the compound according to the present invention, specific examples of the term “halogen group” include fluorine (F), chlorine (Cl), bromine (Br), and the like, and preferably fluorine (F).

By "treatment" is meant to stop or delay the progression of the disease when used in subjects with symptoms of onset.

The "pharmaceutical composition" may include a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof as necessary with the compound of the present invention.

The term "carrier" refers to a substance that facilitates the addition of a compound into a cell or tissue.

The term "diluent" is defined as a substance that not only stabilizes the biologically active form of a compound of interest, but also is diluted in water to dissolve the compound.

The term "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of the compound.

Other terms and abbreviations used herein may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs unless otherwise defined.

Imidazopyridine compounds according to the invention and their pharmaceutically acceptable salts are inhibitors against PI3K and / or mTOR kinase which are caused by abnormal cell growth, function or behavior, in particular cancer, proliferative diseases, immune diseases, cardiovascular It can be used to treat diseases, viral infections, inflammatory diseases, endocrine diseases, metabolic diseases and neurological diseases.

1 is a graph showing the results of measuring the activity of mTOR.

Hereinafter, the present invention will be described in detail.

It is known that p110δ of PI3K Class Ia is involved in differentiation or function of T-cells and B-cells, and p110γ of Class Ib is involved in neutrophils, mast cells, platelets and cardiomyocytes. In addition, p110δ and p110γ are involved in immune diseases, inflammation, asthma, and heart diseases, and in particular, in recent years, it is known that p110α expression is involved in many carcinomas (particularly, ovarian cancer, colorectal cancer, and breast cancer). mTOR is a 289 kDa serine and threonine kinase and is a PI3K-like kinase that associates mitogen stimulation and nutritional status with cell growth and division.

Accordingly, various pyridine derivative compounds, compounds such as LY294002 and wortmannin are known as PI3K-specific inhibitors, but there is a problem that a large amount of administration is required for PI3K activity inhibition.

According to one embodiment of the present invention, the imidazopyridine compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof according to the present invention simultaneously inhibits PI3K and mTOR kinase in a biological test even with a small amount of administration. It is excellent in activating effect and can suppress p110 isoforms including alpha, beta, gamma and delta as pan inhibitors.

[Formula 1]

Wherein X is carbon or nitrogen, R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, an acetyl group, a pyrazole group, a morpholine group, an ester group, a cyano group, a tetrazole group, an oxadiazole group, a substitution or It is selected from an unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, R ₂ is selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

According to a preferred embodiment of the present invention, R ₁ and R ₂ may each independently be a substituted or unsubstituted aryl group having 6 to 12 carbon atoms or a substituted or unsubstituted heteroaryl group having 5 to 24 carbon atoms.

According to an embodiment of the present invention, R ₁ may be hydrogen, an acetyl group, a pyrazole group, a morpholine group, an ester group, a cyano group, a tetrazole group, or an oxadiazole group. When R ₁ is an oxadiazole group, it may be optionally substituted, and the substituent may be an alkyl group. In addition, when R ₁ is an aryl group or heteroaryl group may be optionally substituted, the substituent may be a cyano group.

According to a preferred embodiment of the present invention, when R ₂ is an aryl group or heteroaryl group, it may be substituted with one or more selected from the group consisting of amine group, arylsulfonamide group and morpholinosulfonyl group.

In the arylsulfonamide group, aryl may be a substituted or unsubstituted group, the group may be preferably benzene, and the substituent may be at least one selected from the group consisting of halogen or alkyl groups.

According to a preferred embodiment of the present invention, R ₁ may be any one selected from the group represented by the following [Formula 1], and R ₂ is any one selected from the group represented by the following [Formula 2] Can be.

[Structural formula 1]

[Formula 2]

It will be apparent to those skilled in the art that the present invention is not limited thereto, but according to a preferred embodiment of the present invention, the compound of [Formula 1] according to the present invention is specifically It can be either.

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfon Amide [Compound 1]

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 2]

N- (5- (3-morpholininoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 3]

N- (5- (3-acetylimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 4]

N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 5]

5- (3-morpholinioimidazo [1,2- a ] pyridin-6-yl) -3- (morpholinosulfonyl) pyridin-2-amine [Compound 6]

3,5-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide [Compound 7]

2,4-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide [Compound 8]

N- (5- (3- (3-cyanophenyl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 9]

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 10]

N- (5- (3- (pyridin-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 11]

N- (5- (3- (pyridin-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 12]

3- (imidazo [1,2- a ] pyridin-6-yl) aniline [Compound 13]

5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine [Compound 14]

N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 15]

Ethyl 6- (5- (phenylsulfonamido) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carboxylate [Compound 16]

6- (6-amino-5- (morpholinosulfonyl) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carbonitrile [Compound 17]

N- (5- (3- ( 1H -pyrazol-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 18]

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulfonamide [Compound 19]

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulphone Amide [Compound 20]

N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 21]

N- (5- (imidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 22]

Ethyl 6- (5- (2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate [Compound 23]

According to a preferred embodiment of the present invention, the imidazopyridine compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof may be a p110 isotype selective inhibitor by selective inhibition of one of the p110 isotype, The compound is more selective for type Ia PI3 kinase than Form Ib, and preferably the compound is more selective for p110δ over p110δ isoforms, such as p110γ.

Inhibitory activity of the PI3K kinase of the imidazopyridine compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof was tested in comparison with LY294002, which is an inhibitor of the conventional PI3K kinase, and PI3K was manufactured by Signachem ( The reaction buffer and the compound according to the present invention can be measured by culturing with phosphatidylinositol-4,5-bisphosphate (PI (4,5) P ₂ ) medium of Richmond, BC, CANADA. This will be described later.

According to another embodiment of the invention, the pharmaceutically acceptable salt is an acid forming a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, Inorganic acids such as hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, Acid addition salts formed by organic acids such as citric acid and the like, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like, and according to the present invention comprising a free carboxyl substituent. The imidazopyridine compound represented by [Formula 1] may be the acid addition salts and salts of sodium, calcium, and ammonium, Alkali metal or alkaline earth metal salts formed by, for example, a base addition salt which is acceptable, for example, lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N-methyl Organic salts such as -D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethyl amine and the like.

The imidazopyridine compound of [Formula 1] according to the present invention can be converted to its salt by a conventional method, and the preparation of the salt can be easily made by those skilled in the art based on the structure of [Formula 1] without further explanation. Can be performed

Unless otherwise stated below, the imidazopyridine compound of Formula 1 includes pharmaceutically acceptable salts thereof, all of which are to be construed as being included in the scope of the present invention. For convenience of description, these are simply expressed as compounds of [Formula 1].

According to another embodiment of the invention, the imidazopyridine compound according to the invention is a simultaneous inhibitor of PI3K and / or mTOR kinase, resulting from abnormal cell growth, function or behavior associated with PI3K and / or mTOR kinase. It can be used to treat proliferative diseases, immune diseases, cardiovascular diseases, neurological diseases, inflammatory diseases, endocrine diseases, metabolic diseases and viral infection diseases.

 According to a preferred embodiment of the present invention, the proliferative disease is cancer, the cancer is leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon Cancer, peritoneal cancer, peritoneal metastasis cancer and pancreatic cancer, the immune disease may be rheumatoid arthritis, autoimmune pernicious anemia, type I diabetes, the cardiovascular disease may be myocardial infarction, hypertension and angina pectoris, the neurological disease May be neurological gastritis, irritable bowel syndrome, the inflammatory disease may be degenerative arthritis, sinusitis, endocrine disease may be diabetes, metabolic disease may be obesity or hereditary metabolic disease, viral infection disease may be AIDS, It can be bird flu and swine flu.

Hereinafter, a method for preparing the compound of [Formula 1] to help the understanding of the present invention.

The following 2-amino-5-bromopyridine is used as a starting material to obtain various imidazopyridine intermediates in which the R ₁ group is introduced at the C3 site through a condensation reaction. This intermediate can be transformed into another imidazopyridine intermediate via extra condensation. In addition, the synthesis of the imidazopyridine intermediate in which the aryl group is introduced into the R ₁ site may be performed by replacing the compound in which R ₁ is hydrogen with iodine using N -iodosuccinimide, followed by subsequent Suzuki coupling. .

C6 place already from the imidazo pyridine intermediate is via a Suzuki coupling of a palladium catalyst to R ₂ An aryl group is introduced to prepare an imidazopyridine compound represented by [Formula 1] according to the present invention.

 [Starting Materials] [Imidazopyridine Intermediates] [Formula 1]

Specifically, the synthesis of C3 substituted 6-bromoimidazo [1,2- a ] pyridine derivatives can be achieved through several condensation reactions from 2-amino-5-bromopyridine.

Specifically, the synthesis of the derivative of C3 site includes condensation reaction of 2-amino-5-bromopyridine with 1,1-dimethoxy- N , N -dimethylmethanamine, followed by alkyl halide with R ₁ group, This can be done through a condensation reaction using sodium bicarbonate base.

Synthesis of derivatives in which methyloxadiazole group is introduced at C3 site may be accomplished by condensation reaction of hydroxylamine hydrochloric acid and triethylamine in derivative having cyan group at C3 site, followed by condensation reaction with acetic anhydride added thereto. .

The synthesis | combination of the derivative | guide_body which introduce | transduced the morpholine group in C <3> site | part is made by making 2-amino-5-bromopyridine react with the solid produced by condensing benzotriazole, glyoxal, and morpholine.

The derivative | guide_body synthesis | combination which ethyl ester group was introduce | transduced into C <3> site | part is made by making 2-amino-5-bromopyridine react with the solid produced by condensation of ethyl formate, ethyl chloroacetate, and t-butoxy potassium.

Synthesis of a derivative in which hydrogen is introduced into the C3 site may be accomplished by heating and stirring at 100 ° C. under an isopropanol solvent using 2-amino-5-bromopyridine, chloroacetaldehyde, and sodium hydrogen carbonate. This is reacted with N -iodosuccinimide to introduce iodine at the C3 site, and an aryl group is introduced at the R ₁ site through a Suzuki type coupling reaction using various arylboronic acids, palladium catalyst (II) and potassium carbonate base. do.

R _{2 in} place of C6 In the reaction for introducing aryl, a 1,4-dioxane and water (ratio 3: 1) are used as a arylboron ester or an arylboronic acid, a palladium catalyst (II), or a Suzuki-type coupling reaction using a potassium carbonate base. and a C6 position of R _2, heated to 100 and stirred ℃ Substitute the aryl group. Additionally R ₂ When introducing a sulfonyl group into an amine group in an aryl group, benzenesulfonyl chloride or 3,5-difluorobenzenesulfonyl chloride and pyridine are stirred at room temperature under dichloromethane as a solvent to introduce a desired arylsulfonamide group. .

R ₁ is selected from hydrogen, an alkyl group, an acetyl group, a pyrazole group, a morpholin group, an ester group, a cyano group, a tetrazole group, an oxadiazole group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. .

R ₂ is selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

Preferably, R ₁ and R ₂ may each independently be a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaryl group having 5 to 24 carbon atoms.

However, one of ordinary skill in the art can prepare the compound of [Formula 1] by various methods based on the structure of [Formula 1], all of these methods are in the scope of the present invention It should be interpreted as being included.

That is, the compound of [Formula 1] may be prepared by arbitrarily combining various synthesis methods described in the present specification or disclosed in the prior art, which is understood to be within the scope of the present invention. It is not limited to what is described below.

According to a preferred embodiment of the present invention, the salt dissolved in the buffer solution is used as a diluent, and the buffer solution usually used may be phosphate buffer saline that mimics the salt form of the human solution. Since buffer salts can control the pH of the solution at low concentrations, the buffer diluent does not modify the biological activity of the compound.

The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions also containing a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention can be generally prepared according to a conventional method, and can be administered in a pharmaceutically or veterinarily appropriate form.

According to a preferred embodiment of the invention, it can be administered orally, such as in the form of tablets, capsules, sugar-coated, film-coated tablets, liquid solutions or suspensions, or by injection or infusion subcutaneously or intramuscularly or intravenously. It can also be administered parenterally via the method.

Dosage can be determined by various factors, including the age, weight and condition of the patient and the route of administration. The daily dosage may vary within wide limits and may be adjusted to individual requirements in each individual case. In general, however, when the compound is administered alone to an adult, the dosage adopted for each route of administration is 0.0001 to 50 mg / kg body weight, for example 0.01 to 1 mg / kg in the range of 0.001 to 10 mg / kg body weight. You can do it by weight.

Such dosages may be given, for example, 1 to 5 times a day. For intravenous injections, a suitable daily dose is 0.0001 to 1 mg / kg body weight, preferably 0.0001 to 0.1 mg / kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments of the present invention and PI3K inhibitory activity. However, these examples are intended to illustrate the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited thereby.

<Production Example>

The imidazopyridine compound represented by [Formula 1] according to the present invention was prepared according to the following general preparation procedure.

<General Manufacturing Procedure 1>

The obtained imidazopyridine derivative (1 equiv), arylboronic acid (1.2 equiv), potassium carbonate (4 equiv) and bis (diphenylphosphine) ferrocene-palladium (II) (0.5 equiv) were placed in a round bottom flask, The mixture was heated at 70-120 ° C. for 2 to 36 hours under a solvent in which the ratio of 4-dioxane to water was 3: 1. After completion of the reaction, the mixture was dissolved with dichloromethane and methanol, and then filtered under silica and celite. The desired material was obtained through silica gel column chromatography.

<General Manufacturing Procedure 2>

Arylsulfonyl chloride (0.3 equiv) and pyridine were reacted with the imidazopyridine derivative (1 equiv) obtained by the general preparation procedure 1. After stirring for 12 hours at room temperature, the desired material was obtained by silica gel column chromatography.

<Example> Synthesis of the imidazopyridine compound represented by the above [Formula 1]

Example 1 Preparation of 5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine [Compound 14]

[Reaction Scheme 1]

According to Scheme 1 above, 6-bromoimidazo [1,2- a ] pyridine (160 mg, 0.83 mmol), 5- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) pyridin-3-amine (180 mg, 0.83 mmol), potassium carbonate (460 mg, 3.3 mmol) bis (diphenylphosphine) ferrocene-palladium (II) (34 mg, 0.041 mmol) was reacted for 12 hours under <General Preparation Procedure 1> in a solvent in which the ratio of 1,4-dioxane and water was 3: 1. After removing the solvent under low pressure, the residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1/20) to give 5- (imidazo [1,2- a ] pyridin-6-yl) pyridine- After 3-amine (33 mg, 19% yield) was obtained by NMR, the measurement results are shown in the following NMR data.

¹ H NMR (DMSO-d6, 300 MHz) δ5.45 (s, 2H), 7.15 (t, 1H, J = 2.2 Hz), 7.46 (dd, 1H, J = 1.8, 8.5 Hz), 7.63 (t, 2H, J = 7.9 Hz), 7.94-8.05 (m, 2H), 8.05 (d, 1H, J = 2.5 Hz), 8.05 (s, 1H), 8.86 (s, 1H). HRMS calcd for C ₁₂ H ₁₀ N ₄ [M + H] 211.0984, obsd 211.0994.

Example 2 Preparation of N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 15]

 Scheme 2

5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine (20 mg, 0.10 mmol), pyridine (12 mL, 0.14 mmol), benzenesulfonyl chloride (15 mL, 0.16 mmol ) Was reacted at room temperature for 24 hours according to <General Preparation Procedure 2> and the solvent was evaporated under low pressure. The obtained residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1/20) to give N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl. ) Benzenesulfonamide (10 mg, 30% yield) was obtained and measured by NMR, the measurement results are shown in the following NMR data.

¹ H NMR (DMSO- d ₆ , 300 MHz) δ 7.45 (d, 1H, J = 1.6 Hz), 7.57-7.64 (m, 5H), 7.66-7.83 (m, 3H), 8.00 (s, 1H), 8.25 (d, 1H, J = 2.2 Hz), 8.60 (d, 1H, J = 1.7 Hz), 8.92 (s, 1H), 10.75 (br, 1H). HRMS calcd for C ₁₈ H ₁₄ N ₄ O ₂ S [M + H] 351.0916.

Example 3 Preparation of N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 10]

 Scheme 3

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide with sodium azide (15 mg, 0.22 mmol) in DMF (5 mL C) chloride (4.0 mg, 0.023 mmol) was added thereto and reacted at 80 ° C. for 12 hours. After removing the solvent under low pressure, the residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1/3) to give N- (5- (3- ( 2H -tetrazol-5-yl) Dazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide (19 mg, 40% yield) was obtained and measured by NMR, the measurement results are shown in the following NMR data. .

_{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ 6.85 (d, 1H, J = 2.3 Hz), 7.45-7.60 (m, 6H), 7.82 (s, 1H), 7.98-8.00 (m, 2H), 8.03 (s, 1H), 8.16 (d, 1H, J = 8.2 Hz), 8.36 (s, 1H), 8.41 (d, 1H, J = 2.4 Hz), 8.78 (s, 1H), 10.1 (s, 1H ). C ₁₉ H ₁₄ N ₈ O ₂ S [M + Na] 441.0858, obsd 441.0834.

Example 4 N- (5- (3- ( 1H -pyrazol-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide [Compound 18]

 [Reaction Scheme 4]

1,1-dimethoxy- N in N- (5- (3-acetylimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide (59 mg, 0.15 mmol) , N -dimethylmethanamine (3 mL, 23 mmol) was reacted at 100 ° C. for 16 hours, and then cooled to room temperature. After the solvent was blown off under low pressure, the residue was dissolved in ethanol (10 mL), and hydrazine hydrate (17 mL, 0.33 mmol) was added thereto and reacted at 80 ° C. for 7 hours. After removing the solvent under low pressure, the residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1/20) to give N- (5- (3- ( 1H -pyrazol-4-yl) Dazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide (12 mg, 19% yield) was obtained and measured by NMR, the measurement results are shown in the following NMR data. .

_{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ 6.85 (d, 1H, J = 2.3 Hz), 7.45-7.60 (m, 6H), 7.82 (s, 1H), 7.98-8.00 (m, 2H), 8.03 (s, 1H), 8.16 (d, 1H, J = 8.2 Hz), 8.36 (s, 1H), 8.41 (d, 1H, J = 2.4 Hz), 8.78 (s, 1H), 10.1 (s, 1H ). HRMS calcd for C ₂₁ H ₁₆ N ₆ O ₂ S [M + H] 417.1134, obsd 417.1122.

&Lt; Comparative Example 1 &

LY294002 compound was prepared.

Specific compounds of the present invention obtained from Preparation Examples and Examples 1 to 4 are shown in Table 1 below.

Compound number rescue name NMR; MS One

N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulphone amides ¹ H NMR (DMSO- d ₆ , 300 MHz) δ2.73 (s, 3H), 7.59-7.61 (m, 3H), 7.81 (m, 2H), 7.87 (d, 2H, J = 6.5 Hz), 7.95 (d, 1H, J = 9.4 Hz), 8.33 (d, 1H, J = 2.4 Hz), 8.37 (s, 1H), 8.61 (s, 1H), 9.21 (s, 1H). HRMS calcd for C ₂₁ H ₁₆ N ₆ O ₃ S [M + H] 433.1084, obsd 433.1078. 2

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ7.56-7.65 (m, 3H), 7.79-7.85 (m, 4H), 7.95 (d, 1H, J = 9.4 Hz), 8.31 (s, 1H) , 8.49 (s, 1H), 8.70 (s, 1H), 8.79 (s, 1H), 10.74 (s, 1H). HRMS calcd for C ₁₉ H ₁₃ N ₅ O ₂ S [M + H] 376.0869, obsd 376.0862 3

N- (5- (3-morpholininoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ3.01 (t, 4H, J = 4.5 Hz), 3.80 (t, 4H, J = 4.4 Hz), 7.36 (m, 2H), 7.57-7.72 (m , 4H), 7.80 (t, 1H), 7.83 (d, 2H, J = 6.8 Hz), 8.29 (d, 2H, J = 2.4 Hz), 8.64 (d, 1H, J = 1.9 Hz), 11.75 (br , 1H). HRMS calcd for C ₂₂ H ₂₁ N ₅ O ₃ S [M + H] 436.1444, obsd 436.1450. 4

N- (5- (3-acetylimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ 2.60 (s, 3H), 7.60-7.65 (m, 3H), 7.78 (m, 1H), 7.84-7.97 (m, 4H), 8.34 (d, 1H, J = 2.3 Hz), 8.62 (d, 1H, J = 2.0 Hz), 8.68 (s, 1H), 9.71 (s, 1H), 10.82 (s, 1H). HRMS calcd for C ₂₀ H ₁₆ N ₄ O ₃ S [M + Na] 415.0841, obsd 415.0842. 5

N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ2.61 (s, 3H), 7.60-7.65 (m, 3H), 7.82-7.87 (m, 3H), 8.36 (d, 1H, J = 2.4 Hz) , 8.68 (d, 1H, J = 2.0 Hz), 8.83 (s, 1H), 9.10 (d, 1H, J = 2.6 Hz), 9.85 (d, 1H, J = 2.6 Hz), 10.84 (s, 1H) . HRMS calcd for C ₁₉ H ₁₅ N ₅ O ₃ S [M + H] 394.0975, obsd 394.1016. 6

5- (3-morpholinioimidazo [1,2- a ] pyridin-6-yl) -3- (morpholinosulfonyl) pyridin-2-amine ¹ H NMR (CDCl ₃ , 300 MHz) δ3.05-3.08 (m, 4H), 3.14-3.17 (m, 4H), 3.72-3.75 (m, 4H), 3.88-3.91 (m, 4H), 5.90 ( br, 2H), 7.24 (dd, 1H, J = 1.9, 8.3 Hz), 7.35 (s, 1H), 7.61 (dd, 1H, J = 0.7, 8.9 Hz), 7.98 (d, 1H, J = 2.3 Hz ), 8.04 (m, 1 H), 8.47 (d, 1 H, J = 2.3 Hz). HRMS calcd for C ₂₀ H ₂₄ N ₆ O ₄ S [M + H] 445.1659, obsd 445.1667 7

3,5-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ2.71 (s, 3H), 7.53 (m, 2H), 7.62 (m, 1H), 7.82 (m, 2H), 7.95 (d, 1H, J = 3.1 Hz), 8.36 (s, 1H), 8.38 (d, 1H, J = 7.8 Hz), 8.70 (d, 1H, J = 6.5 Hz), 9.22 (s, 1H), HRMS calcd for C ₂₁ H ₁₄ F ₂ N ₆ O ₃ S [M + H] 469.0895
HRMS calcd for C ₂₁ H ₁₄ F ₂ N ₆ O ₃ S [M + H] 469.0895, obsd 469.1. 8

2,4-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ2.73 (s, 3H), 7.59-7.61 (m, 3H), 7.81 (m, 2H), 7.87 (d, 2H, J = 6.5 Hz), 7.95 (d, 1H, J = 9.4 Hz), 8.33 (d, 1H, J = 2.4 Hz), 8.37 (s, 1H), 8.61 (s, 1H), 9.21 (s, 1H). HRMS calcd for C ₂₁ H ₁₆ N ₆ O ₃ S [M + H] 433.1084, obsd 433.1078. 9

N- (5- (3- (3-cyanophenyl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz)
δ 7.44-7.53 (m, 5H), 7.70-7.78 (m, 7H), 7.95 (m, 1H), 8.06 (s, 1H), 8.22 (d, 1H, J = 2.4 Hz), 8.48 (d, 1H, J = 2.0 Hz), 8.55 (s, 1H). HRMS calcd for C ₂₅ H ₁₇ N ₅ O ₂ S [M + H] 452.1182, obsd 452.1203. 10

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ6.85 (d, 1H, J = 2.3 Hz), 7.45-7.60 (m, 6H), 7.82 (s, 1H), 7.98-8.00 (m, 2H) , 8.03 (s, 1H), 8.16 (d, 1H, J = 8.2 Hz), 8.36 (s, 1H), 8.41 (d, 1H, J = 2.4 Hz), 8.78 (s, 1H), 10.1 (s, 1H). C ₁₉ H ₁₄ N ₈ O ₂ S [M + Na] 441.0858, obsd 441.0834. 11

N- (5- (3- (pyridin-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ6.86-6.91 (m, 5H), 7.18-7.25 (m, 5H), 7.45 (m, 1H), 7.68 (d, 1H, J = 2.4 Hz) , 7.83-7.84 (m, 1H), 7.87 (d, 1H, J = 2.0 Hz), 8.10 (m, 1H), 8.25 (s, 1H). HRMS calcd for C ₂₃ H ₁₇ N ₅ O ₂ S [M + Na] 450.1001, obsd 450.1011. 12

N- (5- (3- (pyridin-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ7.54-7.61 (m, 4H), 7.74 (s, 1H), 7.81 (d, 4H, J = 6.0 Hz), 7.85 (s, 1H), 8.07 (s, 1H), 8.28 (d, 1H, J = 2.3 Hz), 8.65 (s, 1H), 8.69 (d, 2H, J = 6.1 Hz), 8.80 (s, 1H). 13

3- (imidazo [1,2- a ] pyridin-6-yl) aniline ¹ H NMR (CDCl ₃ , 300 MHz) δ3.81 (br, 2H), 6.73 (dd, 1H, J = 2.2, 6.8 Hz), 6.87 (t, 1H, J = 1.9 Hz), 6.95 (dt, 1H , J = 0.7, 0.9, 7.7 Hz), 7.28 (t, 1H, J = 3.8 Hz), 7.42 (dd, 1H, J = 1.7, 8.5 Hz), 7.66 (m, 3H), 8.29 (t, 1H, J = 1.0 Hz). HRMS calcd for C ₁₃ H ₁₁ N ₃ [M + Na] 232.0851, obsd 232.0853. 14

5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine ¹ H NMR (DMSO- d ₆ , 300 MHz) δ5.45 (s, 2H), 7.15 (t, 1H, J = 2.2 Hz), 7.46 (dd, 1H, J = 1.8, 8.5 Hz), 7.63 (t , 2H, J = 7.9 Hz), 7.94-8.05 (m, 2H), 8.05 (d, 1H, J = 2.5 Hz), 8.05 (s, 1H), 8.86 (s, 1H). HRMS calcd for C ₁₂ H ₁₀ N ₄ [M + H] 211.0984, obsd 211.0994. 15

N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ7.45 (d, 1H, J = 1.6 Hz), 7.57-7.64 (m, 5H), 7.66-7.83 (m, 3H), 8.00 (s, 1H) , 8.25 (d, 1H, J = 2.2 Hz), 8.60 (d, 1H, J = 1.7 Hz), 8.92 (s, 1H), 10.75 (br, 1H). HRMS calcd for C ₁₈ H ₁₄ N ₄ O ₂ S [M + H] 351.0916, obsd 351.0913. 16

Ethyl 6- (5- (phenylsulfonamido) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carboxylate ¹ H NMR (DMSO- d ₆ , 300 MHz) δ 1.36 (t, 3H, J = 7.1 Hz), 4.40 (q, 2H, J = 7.1 Hz), 7.76-7.63 (m, 3H), 7.79-7.86 (m, 4H), 7.92 (d, 1H, J = 9.4 Hz), 8.33 (s, 1H), 8.34 (s, 1H), 8.62 (d, 1H, J = 1.9 Hz), 9.38 (s, 1H) , 10.81 (br, 1 H). HRMS calcd for C ₂₁ H ₁₈ N ₄ O ₄ S [M + H] 423.1128, obsd 423.1123. 17

6- (6-amino-5- (morpholinosulfonyl) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carbonitrile ¹ H NMR (DMSO- d ₆ , 300 MHz) δ3.07 (m, 4H), 3.60 (m, 4H), 6.90 (br, 2H), 7.77 (s, 2H), 7.98 (d, 1H, J = 2.2 Hz), 8.35 (s, 1H), 8.60 (d, 1H, J = 2.4 Hz), 9.66 (s, 1H). 18

N- (5- (3- ( 1H -pyrazol-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ6.85 (d, 1H, J = 2.3 Hz), 7.45-7.60 (m, 6H), 7.82 (s, 1H), 7.98-8.00 (m, 2H) , 8.03 (s, 1H), 8.16 (d, 1H, J = 8.2 Hz), 8.36 (s, 1H), 8.41 (d, 1H, J = 2.4 Hz), 8.78 (s, 1H), 10.1 (s, 1H). 19

N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ7.24-7.29 (m, 1H), 7.50-7.56 (m, 1H), 7.80-7.83 (m, 2H), 7.94-8.05 (m, 2H), 8.33 (s, 1 H), 8.50 (s, 1 H), 8.67 (s, 1 H), 8.78 (s, 1 H), 11.15 (br, 1 H). HRMS calcd for C ₁₉ H ₁₁ F ₂ N ₅ O ₂ S [M + H] 412.0681, obsd 412.0679. HPLC purity 97.33%. 20

N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulphone amides ¹ H NMR (DMSO- d ₆ , 300 MHz) δ7.13 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 9.3 Hz), 7.80-7.83 (m, 2H), 7.90-7.97 (m, 2H), 8.34 (s, 1H), 8.49 (s, 1H), 8.69 (s, 1H), 8.77 (s, 1H), 11.07 (br, 1H), 21

N- (5- (3-acetylimidazo [1,2-a] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide
¹ H NMR (DMSO- d ₆ , 300 MHz) δ2.61 (s, 3H), 7.60-7.65 (m, 3H), 7.82-7.87 (m, 3H), 8.36 (d, 1H, J = 2.4 Hz) , 8.68 (d, 1H, J = 2.0 Hz), 8.83 (s, 1H), 9.10 (d, 1H, J = 2.6 Hz), 9.85 (d, 1H, J = 2.6 Hz), 10.84 (s, 1H) . HRMS (EI +) m / z calcd. for C ₁₉ H ₁₅ N ₅ O ₃ S [M + H] ⁺ : 394.0975, found: 394.1016 22

N- (5- (imidazo [1,2-a] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide ¹ H NMR (DMSO- d ₆ , 300 MHz) δ7.78-7.57 (m, 3H), 7.83 (s, 1H), 7.84-7.85 (m, 3H), 7.96 (s, 1H), 8.28 (d, 1H, J = 8 Hz), 8.65 (s, 1H), 8.76 (d, 1H, J = 8.5 Hz), 9.31 (s, 1H) 23

Ethyl 6- (5- (2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate ¹ H NMR (CDCl ₃ , 300 MHz) δ1.43 (t, 3H, J = 23.7 Hz), 4.44 (dd, 2H, J = 23.5 Hz), 6.95-7.02 (m, 2H), 7.59 (dd, 1H , J = 31 Hz), 7.83 (s, 1H), 7.87 (t, 1H, J = 7.6 Hz), 7.95-7.97 (m, 1H), 8.34 (s, 1H), 8.41 (d, 1H, J = 8.1 Hz), 8.65 (d, 1H, J = 3.2 Hz), 9.49 (s, 1H)

< Experimental Example  1> PI3K  Inhibition activity measurement

Measurement of the effect of PI3K inhibitory activity on the specific compound represented by [Formula 1] according to the present invention was carried out as follows.

PI3Ka activity was measured using a PI3-kinase ELISA kit (Echelon Bioscience Inc., Salt Lake City, UT, USA) to determine the measure of the biological and biochemical inhibitory effects of PI3K and / or mTOR co-inhibitors according to the present invention. MTOR was measured by requesting KINOMEscan (San Diego, CA, USA).

PI3K was used phosphatidylinositol-4,5-bisphosphate (PI (4,5) P ₂ ) medium from Signachem (Richmond, BC, CANADA), and the reaction buffer was added to the medium. Incubated with the compound synthesized for 3 hours, PI3Ka activity was measured by the process of changing the PI (4,5) P ₂ to PI (3,4,5) P ₃ . The measured results are shown as IC ₅₀ in Table 2 below.

IC ₅₀ is the molarity of the compound used when the activity of the enzyme or cell is inhibited by 50%.

Compound number PI3K
IC ₅₀ (μM) mTOR
Kd (μM) Compound number PI3K
IC ₅₀ (μM) mTOR
Kd (μM) One > 0.1 > 1 16 > 0.1 > 1 2 > 0.1 > 1 19 > 0.1 > 1 8 > 0.1 > 1 20 > 0.1 > 1 10 > 0.1 > 1 23 > 0.1 > 1

In Experimental Example 1 and Table 2, the imidazopyridine compound represented by the above [Formula 1] according to the present invention is the degree of PI (4,5) P ₂ is modified to PI (3,4,5) P ₃ In 50% inhibition, it was confirmed that there was an inhibitory effect of PI3-kinase even in a small amount of 0.1 μm or less, compared with the conventional PI3-kinase inhibitor, and it was also confirmed that there was also an mTOR inhibitory effect.

< Comparative example  1> person LY294002 And represented by [Formula 1] according to the present invention Imidazo Of ridine compounds PI3K  Inhibitory effect measurement

In Experimental Example 1, except that LY294002 compound was used instead of the compound synthesized in Example in phosphatidylinositol-4,5-bisphosphate (PI (4,5) P ₂ ) medium, the same procedure as in Experimental Example 1 It was measured by the method.

The PI3K inhibitory effect was measured by measuring the degree of PI (4,5) P ₂ transformation into PI (3,4,5) P ₃ by adding 0.1 μm, 1 μm, and 10 μm of the LY294002 compound, respectively. The degree of deformation of PI (4,5) P ₂ to PI (3,4,5) P ₃ by adding 0.1 μm and 1 μm of the amount of the imidazopyridine compound synthesized in Example 2, respectively PI3K inhibitory effect was measured. The measurement results are shown in Table 3 below.

Amount of Comparative Example 1 (LY294002) To PI (3,4,5) P ₃
Strain Amount of Example 2 To PI (3,4,5) P ₃
Strain 0.1 μm 79% 0.1 μm 56% 1 μm 42% 1 μm 24%

As shown in Table 3, the LY294002 compound has a degree of modification of PI (3,4,5) P ₃ at 79% when injected into 0.1 μm, and a degree of PI3K inhibition is only 21%, but in Example 2 according to the present invention. The imidazopyridine compound synthesized by the present invention exhibited a PI (3,4,5) P ₃ modification degree of 56% and a PI3K inhibitory effect of 44% when 0.1 µm was added.

In addition, the degree of PI (3,4,5) P ₃ strain was 42% and the degree of PI3K inhibition was 58% when 1 μm of Comparative Example 1 was added, but the imidazo synthesized according to Example 2 of the present invention was used. The pyridine compound had a PI (3,4,5) P ₃ modification degree of 24% when 1 μm was added, and a PI3K inhibitory effect was 76%, indicating that the PI3K inhibitory effect was very excellent.

In addition, referring to Figure 1, mTOR activity was measured by KINOMEscan (San Diego, CA, USA) to measure the activity according to the concentration, and the Kd value of the imidazopyridine compound according to Example 2 was measured according to the concentration. As a result, the Kd value was 58 nM, indicating an excellent activity result.

Claims (10)

An imidazopyridine compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof:
[Formula 1]

Wherein X is carbon or nitrogen, R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, an acetyl group, a pyrazole group, a morpholine group, an ester group, a cyano group, a tetrazole group, an oxadiazole group, a substitution or It is selected from an unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, R ₂ is selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The imidazopyridine of claim 1, wherein R ₁ and R ₂ are each independently a substituted or unsubstituted aryl group having 6 to 12 carbon atoms or a substituted or unsubstituted heteroaryl group having 5 to 24 carbon atoms. Compound or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein in R ₁ , the substituted aryl group or substituted heteroaryl group is an aryl group or heteroaryl group substituted with a cyano group,
In R ₂ , a substituted aryl group or substituted heteroaryl group is an imidazopyridine compound or a pharmaceutical thereof, wherein the substituted aryl group or substituted heteroaryl group is substituted with at least one selected from an amine group, an arylsulfonamide group, and a morpholinosulfonyl group. Salts acceptable. The method according to claim 1, wherein R ₁ is any one selected from the group represented by the following [Formula 1], and R ₂ is already selected from the group represented by the following [Formula 2] Dazopyridine compound or a pharmaceutically acceptable salt thereof.
[Structural formula 1]

[Structural formula 2]

The method of claim 1,
N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfon amides;
N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3-morpholininoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3-acetylimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide;
5- (3-morpholinioimidazo [1,2- a ] pyridin-6-yl) -3- (morpholinosulfonyl) pyridin-2-amine;
3,5-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide;
2,4-difluoro- N- (5- (3- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo [1,2- a ] pyridin-6-yl) Pyridin-3-yl) benzenesulfonamide;
N- (5- (3- (3-cyanophenyl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3- (pyridin-3-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3- (pyridin-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
3- (imidazo [1,2- a ] pyridin-6-yl) aniline;
5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-amine;
N- (5- (imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
Ethyl 6- (5- (phenylsulfonamido) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carboxylate;
6- (6-amino-5- (morpholinosulfonyl) pyridin-3-yl) imidazo [1,2- a ] pyridine-3-carbonitrile;
N- (5- (3- ( 1H -pyrazol-4-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (3-cyanoimidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulfonamide;
N- (5- (3- ( 2H -tetrazol-5-yl) imidazo [1,2- a ] pyridin-6-yl) pyridin-3-yl) -2,4-difluorobenzenesulphone amides;
N- (5- (3-acetylimidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide;
N- (5- (imidazo [1,2- a ] pyrimidin-6-yl) pyridin-3-yl) benzenesulfonamide;
Any compound selected from the group consisting of ethyl 6- (5- (2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate An imidazopyridine compound or a pharmaceutically acceptable salt thereof. The method of claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoro acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Imidazopyridine selected from the group consisting of maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid, gluconic acid, lactic acid, benzoic acid, salicylic acid, citric acid, propionic acid, P-toluenesulfonic acid, naphthalenesulfonic acid and glutamic acid Compound or a pharmaceutically acceptable salt thereof. A composition which inhibits PI3K and / or mTOR kinase containing a compound according to any one of claims 1 to 6 as an active ingredient together with a pharmaceutically acceptable carrier or diluent. Proliferative disease, immune disease, cardiovascular disease, neurological disease, inflammatory disease, endocrine disease, metabolism containing the compound according to any one of claims 1 to 6 as an active ingredient together with a pharmaceutically acceptable carrier or diluent Compositions for the treatment of diseases and viral infectious diseases. 9. The method of claim 8,
The proliferative disease is cancer, the cancer is leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon cancer, peritoneal cancer, peritoneal metastasis cancer, Angina, myocardial infarction and pancreatic cancer is a composition for treating a disease, characterized in that any one selected from the group consisting of. 9. The method of claim 8,
The immune disease is any one selected from the group consisting of rheumatoid arthritis, autoimmune pernicious anemia and type I diabetes,
The cardiovascular disease is any one selected from the group consisting of myocardial infarction, hypertension and angina pectoris,
The neurological disease is neurological gastritis or irritable bowel syndrome,
The inflammatory disease is degenerative arthritis or sinusitis,
The endocrine disease is diabetes,
The metabolic disease is obesity or hereditary metabolic disease,
The viral infection disease is a composition for treating a disease, characterized in that any one selected from the group consisting of AIDS, bird flu and swine flu.

Images