KR101789430B1 - Novel compound having SMO-inhibitory activity and composition for preventing or treating cancer comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel compound having an SMO inhibitory activity. It is an object of the present invention to provide a novel compound having an SMO inhibitory activity and exhibiting an excellent anticancer effect by controlling the hedge signaling pathway and inhibiting SMO activity of isoindolinone derivatives and quinazolinone derivatives It has the advantage of being able to prevent, improve or treat cancer of bar and cancer.

Description

TECHNICAL FIELD The present invention relates to a novel compound having SMO inhibitory activity and a composition for preventing or treating cancer comprising the same as an active ingredient.

The present invention relates to novel isoindolinone or quinazolinone derivative chemistries which act as SMO (smoothened) inhibitors to inhibit cancer caused by Hedgehog signaling hyperactivity, The present invention relates to a pharmaceutical composition for preventing or treating cancer.

Hedgehog (Hh) is a protein that plays an important role in embryogenesis. It is a protein that regulates cell proliferation, migration, and differentiation, and is involved in development of various organs including dorsal and ventral axis formation, nervous system and musculoskeletal system . It is involved in the hedging of the adult body or the maintenance of the stem cells, and abnormal hyperactivity in the hedgehog adult tissues causes various cancers such as basal cell carcinoma, squamous cell carcinoma and the like.

Hedging or signaling abnormalities in the human development stage cause stillbirth or long-term developmental disability because it affects extensively from the onset of fetal development to the formation of terminal organs. The hedge or signaling activity after development is maintained only in some specific tissues such as adult stem cells in the adult, and is decreased in most tissue somatic cells. On the contrary, excessive signal transduction activity by mutation of hedge or signal transduction genes (Ptch, Smo, Sufu, Gli, etc.) at the somatic stage promotes cell proliferation and induces cancer development.

There are three types of mammalian hedge, Sonic Hedgehog, Indian Hedgehog and Desert hedgehog. The most studied of them is the Sonic Hedgehog (SHH) signaling pathway, which can be expressed in whole body.

The Sonic Hedgehog signaling pathway is initiated by the binding of Sonic Hedgehog to Patched1 (Ptch1), a 12-membrane transmembrane receptor in the plasma membrane. Ptch1 inhibits the 7-membrane-penetrating Gli protein-coupled receptor, SMO, When combined with Sonic Hedgehog, Ptch1 loses its ability to inhibit SMO. As a result, SMO is activated and Gli activated by the activated SMO activates hedge or target gene expression. In other words, the hedgehog functioning as a ligand promotes the migration of primary GPCR-like membrane protein, SMO, into the primary ciliate, which binds to the Ptch1 receptor present in the cell membrane and is inhibited by Phch1, Promotes the activity of the role of Gli transcription factor.

The mechanism by which SMO regulates the activity of Gli transcription factor is that the SMO that migrated to the primary ciliate by hedge hump regulates the Sufu that inhibits the Gli transcription factor from migrating to the nucleus at the lower signaling stage or the stability of Gli protein in the primary ciliate And induces the conversion of the inactive Gli to a state having transcriptional activity, thereby inducing an increase in gene expression under hedgehog function by the Gli transcription factor, thereby allowing cell migration, proliferation and differentiation to proceed.

The types of cancer associated with hedge or signaling are wide and diverse. For example, basal cell carcinoma, medulloblastoma, glioblastoma, breast cancer, prostate cancer, melanoma, lung cancer, And pancreatic cancer.

Clinical studies and hypothesis validation of the causal relationship of cancer development by hedge or signal transduction abnormality in the human body are well established. Recently, there have been a lot of researches on the development of cancer and recurrence by cancer stem cells as an epoch-making result related to the development of cancer. Appropriate control or elimination of cancer stem cells is emerging as an important method of cancer treatment. Cancer stem cells share the characteristics of stem cells in development stage, and hedge or signaling is acting as an important regulator.

Based on this fact, as a target for treating cancer, a method of using as a control target of cancer stem cells a development regulator that plays an important role in growth and differentiation of cells in the developmental stage and whose mechanism is well known is rapidly emerging as a cancer treatment. Therefore, the development of a new drug that can control developmental factors such as hedgehog is a new concept, and now the first-generation drug, Erivedge (Vismodegib), was launched in 2012 and its efficacy has been clinically proven.

At the same time, it acts as a factor controlling the function of stromal cells that control the microenvironment of cancer stem cells as well as hedge or cancer cells and cancer stem cells. Therefore, inhibition of hedge or signaling is one of the drugs that are attractive and effective, as many target control drugs can simultaneously control the growth of cancer cells at various stages.

The launch of the first-generation drug Vismodegib (Bismode) proved a hypothesis that cancer could be controlled by hedge-to-target, resulting in a major ripple effect as a clinical drug development target. Clinically, the Bismude family has also been studied for the treatment of a variety of other cancers, including colorectal cancer, small cell lung cancer, gastric cancer, pancreatic cancer, hematoblastoma, and chondrosarcoma. Recently, WO 2010/147917 discloses hedgehog or signaling pathway inhibitors for treating a variety of cancers, and Novartis Cancer Research Center (Novatis Oncology) has finalized the approval of the SMO receptor inhibitor Sonidegib as a treatment for basal cell carcinoma. Thus, inhibition of abnormal hedge or signaling pathways and inhibition of SMO expression has emerged as a desirable target for chemotherapy.

Inhibition of hedge or signaling pathways using low molecules has been an important target for clinicians to treat clinically significant cancers such as solid tumors through reversal or regulation of abnormal cell growth. However, effective hedging or signaling pathway inhibitors and SMO inhibitors are still needed as effective treatments for a variety of cancer types (see Korean Patent Publication No. 10-1217316).

DISCLOSURE OF THE INVENTION The present invention has been made in order to solve the problems of the prior art as described above. As a result of intensive efforts to develop an anticancer agent having SMO inhibitory activity, the present inventors have found that the novel SMO inhibitory activity of the novel compound Thereby completing the invention.

Accordingly, an object of the present invention is to provide a novel compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Another object of the present invention is to provide a novel compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof.

(2)

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises the novel compound of formula (1) or (2) or a pharmaceutically acceptable salt thereof as an active ingredient.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the above object, the present invention provides a novel compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

,

또는

이고;R1 is

,

or

ego;

또는

이다.R2 is

or

to be.

The present invention also provides a novel compound represented by the following general formula (2) or a pharmaceutically acceptable salt thereof.

(2)

In Formula 2,

,

,

,

,

,

,

또는

이고;R1 is Cl,

,

,

,

,

,

,

or

ego;

,

,

,

,

,

,

,

,

또는

이다.R2 is

,

,

,

,

,

,

,

,

or

to be.

As a specific example, the compound represented by Formula 1 may be selected from the group consisting of the following compounds.

Isoindolin-1-one, 2- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-

Pyridin-3-yl) -4- (pyridin-3-yl) isoindolin-1-one, 2- (6- ((2S, 6R)

6-dimethylmorpholino) pyridin-3-yl) isoindolin-1-one, 4- (2,4-difluorophenyl) -2-

2- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyrimidin-4-yl) -4- (4- (trifluoromethoxy) phenyl) isoindolin-1-one.

As a specific example, the compound represented by Formula 2 may be selected from the group consisting of the following compounds.

8-chloro-3- (4-fluorophenyl) quinazolin-4 (3H)

8-chloro-3- (4-morpholinophenyl) quinazolin-4 (3H)

8-chloro-3- (6-morpholinopyridin-3-yl) quinazolin-4 (3H)

Pyridin-3-yl) quinazolin-4 (3H) -one, 6-chloro-

4-yl) quinazolin-4 (3H) -one, which has the structural formula: <

3- (4-morpholinophenyl) -8-phenylquinazolin-4 (3H) -one,

8- (3-methoxyphenyl) -3- (4-morpholinophenyl) quinazolin-4 (3H)

(3- (4-morpholinophenyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (6-morpholinopyridin-3-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8-phenylquinazolin-4 (3H)

4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (6 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ,

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8- (naphthalen- 1 -yl) quinazolin-

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8-p-tolylquinazolin-4 (3H)

3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-3- yl) -8- (4- methoxyphenyl) quinazolin-

4- (3H) -one, 3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8- (4- fluorophenyl) quinazolin-

4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (5 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ,

4- (3H) -one, 3- (6- (4-methylpiperazin-1-yl) pyridin-

4- (3H) - (4-fluorophenyl) piperazin-1-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin- On,

4 - (3 (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one,

3- (2-morpholinoethyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (3- (1H-imidazol-1-yl) propyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one.

Also, the present invention provides a pharmaceutical composition for preventing or treating cancer diseases, which comprises the compound of formula (1) or (2) as an active ingredient.

Also, the present invention provides a health functional food composition for improving cancer diseases, which comprises the compound of formula (1) or (2) as an active ingredient.

In one embodiment of the present invention, the cancer is selected from the group consisting of basal cell carcinoma, hematoblastoma, rhabdomyosarcoma, chondrosarcoma, melanoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, Cancer, stomach cancer, colon cancer, liver cancer, kidney cancer, head and neck cancer, mesothelioma, soft tissue sarcoma, osteosarcoma, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone cancer, acute leukemia, chronic leukemia, glioma, , Cancer of the bladder, endocrine cancer, pituitary cancer, thyroid cancer, cervical cancer, endometrial cancer, ovarian cancer, skin cancer, renal cell carcinoma, pituitary adenoma, spinal axis tumor, uterine cancer, stomach cancer and bile duct cancer.

In another embodiment of the present invention, the composition may inhibit a hedgehog signaling pathway.

In another embodiment of the present invention, the composition may inhibit SMO (Smoothened) activity.

In another embodiment of the present invention, the composition may inhibit Gli2 expression.

In another embodiment of the present invention, the composition may inhibit the hedgehog signaling pathway to SMO (smoothened) variant (D477H).

The present invention also provides a method of treating cancer diseases comprising administering to a subject in need of treatment of cancer a pharmaceutical composition comprising a compound of Formula 1, Formula 2, or a pharmaceutically acceptable salt thereof .

The present invention also provides a therapeutic use of a pharmaceutical composition comprising a compound of the general formula (1), (2) or a pharmaceutically acceptable salt thereof, for cancer diseases.

The present invention relates to a novel compound having an SMO inhibitory activity. It is an object of the present invention to provide a novel compound having an SMO inhibitory activity and exhibiting an excellent anticancer effect by controlling the hedge signaling pathway and inhibiting SMO activity of isoindolinone derivatives and quinazolinone derivatives It has the advantage of being able to prevent, improve or treat cancer of bar and cancer.

Figure 1 shows the type of drug currently inhibiting or releasing SMOs.
FIG. 2 is a graph showing the IC ₅₀ analyzing the degree of inhibition of Hedgehog signal of four isoindolinone derivatives. FIG.
FIG. 3 is a graph showing the IC ₅₀ analyzing the degree of suppression of Hedgehog signal of 22 quinazolinone derivatives. FIG.
FIG. 4 shows representative examples of quinazolinone derivatives (Compound 14 and Compound 20) inhibiting Hedgehog signaling activated by SHh (Sonic Hedgehog) ligand.
FIG. 5 is a graph showing a representative example of a quinazolinone derivative inhibiting the increase of Gli1 protein expression by activating signal transduction in the cells from which Ptch1 has been removed without SHh ligand.
FIG. 6 shows that quinazolinone derivatives inhibit the migration of SMO protein, a sub-action gene of hedgehog signaling, to ciliates, similarly to Vismodegib and Sonidegib.
FIG. 7 is a result of quantitative analysis of the inhibition of ciliate migration of the SMO protein shown in FIG.
Figure 8 shows that quinazolinone derivatives inhibit the migration of Gli2, a sub-acting transcription factor of hedgehog signaling, to ciliates, similar to Vismodegib and Sonidegib.
Figure 9 compares the inhibition of the hedge or signaling pathway to the SMO (D477H) mutants that cause resistance to Vismodegib for Vismodegib, Sonidegib, and Quinazolinone derivatives.

Based on the ability to inhibit Hedgehog signaling when treated with the novel compounds prepared in the examples, the present inventors have found that the SMO inhibition, Gli transcription factor inhibition and SMO variant (D477H) inhibitory effect , And the present invention has been completed on the basis thereof.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

,

또는

이고;R1 is

,

or

ego;

또는

이다.R2 is

or

to be.

Preferable examples of the compound represented by the formula (1) according to the present invention are as follows.

Isoindolin-1-one, 2- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-

Pyridin-3-yl) -4- (pyridin-3-yl) isoindolin-1-one, 2- (6- ((2S, 6R)

6-dimethylmorpholino) pyridin-3-yl) isoindolin-1-one, 4- (2,4-difluorophenyl) -2-

2- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyrimidin-4-yl) -4- (4- (trifluoromethoxy) phenyl) isoindolin-1-one.

The present invention also provides a compound represented by the following general formula (2) or a pharmaceutically acceptable salt thereof.

(2)

In Formula 2,

, ,

,

,

,

,

또는

이고;R1 is Cl,

, ,

,

,

,

,

or

ego;

,

,

,

,

,

,

,

,

또는

이다.R2 is

,

,

,

,

,

,

,

,

or

to be.

Preferable examples of the compound represented by the formula (2) according to the present invention are as follows.

8-chloro-3- (4-fluorophenyl) quinazolin-4 (3H)

8-chloro-3- (4-morpholinophenyl) quinazolin-4 (3H)

8-chloro-3- (6-morpholinopyridin-3-yl) quinazolin-4 (3H)

Pyridin-3-yl) quinazolin-4 (3H) -one, 6-chloro-

4-yl) quinazolin-4 (3H) -one, which has the structural formula: <

3- (4-morpholinophenyl) -8-phenylquinazolin-4 (3H) -one,

8- (3-methoxyphenyl) -3- (4-morpholinophenyl) quinazolin-4 (3H)

(3- (4-morpholinophenyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (6-morpholinopyridin-3-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8-phenylquinazolin-4 (3H)

4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (6 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ,

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8- (naphthalen- 1 -yl) quinazolin-

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8-p-tolylquinazolin-4 (3H)

3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-3- yl) -8- (4- methoxyphenyl) quinazolin-

4- (3H) -one, 3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-

3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3- yl) -8- (4- fluorophenyl) quinazolin-

4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (5 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ,

4- (3H) -one, 3- (6- (4-methylpiperazin-1-yl) pyridin-

4- (3H) - (4-fluorophenyl) piperazin-1-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin- On,

4 - (3 (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one,

3- (2-morpholinoethyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H)

3- (3- (1H-imidazol-1-yl) propyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one.

As used herein, the term " pharmaceutically acceptable "means that the benefit / risk ratio is reasonable without undue toxicity, irritation, allergic response or other problems or complications and is suitable for use in contact with the tissues of a subject (e.g., a human) Quot; means a compound or composition within the scope of sound medical judgment.

As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the compound represented by the general formula (1) or (2) in an excess amount of an aqueous acid solution and then dissolving the salt in a water-miscible organic solvent such as methanol, And precipitating with acetonitrile. It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, the base may be used to make a pharmaceutically acceptable metal salt. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In one embodiment of the present invention, the SMO inhibitory activity of the compound of Formula 1 or 2 was found to inhibit SMO activity. In particular, It was found that the non-derivative compound exhibited an SMO inhibitory activity superior to that of the positive control group Vismodegib (see Example 29).

Therefore, the compound of formula (1) or (2) according to the present invention inhibits SMO (Smoothened) activity through the hedge signaling pathway regulation and inhibits the transcription factor Gli2 expression, And can be used for various purposes and purposes.

Accordingly, the present invention provides a composition for preventing, ameliorating or treating cancer diseases, which comprises the compound of Chemical Formulas 1 and 2 or a pharmaceutically acceptable salt thereof as an active ingredient, Food compositions.

As used herein, the term "prevention" refers to all actions that inhibit or delay the onset of cancer by administration of the pharmaceutical composition according to the present invention.

The term "treatment" used in the present invention means all the actions for improving or alleviating symptoms of cancer by administration of the pharmaceutical composition according to the present invention.

In the present invention, cancer diseases are cancerous diseases such as basal cell carcinoma, hematoblastoma, rhabdomyosarcoma, chondrosarcoma, melanoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, esophageal cancer, breast cancer, Osteosarcoma, osteosarcoma, prostate cancer, pancreatic cancer, bone cancer, bone cancer, acute leukemia, chronic leukemia, glioma, hodgkin's disease, skin melanoma, bladder cancer, endocrine gland, liver cancer, liver cancer, kidney cancer, head and neck cancer, mesothelioma, soft tissue sarcoma, But are not limited to, one or more selected from the group consisting of pancreatic cancer, pancreatic cancer, papillary cancer, thyroid cancer, cervical cancer, endometrial cancer, ovarian cancer, skin cancer, renal cell carcinoma, pituitary adenoma, spinal axis tumor, uterine cancer, gastric cancer, no. In addition to the diseases exemplified herein, all diseases associated with the hedgehog signaling pathway control known in the art are considered to be included in cancer diseases that can be prevented or treated with the compounds having the structure of Formula 1 or 2 of the present invention . In one specific example, the cancer may be any cancer caused by hedge or signal transduction hyperactivity.

In one embodiment, when the anti-cancer composition according to the present invention is used in the form of a pharmaceutical composition, the pharmaceutical composition comprises a pharmaceutically effective amount of a compound of formula (1) or (2) or a pharmaceutically acceptable salt thereof , And may further comprise a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutically effective amount as used herein refers to an amount sufficient to prevent or treat symptoms of cancer.

The pharmaceutical composition of the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, the degree of absorption of the active ingredient in the body, the rate of inactivation and excretion, the type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per 1 kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

The present invention also provides a method for treating cancer diseases, comprising administering the pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse and cattle .

In another aspect, the anticancer composition according to the present invention can be used in the form of a food having an effect on the improvement of cancer diseases, for example, a health food composition used for the production of a raw material, additives, food additives, have.

As used herein, the term " food " means a natural or processed product containing one or more nutrients. Preferably, the term " food " Additives, functional foods and beverages.

Foods to which the composition according to the present invention can be added include, for example, various foods, drinks, gums, tea, vitamin complexes, and functional foods. In addition, the above foods may include special nutritional foods (eg, crude oil, spirit, baby food, etc.), meat products, fish products, tofu, jelly, noodles (eg, ramen, noodles, etc.) (Such as soy sauce, soybean paste, hot pepper paste, mixed sauce, etc.), sauces, confectionery (eg snacks), candy, chocolate, gums, ice cream, milk products (E.g., various kinds of kimchi, pickles, etc.), beverages (e.g. fruit drinks, vegetable beverages, beverages, fermented beverages, etc.) The additive can be produced by a conventional production method.

In addition, the functional food refers to a food group imparted with added value to function and express the function of the food by using physical, biochemical, biotechnological techniques, etc., or to control the biological defense rhythm of the food composition, And the like, and is preferably processed to be a health functional food. The functional food may include a food-acceptable food-aid additive, and may further comprise suitable carriers, excipients and diluents conventionally used in the production of functional foods.

Also, in the present invention, the beverage refers to a general term for drinking or enjoying a taste, and includes functional beverages. The beverage includes, as an essential ingredient, a composition containing a compound of the formula (1) or (2) or a pharmaceutically acceptable salt thereof for preventing or ameliorating cancer symptoms, and there is no particular limitation on other ingredients, Various flavoring agents, natural carbohydrates, and the like as additional components.

In addition, the food containing the composition of the present invention in addition to the above-mentioned composition can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and fillers (cheese, An organic acid, a protective colloid thickener, a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, a carbonating agent used in a carbonated beverage, and the like, Can be used in combination.

In the food containing the food composition according to the present invention, the amount of the composition may be 0.001% by weight to 90% by weight, preferably 0.1% by weight to 40% by weight of the total food, And in the case of beverages, it may be contained in a proportion of 0.001 g to 2 g, preferably 0.01 g to 0.1 g based on 100 ml. When it is intended for long-term intake, it may be less than the above range. However, It can be used in an amount of more than the above-mentioned range, so it is not limited to the above range.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[Example]

Example  1: (Compound 1) 2- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -4- (4- ( Trifluoromethoxy ) Phenyl) isoindolin-1-one

Step 1: Ethyl 3- bromo- 2- methyl Preparation of benzoate

A mixture of 3-bromo-2-methylbenzoic acid (2.00 g, 9.30 mmol), concentrated sulfuric acid (0.20 mL) and ethanol (3.00 ml) was refluxed under benzene (10.0 mL) for 18 hours to prepare an azeotropic mixture. The reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution and water. The organic phase was recovered, dried and concentrated. The crude product was purified by flash column chromatography (Hex: EA 5: 1) to give a colorless liquid with 1.99 g (88.0%) of pure compound.

Step 2: Preparation of ethyl 3-bromo-2- (bromomethyl) benzoate

NBS (1.75 g, 9.82 mmol) and AIBN (0.14 g, 0.81 mmol) were added to a mixture of ethyl 3-bromo-2-methylbenzoate (1.99 g, 8.18 mmol) under benzene (step 1). After refluxing the reaction solution for 5 hours, the solution was cooled to room temperature and the precipitate was filtered. The filtrate was washed with saturated Na ₂ S ₂ O ₃ Solution and water. The organic phase was dried and concentrated and then purified by flash column chromatography (Hex: EA 5: 1) to give 2.54 g (96.0%) of pure compound as a colorless oil.

Step 3: 4-Bromo-2 - Preparation of (6 ((2S, 6R) -2,6- dimethyl-morpholinophenyl) pyridin-3-yl) isoindoline-1-one

A mixture of ethyl 3-bromo-2- (bromomethyl) benzoic acid (0.50 g, 1.55 mmol) (step 2), 6 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- (0.39 g, 1.89 mmol) and DIPEA (0.18 ml, 1.89 mmol) were sealed in a sealed tube with ethanol. The reaction mixture was heated to 100 < 0 > C overnight, then cooled to room temperature, and the ethanol was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash column chromatography (MC: EA: Hex 1: 1: 2) to give 0.48 g (77.0%) of pure compound as a white cream solid.

Step 4: 2 - (6 - ( (2S, 6R) -2,6- dimethyl-morpholinophenyl) pyridin-3-yl) -4- (4- (trifluoromethoxy) phenyl) isoindoline-1- Manufacture of onions

Isoindolin-1-one (step 3), (4- ((2S, 6R) -2,6-dimethylmorpholino) pyridin- Trifluoromethoxy) phenyl) methanediol (1.5 eq.) And a 2M aqueous sodium bicarbonate solution were sealed with DME in a sealed tube. The solution was bubbled under argon for 15 minutes and palladium catalyst (15.0 mg, 5 mol%) was added. The reaction solution was further bubbled under argon for 5 minutes, the sealed tube was heated to 130 < 0 > C overnight, cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash column chromatography to give a pure compound.

Cream white solid (93%);

mp 191.4-192.6 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.44 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 3.0, 9.4 Hz, 1H), 7.91 (dd, J = 2.2, 6.6 Hz, 1H) 2H), 7.61-7.56 (m, 2H), 7.53-7.51 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 9.2 Hz, 2H), 3.74-3.69 (m, 2H), 2.54-2.48 (m, 2H), 1.27 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 167.08, 156.55, 149.06, 139.73, 137.81, 137.14, 135.77, 133.51, 132.06, 130.68, 129.53, 129.22, 127.00, 123.36, 121.46, 106.89, 71.52, 51.00, 18.98;

HRMS (EI) m / z calcd for C ₂₆ H ₂₅ F ₃ N ₃ O ₃ [M ⁺ ] 484.1848, found: 484.1883.

Example  2: (Compound 2) 2- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -4- (pyridin-3-yl) Isoindoline -1-one

The title compound was prepared in the same manner as in Example 1, except that pyridin-3-ylmethanediol was used in place of (4- (trifluoromethoxy) phenyl) methanediol in Step 4 to obtain a pure compound.

Cream white solid (92%);

mp 219.9-203.0 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.79 (d, J = 1.6 Hz, 1H), 8.69 (dd, J = 1.6, 4.8 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 4.8,7.2 Hz, 1H), 7.96 (dd, J = 1.6, 7.2 Hz, 1H), 7.84-7.81 (m, 1H), 7.66-7.51 (m, 2H), 7.47-7.44 , 1H), 6.69 (d, J = 9.2 Hz, 1H), 4.85 (s, 2H), 4.04-4.00 (m, 2H), 3.75-3.70 (m, 2H), 2.55-2.49 (m, 2H), 1.27 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.95, 156.60, 149.41, 148.86, 139.84, 138.10, 135.40, 134.25, 133.69, 133.57, 132.17, 130.76, 129.42, 126.88, 123.83, 123.80, 106.91, 71.53, 50.61, 18.99;

HRMS (EI) m / z calcd for C ₂₄ H ₂₅ N ₄ O ₂ [M ⁺ ] 401.1978, found: 401.2008.

Example  3: (Compound 3) 4- (2,4- Difluorophenyl ) -2- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) isoindolin-1-one

The title compound was prepared in the same manner as in Example 1, except that (2,4-difluorophenyl) methanediol was used instead of (4- (trifluoromethoxy) phenyl) methanediol in Step 4 to obtain a pure compound .

Cream white solid (75%);

mp 176.0177.2 DEG C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.42 (d, J = 2.8 Hz, 1H), 8.12 (dd, J = 3.0, 9.0 Hz, 1H), 7.95 (dd, J = 1.0, 7.4 Hz, 1H) , 7.60 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.407.34 (m, 1H), 7.056.96 (m, 2H), 6.68 (d, J = 9.6 2H, J = 6.4 Hz, 6H), 4.71 (s, 2H) .

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 167.07, 156.55, 139.72, 139.25, 133.27, 133.18, 131.95, 131.90, 131.85, 131.80, 130.73, 130.48, 128.91, 127.10, 123.79, 112.20, 112.16, 111.99, 106.92, 104.85, 104.58, 104.33, 71.53, 51.03, 50.54, 50.47, 18.99;

HRMS (EI) m / z calcd for C 25 H 24 F 2 N 3 O 2 [M +] 436.1837, found: 436.1849.

Example  4: (Compound 4) 2- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyrimidin-4-yl) -4- (4- ( Trifluoromethoxy ) Phenyl) isoindolin-1-one

Step 1: Ethyl 3- bromo- 2- methyl Preparation of benzoate

The compound was prepared in the same manner as in Example 1 (step 1) to obtain a pure compound.

^{1 H-NMR (400Mz, CDCl} 3) δ 7.727.66 (s, 2H), 7.09 (t, J = 7.8 Hz, 1H), 4.394.33 (m, 2H), 2.62 (s, 3H), 1.39 ( t, J = 7.0 Hz, 3H).

Preparation of (trifluoromethoxy) biphenyl-3-carboxylate - Ethyl 2-methyl-4 ': Step 2

Was prepared in the same manner as in Example 1 (step 4) to obtain a pure compound.

^{1 H-NMR (400Mz, CDCl} 3) δ 7.81 (dd, J = 1.8, 7.4 Hz, 1H), 7.33-7.25 (m, 6H), 4.39 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H).

Preparation of (trifluoromethoxy) biphenyl-3-carboxylate ethyl 2- (bromomethyl) -4 ': Step 3

The compound was prepared in the same manner as in Example 1 (Step 2) to obtain a pure compound.

^{1 H-NMR (400Mz, CDCl} 3) δ 7.93 (dd, J = 1.8, 8.2 Hz, 1H), 7.47-7.29 (m, 6H), 4.84 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H).

Step 4: 2 - (6 - ( (2S, 6R) -2,6- dimethyl-morpholinophenyl) pyrimidin-4-yl) -4- (4- (trifluoromethoxy) phenyl) isoindoline -1 - Manufacture of onions

A mixture of ethyl 2- (bromomethyl) -4 '- (trifluoromethoxy) biphenyl-3-carboxylate (0.10 g, 0.28 mmol) (step 3), 6 - ((2S, 6R) (0.07 g, 0.34 mmol) and DIPEA (0.06 ml, 0.34 mmol) were sealed with a sealed tube along with ethanol. The reaction mixture was heated to 100 < 0 > C overnight, then cooled to room temperature, and the ethanol was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash column chromatography (MC: EA: Hex 1: 1: 2) to give 0.02 g (14.7%) of pure compound as a white cream solid.

White solid (15%);

mp 249.0-250.1 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.43 (s, 1H), 7.94-7.92 (m, 2H), 7.64-7.60 (m, 2H), 7.55-7.51 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.10 (s, 2H), 4.24 (brs, 2H), 3.71-3.63 (m, 2H), 2.67-2.61 (m, 2H), 1.28 (d, J = 6.4 Hz, 6H) .

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 168.48, 162.91, 157.43, 157.14, 138.66, 136.90, 136.41, 133.24, 133.21, 129.62, 129.24, 123.54, 121.55, 90.07, 76.69, 71.54, 49.48, 49.40, 18.87. ;

HRMS (EI) m / z calcd for C 25 H 24 F 3 N 4 O 3 [M +] 485.1801, found: 485.1837.

Example  5: (Compound 5) 8- Chloro -3- (4- Fluorophenyl ) Quinazoline -4 (3H) -one < / RTI >

3-Chloroanthranilic acid was sealed in a sealed tube with triethylorthoformate (1.2 eq), 4-fluoroaniline (1.2 eq) and THF and the reaction mixture was heated to 110 [deg.] C for 18 h. It was cooled to room temperature, saturated sodium bicarbonate solution was added, and the crude product was extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtered, and concentrated under reduced pressure, which was purified by flash column chromatography.

White solid (22%);

mp 232.5233.2 DEG C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.29 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.8 Hz , ≪ / RTI > 1H), 7.427.39 (m, 2H), 7.287.23 (m, 2H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 164.02, 161.54, 160.22, 146.51, 144.56, 135.04, 133.02, 132.98, 132.06, 128.87, 128.78, 127.94, 126.06, 123.89, 116.99, 116.75;

HRMS (EI) m / z calcd for C ₁₄ H ₉ ClFN ₂ O [M ⁺ ] 275.0387, found: 275.0382.

Example  6: (Compound 6) 8- Chloro -3- (4- Molopolynophenyl ) Quinazoline -4 (3H) -one < / RTI >

A pure compound was obtained in the same manner as in Example 5 except that 4-morpholinoaniline was used instead of 4-fluoroaniline.

White solid (33%);

mp 275.0275.8 DEG C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.28 (dd, J = 1.4, 8.2 Hz, 1H), 8.22 (s, 1H), 7.88 (dd, J = 1.4, 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 12.0 Hz, 2H), 7.03 (d, J = 12.0 Hz, 2H), 3.89 (t, J = 4.8 Hz, 3H), 3.25 (t, J = 5.0 Hz, 3H);

HRMS (EI) m / z calcd for C 18 H 17 ClN 3 O 2 [M +] 342.1009, found: 342.0997.

Example  7: (Compound 7) 8- Chloro -3- (6- Molopolypyridine -3 days) Quinazoline -4 (3H) -one < / RTI >

Pyrrolidin-3-amine instead of 4-fluoroaniline to obtain a pure compound.

White solid (14%);

mp 264.9266.2 DEG C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.28 (d, J = 8.0 Hz, 1H), 8.19 (s, 2H), 7.89 (d, J = 7.2 Hz, 1H), 7.59 (dd, J = 2.8, 9.2 Hz, 1H), 7.48 ( t, J = 7.8 Hz, 1H), 6.76 (d, J = 9.2 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.61 (t, J = 5.0 Hz , 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 160.51, 159.14, 146.75, 145.37, 144.66, 136.17, 134.94, 132.01, 127.82, 126.04, 124.19, 123.85, 106.59, 66.63, 45.33);

HRMS (EI) m / z calcd for C 17 H 16 ClN 4 O 2 [M +] 343.0962, found: 343.0984.

Example  8: (Compound 8) 8- Chloro -3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) Quinazoline -4 (3H) -one < / RTI >

The pure compound was obtained in the same manner as in Example 5 except that 6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-3-amine was used instead of 4-fluoroaniline.

White solid (30%);

mp 200.0200.8 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.26 (dd, J = 1.4, 7.8 Hz, 1H), 8.18 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.88 (dd, J = 1.6, 8.0 Hz, 1H), 7.58 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 9.2 Hz, 1H), 4.154.11 ( m, 2H), 3.743.70 (m, 2H), 2.652.59 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 160.47, 158.71, 146.76, 145.29, 144.61, 136.13, 134.89, 131.96, 127.76, 125.99, 123.86, 123.80, 106.61, 71.52, 50.45, 18.94;

HRMS (EI) m / z calcd for C 19 H 20 ClN 4 O 2 [M +] 371.1275, found: 371.1284.

Example  9: (Compound 9) 8- Chloro -3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyrimidin-4-yl) Quinazoline -4 (3H) -one < / RTI >

The pure compound was obtained in the same manner as in Example 5 except that 6 - ((2S, 6R) -2,6-dimethylmorpholino) pyrimidin-4-amine was used instead of 4-fluoroaniline .

White solid (5%);

mp 212.8214.1 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.91 (s, 1H), 8.61 (s, 1H), 8.28 (dd, J = 1.4, 8.2 Hz, 1H), 7.89 (dd, J = 1.2, 7.6 Hz, 2H), 2.69 (t, J = 11.6 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.25 ), 1.28 (d, J = 6.0 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 162.61, 159.96, 158.36, 155.53, 144.64, 143.98, 135.33, 132.24, 127.89, 126.04, 123.63, 97.99, 71.46, 49.45, 18.81;

HRMS (EI) m / z calcd for C 18 H 19 ClN 5 O 2 [M +] 372.1227, found: 372.1247.

Example  10 (Compound 10) 3- (4- Molopolynophenyl )-8- Phenylquinazoline -4 (3H) -one < / RTI >

(1) Step 1

Under DME and water, sodium carbonate (2 eq) and phenylmethane diol (1.1 eq.) Were added to the 7-bromo-satin solution. The reaction mixture was degassed with argon for 30 minutes, then Pd (PPh3) 4 (5 mol%) was added and the solution was refluxed for 3 hours. After the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure. The aqueous phase was extracted with methylene chloride, and the combined organic layers were dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (MC: methanol 50: 1).

Preparation of on-3 - (4-morpholinophenyl) -8-phenyl-quinazolin -4 (3H): (2) Step 2

Allyl satine (1 mmol) was dissolved in 5% NaOH (5 mL) and hydrogen peroxide (30% aqueous solution) (5 mL) was dropwise added with stirring at room temperature. After stirring at 50 < 0 > C for 30 min, the solution was cooled to room temperature and acidified to pH 2 with 2N HCl solution. The resulting white precipitate was recovered and used directly in the next step. (1.2 mmol), 4-morpholinoaniline (1.2 mmol) and THF were placed in a sealed tube and the resulting reaction mixture was heated to 110 DEG C for 18 hours. Saturated sodium bicarbonate solution was added thereto, and after cooling to room temperature, the crude product was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, dried over magnesium sulfate, and purified by flash column chromatography (MC: methanol 40: 1).

White solid (12%);

mp 143.9144.5 [deg.] C .;

¹ H-NMR (400 Mz, CDCl ₃ ) ? 8.40 (dd, J = 0.4, 9.6 Hz, 1H), 8.11 (s, 1H), 7.81 (dd, J = 1.6, 7.2 Hz, 1H), 7.627.57 m, 3H), 7.49 (t , J = 7.6 Hz, 2H), 7.437.25 (m, 3H), 7.02 (d, J = 8.8 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.23 (t, J = 4.6 Hz, 4 H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.26, 151.47, 145.87, 145.18, 139.73, 138.38, 135.40, 130.29, 129.04, 128.09, 127.65, 127.59, 127.23, 126.62, 122.97, 115.83, 66.75, 48.76;

HRMS (EI) m / z calcd for C ₂₄ H ₂₂ N ₃ O ₂ [M ⁺ ] 384.1712, found: 384.1681.

Example  11: (Compound 11) 8- (3- Methoxyphenyl ) -3- (4- Molopolynophenyl ) Quinazoline -4 (3H) -one < / RTI >

The procedure of Example 10 was repeated except that (3-methoxyphenyl) methanediol was used instead of the phenylmethanediol of Step 1 to obtain a pure compound.

White solid (12%);

mp 184.2185.5 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.40 (dd, J = 1.4, 7.8 Hz, 1H), 8.11 (s, 1H), 7.80 (dd, J = 1.6, 7.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.327.28 (m, 2H), 7.197.16 (m, 2H), 7.02 (d, J = 8.8 Hz, 2H), (D, J = 2.4, 8.4 Hz, 1H), 3.88 (t, J = 5.8 Hz, 4H), 3.86 (s, 3H), 3.24 (t, J = 4.8 Hz, 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.25, 159.22, 151.49, 145.91, 145.20, 139.75, 139.60, 135.35, 129.07, 129.04, 127.59, 127.18, 126.70, 122.96, 122.75, 116.16, 115.85, 113.11, 55.30, 48.77;

HRMS (EI) m / z calcd for C 25 H 24 N 3 O 3 [M +] 414.1818, found: 414.1789.

Example  12: (Compound 12) 3- (4- Molopolynophenyl ) -8- (4- ( Trifluoromethoxy ) Phenyl) Quinazoline -4 (3H) -one < / RTI >

The title compound was prepared in the same manner as in Example 10, except that (4- (trifluoromethoxy) phenyl) methanediol was used in place of the phenylmethanediol in Step 1 to obtain a pure compound.

White solid (7%);

mp 164.8166.0 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.43 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz , 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 9.2 Hz, 4H), 7.02 (d, J = 8.4 Hz, 2H), 3.89 (t, J = 4.8 Hz, 4H ), 3.24 (t, J = 4.8 Hz, 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.13, 151.55, 148.81, 146.10, 145.09, 138.18, 136.94, 135.32, 131.73, 128.90, 127.56, 127.31, 127.11, 123.10, 120.52, 119.25, 115.85, 66.75, 48.74;

HRMS (EI) m / z calcd for C 25 H 21 F 3 N 3 O 3 [M +] 468.1535, found: 468.1510.

Example  13: (Compound 13) 3- (6- Molopolypyridine Yl) -8- (4- ( Trifluoromethoxy ) Phenyl) Quinazoline -4 (3H) -one < / RTI >

Except that (4- (trifluoromethoxy) phenyl) methanediol was used instead of the phenylmethanediol in Step 1 and 6-mololenopyridin-3-amine was used instead of 4-morpholinoaniline in Step 2 And the compound was prepared in the same manner as in Example 10 to obtain a pure compound.

White solid (19 mg, 12%);

mp 135.7137.1 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.42 (dd, J = 1.6, 8.0 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.81 (dd, J = 1.6, 7.2 Hz, 1H), 7.767.59 (m, 4H), 7.34 (dd, J = 1.0, 8.6 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 3.84 (t, J = 5.0 Hz, 4H), 3.60 (t, J = 4.8 Hz, 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.13, 159.06, 148.82, 145.61, 145.31, 145.08, 138.32, 136.81, 136.23, 135.52, 131.72, 127.49, 127.08, 124.50, 122.90, 120.54, 106.60, 66.64, 45.34;

HRMS (EI) m / z calcd for C 24 H 20 F 3 N 4 O 3 [M +] 469.1488, found: 468. 469.1497.

Example  14: (Compound 14) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- Phenylquinazoline -4 (3H) -one < / RTI >

Was prepared in the same manner as in Example 10, except that 6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridine-3-amine was used instead of 4-morpholinoaniline in Step 2 to obtain pure Compound.

White solid (21%);

mp 95.496.1 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.39 (dd, J = 1.4, 7.8 Hz, 1H), 8.17 (d, J = 2.4 Hz, 2H), 8.07 (s, 1H), 7.82 (dd, J = 1.4, 7.4 Hz, 1H), 7.617.58 (m, 4H), 7.49 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.144.09 (m, 2H), 3.763.68 (m, 2H), 2.642.58 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 161.26, 158.62, 145.40, 145.25, 145.16,139.84,138.24,136.25,135.56,130.25,128.10,127,70,127.39,126.56,124.32,122.76,106.63,71.53,50.49, 18.95;

HRMS (EI) m / z calcd for C 25 H 25 N 4 O 2 [M +] 413.1978, found: 413.1950.

Example  15 (Compound 15) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- (4- ( Trifluoromethoxy ) Phenyl) quinazolin-4 (3H) -one

(2S, 6R) -2,6-dimethylpyridine instead of 4-morpholinoaniline in step 2, using (4- (trifluoromethoxy) phenyl) methanediol instead of the phenylmethanediol in step 1 and -Morpholino) pyridine-3-amine was used in place of the compound obtained in Example 10 to obtain a pure compound.

White solid (14%);

mp 188.4189.6 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.42 (dd, J = 1.6, 8.4 Hz, 1H), 8.17 (d, J = 2.0 Hz, 2H), 8.08 (s, 1H), 7.80 (dd, J = 1.6, 7.2 Hz, 1H), 7.667.58 (m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 9.2 Hz, 1H), 4.144.11 (m, 2H), 3.753.70 (m, 2H), 2.652.59 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.15, 158.69, 148.83, 145.65, 145.27, 145.10, 138.32, 136.83, 136.23, 135.51, 131.73, 127.49, 127.08, 124.20, 122.92, 120.54, 106.66, 71.56, 50.50, 18.97;

HRMS (EI) m / z calcd for C ₂₆ H ₂₄ F ₃ N ₄ O ₃ [M ⁺ ] 497.1801, found: 497.1776.

Example  16: (Compound 16) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- (naphthalen-1-yl) Quinazoline -4 (3H) -one < / RTI >

(2S, 6R) -2,6-dimethylmorpholino) pyridine-3-carboxamide was used instead of 4-morpholinoaniline in Step 2, Amine, the compound was prepared in the same manner as in Example 10 to give a pure compound.

White solid (16%);

mp 122.5123.7 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.48 (dd, J = 1.4, 8.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1), 7.928.06 (m, 1H), 7.82 (dd, J = 1.2, 7.2 Hz, 1H ), 7.687.58 (m, 3H), 7.527.43 (m, 3H), 7.397.35 (m, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.114 .09 (m, 2H), 3.723.69 (m, 2H), 2.632.56 (m, 2H), 1.28 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 161.29, 158.61, 146.51, 145.70, 145.26,138.87,136.73,136.57,136.25,133.49,132.37,128.38,128.36,127.68,127.23,127.01,126.19,126.05,125.79, 125.23, 124.33, 122.53, 106.62, 71.54, 50.49, 18.95;

HRMS (EI) m / z calcd for C ₂₉ H ₂₇ N ₄ O ₂ [M ⁺ ] 463.2134, found: 463.2112.

Example  17: (Compound 17) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8-p- Apolyquinazoline -4 (3H) -one < / RTI >

(2S, 6R) -2,6-dimethylmorpholino) pyridine-3-carbaldehyde instead of 4-morpholinoaniline in step 2, Amine, the compound was prepared in the same manner as in Example 10 to give a pure compound.

White solid (14%);

mp 158.7160.1 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.37 (dd, J = 1.4, 8.2 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.80 (dd, J = J = 8.0 Hz, 2H), 6.74 (d, J = 9.2 Hz, 1H), 7.30 (d, 4.144.10 (m, 2H), 3.763.69 (m, 2H), 2.642.58 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 161.33, 158.63, 145.31, 145.25, 139.91, 137.50, 136.28,135.44,135.32,131.12,128.88,127.38,126.33,124.38,122.75,106.64,71.55,50.51,29.69, 22.69, 18.96;

HRMS (EI) m / z calcd for C ₂₆ H ₂₇ N ₄ O ₂ [M ⁺ ] 427.2134, found: 427.2114.

Example  18: (Compound 18) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- (4- Methoxyphenyl ) Quinazoline -4 (3H) -one < / RTI >

((2S, 6R) -2,6-dimethylmorpholino) -acetic acid was used in place of the 4-morpholinoaniline in Step 2, instead of the phenylmethanediol of Step 1 and (3-methoxyphenyl) Pyridine-3-amine in place of pyridine-3-amine, the pure compound was obtained.

White solid (18%);

mp 188.3189.5 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.36 (dd, J = 1.4, 7.8 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.80 (dd, J = 2H), 6.74 (d, J = 9.2 Hz, 1H), 4.144.11 (m, 2H), 3.87 , 3H), 3.753.70 (m, 2H), 2.642.58 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.33, 159.26, 158.63, 145.25, 145.24, 145.18, 139.50, 136.28, 135.35, 131.43, 130.56, 127.40, 50.51, 29.69, 18.96;

HRMS (EI) m / z calcd for C ₂₆ H ₂₇ N ₄ O ₃ [M ⁺ ] 443.2083, found: 443.2061.

Example  19: (Compound 19) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- (4- ( Methylsulfonyl ) Phenyl) quinazolin-4 (3H) -one

(2S, 6R) -2,6-dimethylmorpholinol in place of 4-morpholinoaniline in step 2 and (4- (methylsulfonyl) phenyl) Polyno) pyridin-3-amine was used in place of pyridine-3-amine to obtain a pure compound.

White solid (15%);

mp 113.5115.0 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.47 (dd, J = 1.6, 8.0 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.098.05 (m, 3H), 7.857.81 ( 2H), 3.74 (d, J = 8.8 Hz, 1 H), 4.144 (m, 2H), 3.753.71 , 2.652.59 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 160.96, 158.71, 146.02, 145.25, 145.05, 143.95, 139.47, 137.63, 136.18, 135.55, 131.29, 127.90, 127.59, 127.21, 124.04, 123.02, 110.64, 106.66, 71.54, 50.48, 44.61, 29.70, 18.96;

HRMS (EI) m / z calcd for C ₂₆ H ₂₇ N ₄ O ₄ S [M ⁺ ] 491.1753, found: 491.1731.

Example  20: (Compound 20) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-3-yl) -8- (4- Fluorophenyl ) Quinazoline -4 (3H) -one < / RTI >

((2S, 6R) -2,6-dimethylmorpholino) pyridine instead of 4-morpholinoaniline in Step 2, using (4-fluorophenyl) methanediol in place of the phenylmethanediol in Step 1, -3-amine, the compound was prepared in the same manner as in Example 10 to give a pure compound.

White solid (17%);

mp 138.9140.0 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.40 (dd, J = 1.6, 8.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.79 (dd, J = 2H), 6.74 (d, J = 9.2 Hz, 1H), 4.144.11 (m, 2H), 3.763.68 (m, 2H), 2.642.58 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 163.74, 161.29, 161.22, 158.66, 145.51, 145.27, 145.14, 138.77, 136.25, 135.46, 134.16, 134.13, 131.98, 131.90, 127.44, 126.74, 124.25, 122.86, 115.23, 115.01, 106.65, 71.56, 50.50, 29.70, 18.96;

HRMS (EI) m / z calcd for C 25 H 24 FN 4 O 2 [M +] 431.1883, found: 431.1874.

Example  21: (Compound 21) 3- (5 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-2-yl) -8- (4- ( Trifluoromethoxy ) Phenyl) quinazolin-4 (3H) -one

((2S, 6R) -2,6-dimethylpyridine instead of 4-morpholinoaniline in step 2, using (4- (trifluoromethoxy) phenyl) methanediol in place of phenylmethanediol in step 1 and -Morpholino) pyridin-2-amine was used instead of 2-pyrrolidin-2-ylmethylamine to obtain a pure compound.

White solid (6%);

mp 146.5-147.6 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.53 (s, 1H), 8.43 (dd, J = 1.4, 8.2 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 1H), 7.73-7.65 (m, 3H), 7.59 (t, J = 7.8 Hz, 1H), 7.35-7.32 (m, 3H), 3.85-3.80 (m, 2H), 3.54-3.51 (m, 2H), 2.55 (t, J = 11.4Hz, 2H), 1.30 (d, J = 6.4Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 160.70, 148.78, 146.45, 144.93, 144.88, 140.94, 138.20, 136.93, 136.16, 135.48, 131.78, 127.24, 127.05, 123.51, 123.00, 121.36, 120.50, 71.39, 19.01;

HRMS (EI) m / z calcd for C ₂₆ H ₂₄ F ₃ N ₄ O ₃ [M ⁺ ] 497.1801, found: 497.1790.

Example  22: (Compound 22) 3- (6- (4- Methylpiperazine Yl) pyridin-3-yl) -8- (4- ( Trifluoromethoxy ) Phenyl) quinazolin-4 (3H) -one

(4- (trifluoromethoxy) phenyl) methanediol was used in the place of the phenylmethanediol in Step 1 and 6- (4-methylpiperidin-1-yl) Pyridine-3-amine was used instead of 2-pyridin-3-ylamine to obtain a pure compound.

White solid (5%);

mp 156.4-157.0 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.42 (dd, J = 1.0, 8.2 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 8.09 (s, 1H), 7.80 (dd, J = J = 7.6 Hz, 1H), 7.54 (dd, J = 2.6,9.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.76 (d , J = 8.8 Hz, 1H), 4.35 (d, J = 13.2 Hz, 2H), 2.95-2.88 (m, 2H), 1.76-1.64 (m, 3H), 1.28-1.18 (m, 3H), 0.99 (d, J = 6.0 Hz, 3H).

¹³ C-NMR (CDCl ₃ , 100 MHz) ? 161.20, 158.90, 145.88, 145.20, 145.11,138.25,136.86,135.97,135.42,131.72,127.39,127.08,123.15,122.95,120.55,106.65,45.58,33.73,31.16, 21.90;

HRMS (EI) m / z calcd for C ₂₆ H ₂₄ F ₃ N ₄ O ₂ [M ⁺ ] 481.1851, found: 481.1875.

Example  23 (Compound 23) 3- (6 - (( 2S, 6R ) -2,6- Dimethylmolpolino ) Pyridin-4-yl) -8- (4- ( Trifluoromethoxy ) Phenyl) quinazolin-4 (3H) -one

(2S, 6R) -2,6-dimethylpyridine instead of 4-morpholinoaniline in step 2, using (4- (trifluoromethoxy) phenyl) methanediol instead of the phenylmethanediol in step 1 and -Morpholino) pyrimidin-4-amine, the title compound was obtained in the same manner as in Example 10 to give the pure compound.

White solid (12 mg, 6%);

mp 231.9232.7 [deg.] C .;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.81 (s, 1H), 8.59 (s, 1H), 8.41 (dd, J = 1.2, 8.4 Hz, 1H), 7.82 (dd, J = 1.2, 7.6 Hz, 2H), 3.70 (t, J = 11.8 Hz, 2H), 7.667.60 (m, 3H) , 1.29 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 162.60, 160.63, 158.26, 155.72, 148.86, 144.29, 143.41, 138.37, 136.55, 135.92, 131.77, 127.60, 127.07, 122.66, 120.51, 98.04, 71.47, 49.42, 18.82;

HRMS (EI) m / z calcd for C 25 H 23 F 3 N 5 O 3 [M +] 498.1753, found: 498.1750.

Example  24: (Compound 24) 3- (6- (4- Methylpiperidine Yl) pyrimidin-4-yl) -8- ( 4 (trifluoromethoxy) phenyl ) Quinazolin-4 (3H) -one

(4-methylpiperidin-l-yl) pyridine instead of 4-morpholinoaniline in step 2 and (4- (trifluoromethoxy) Methyl-4-pyridin-4-yl) -methanone was used in place of the compound obtained in Example 10 to obtain a pure compound.

White solid (18 mg, 9%);

mp 201.5202.7 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.41 (dd, J = 1.2, 8.0 Hz, 1H), 7.81 (dd, J = 1.2, 7.2 Hz, 1H), 7.667.58 (m, 3H ), 7.33 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 3.6 Hz, 6H), 4.634.29 (m, 2H), 2.97 (t, J = 11.8 Hz, 2H), 1.791.68 (m, 3H), 1.261.16 (m, 2H), 0.99 (d, J = 6.0 Hz, 3H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 162.45, 160.55, 158.40, 155.57, 144.36, 143.64, 138.30, 136.64, 135.78, 131.78, 127.49, 127.09, 122.77, 120.50, 98.02, 44.78, 33.70, 31.10, 21.71;

HRMS (EI) m / z calcd for C 25 H 23 F 3 N 5 O 2 [M +] 482.1804, found: 482.1809.

Example  25: (Compound 25) 3- (2- Molopolymomethyl ) -8- (4- ( Trifluoromethoxy ) Phenyl) Quinazoline -4 (3H) -one < / RTI >

Except that (4- (trifluoromethoxy) phenyl) methanediol was used instead of the phenylmethanediol in Step 1 and 2-morpholinoethanamine was used instead of 4-morpholinoaniline in Step 2, Was obtained in the same manner as in Example 10 to obtain a pure compound.

White solid (39%);

mp 124.2125.7 [deg.] C;

^{1 H-NMR (400Mz, CDCl} 3) δ 8.37 (dd, J = 1.6, 8.0 Hz, 1H), 8.06 (s, 1H), 7.76 (dd, J = 1.6, 7.2 Hz, 1H), 7.647.62 ( m, 2H), 7.57 (d , J = 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 2.73 (t, J = 6.0 Hz, 2H), 2.52 (t, J = 4.8 Hz, 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.14, 148.77, 146.58, 145.36, 138.02, 136.98, 135.14, 131.69, 126.95, 126.61, 122.74, 120.50, 66.85, 57.03, 53.73, 43.48;

HRMS (EI) m / z calcd for C 21 H 21 F 3 N 3 O 3 [M +] 420.1535, found: 420.1552.

Example  26: (Compound 26) 3- (3- (1H-Imidazol-1-yl) propyl) -8- (4- Trifluoromethoxy ) Phenyl) Quinazoline -4 (3H) -one < / RTI >

(Trifluoromethoxy) phenyl) methanediol was used in place of the phenylmethanediol in Step 1 and 3- (1H-imidazol-1-yl) propane- 1-amine, the procedure of Example 10 was repeated to produce a pure compound.

Colorless viscous oil (41 mg, 29%).

^{1 H-NMR (400Mz, CDCl} 3) δ 8.36 (dd, J = 1.4, 7.8 Hz, 1H), 7.94 (s, 1H), 7.78 (dd, J = 1.6, 7.6 Hz, 1H), 7.627.57 ( m, 4H), 7.32 (d , J = 8.0 Hz, 2H), 7.10 (s, 1H), 6.99 (s, 1H), 4.09 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 7.0 Hz, < / RTI > 2H), 2.352.31 (m, 2H).

¹³ C-NMR (CDCl ₃ , 100 MHz) δ 161.22, 148.83, 145.44, 145.21, 138.25, 137.00, 136.70, 135.35, 131.70, 129.72, 127.41, 126.56, 122.58, 120.47, 118.58, 44.26, 44.19, 30.63;

HRMS (EI) m / z calcd for C 21 H 18 F 3 N 4 O 2 [M +] 415.1382, found: 415.1399.

Example 27: Confirmation of inhibition of hedgehog signaling

Experiments were conducted as follows to confirm whether the compounds of the present invention inhibited hedge or signal transduction.

Cell-based assays were performed in NIH3T3 cells containing a reporter plasmid (8xGliBS-luciferase) conjugated with luciferase at the Gli binding site, a specific nucleotide sequence to which Gli, a transcription factor of the final stage, binds for gene expression. 4x10 ⁴ 8xGliBS-luciferase NIH3T3 cells were cultured in a 24-well plate and cultured in the serum-free DMEM medium for 30 hours to induce ciliary formation. After cilia formation, the hedgehog signaling ligand, Sonic Hedgehog (Shh) -conditioned media, was treated with the compound and the activity was measured after 24 hours using the dual-luciferase reporter assay system.

As a result, as shown in FIGS. 2 and 3, 26 compounds were observed to inhibit Hedgehog signaling, and in particular, 3- (6 - ((2S, 6R) -2,6-dimethyl 3-yl) -8-phenylquinazolin-4 (3H) -one (Compound 14) and 3- (6- (2S, 6R) -2,6- dimethylmorpholino) IC ₅₀ the concentration was confirmed to be the lowest of the one (Compound 20) - pyridin-3-yl) -8- (4-fluorophenyl) quinazolin -4 (3H).

Accordingly, the present inventors have found that the above-mentioned two compounds, i.e., 3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin- Yl) -8- (4-fluorophenyl) quinazolin-4 (3H) -quinolin- -One (see Example 20) was subjected to the following experiment.

Example 28: Confirmation of inhibition of Gli1 expression

In order to confirm whether the compounds of the present invention inhibit the expression of Gli1, experiments were conducted as follows.

Vismodegib, Sonidegib, Compound 14 (3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin- (3-fluorophenyl) quinazolin-4 (3H) -one) A mixture of 20 (3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin- Were assayed for hedgehog signaling activity in 8xGliBS luciferase reporter NIH3T3 at 7 concentration conditions (0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10 μM)

In order to prove that the hedge or activity suppression effect of Compound 14 and Compound 20 occurs hedge or signaling-specific, Ptch1 ^{- / -} skin cells Mouse embryonic fibroblasts (MEFs). The Ptch1 ^{- / -} skin cells were treated with Vismodegib, Sonidegib, Compound 14, and Compound 20 (10 μM each) for 24 h in cells where hedge or signaling activity is always present even without Shh, which is a hedgehog ligand. The amount of Gli1 protein increased by signal transduction activity was measured by western blotting using Gli1 - specific antibody.

As a result, as shown in FIGS. 4 and 5, Compound 14 and Compound 20 were found to inhibit Gli expression, suggesting that quinazolinone derivatives are specific for hedgehog signaling .

Example 29: Confirmation of SMO protein inhibitory activity

In order to confirm whether the compounds of the present invention inhibit the activity of the SMO protein, the following experiment was conducted.

In order to elucidate the mechanism of hedge or signal transduction of compounds, treatment of Shh in NIH3T3 cells overexpressing Smo-EGFP resulted in increased migration of Smo-EGFP protein to the ciliated organelle. At this time, it is known that processing of Vismodegib and Sonidegib suppresses this process and does not hedge or signal transmission.

Smo-EGFP NIH3T3 cells were treated with serum-free DMEM to induce ciliary formation and then treated with Hedgehog ligand and compounds (Vismodegib, Sonidegib, Compound 14 and Compound 20) at the same time. Twenty-four hours after the compound treatment, the cells were fixed with fixative (4% PFA) and fluorescent staining was performed using acetylated-tubulin (Ac-Tub) antibody labeled with cilium. Smo-EGFP Respectively.

As a result, as shown in FIG. 6 and FIG. 7, it was confirmed that Compound 14 and Compound 20 inhibited ciliate migration of Smo-EGFP, suggesting that SMO protein activity is superior to that of the positive control group Vismodegib.

Example 30: Confirmation of Gli2 expression inhibitory ability

In order to confirm whether or not the compounds of the present invention inhibit the expression of Gli2, the following experiment was conducted.

To elucidate the molecular mechanism of hedge or signal transduction of compounds, Shh treatment in NIH3T3 cells resulted in increased migration and transcriptional activity of Gli2 protein, a signal transduction downstream transcription factor, to cilioblast.

Thus, in order to confirm the ability of the compound of the present invention to inhibit Gli2 expression, NIH3T3 cells were treated with no-serum DMEM to induce ciliary formation, and then the hedgehog ligand and compounds (Vismodegib, Sonidegib, Compound 14 and Compound 20) Respectively. Cells were fixed with fixative (4% PFA) 24 hours after compound treatment, and fluorescent staining was performed using acetylated-tubulin (Ac-Tub) antibody and Gli2 antibody that labeled cilium. Respectively.

As a result, as shown in Fig. 8, it was confirmed that Compound 14 and Compound 20 inhibited the migration of Gli2 into cilia.

Example 31: Evaluation of inhibition against SMO variant (D477H)

The following experiments were conducted to confirm whether the compounds of the present invention inhibit the Smo mutation (D477H), which is resistant to the Vismodegib drug targeting the first generation hedge signaling.

Shh-conditioned media and five different concentrations of Vismodegib, Sonidegib, Compound 14, and Compound 20 were treated for 24 hours in NIH3T3 cells expressing Smo (D477H) mutants that induce steady state Smo or Vismodegib drug resistance, respectively. Gli1 mRNA expression was measured by quantitative real-time PCR method on the degree of hedgehog signaling in the drug-resistant Smo mutant (Smo (D477H)).

As a result, as shown in Fig. 9, Compound 14 did not lose the action effect on the SMO mutant.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (10)

A compound represented by the following formula (2), or a pharmacologically acceptable salt thereof.
(2)

In Formula 2,
R1 is Cl,

, ,

,

,

,

,

or

ego;
R2 is

,

,

,

,

,

,

,

,

or

to be.
delete delete The method according to claim 1,
Wherein the compound represented by Formula 2 is a compound selected from the group consisting of the following compounds, or a pharmacologically acceptable salt thereof:
8-Chloro-3- (4-fluorophenyl) quinazolin-4 (3H) -one;
8-Chloro-3- (4-morpholinophenyl) quinazolin-4 (3H) -one;
8-Chloro-3- (6-morpholinopyridin-3-yl) quinazolin-4 (3H) -one;
8-chloro-3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-3-yl) quinazolin-4 (3H) -one;
8-chloro-3- (6 - ((2S, 6R) -2,6-dimethylmorpholino) pyrimidin-4-yl) quinazolin-4 (3H) -one;
3- (4-morpholinophenyl) -8-phenylquinazolin-4 (3H) -one;
8- (3-methoxyphenyl) -3- (4-morpholinophenyl) quinazolin-4 (3H) -one;
3- (4 -morpholinophenyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one;
3- (6-morpholinopyridin-3-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8-phenylquinazolin-4 (3H) -one;
4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (6 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8- (naphthalen-1-yl) quinazolin-4 (3H) -one;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8-p-tolylquinazolin-4 (3H) -one;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8- (4-methoxyphenyl) quinazolin-4 (3H) -one;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8- (4- (methylsulfonyl) phenyl) quinazolin-4 (3H) -one;
3- (6 - ((2S, 6R) -2,6-Dimethylmorpholino) pyridin-3-yl) -8- (4-fluorophenyl) quinazolin-4 (3H) -one;
4 - ((3H) -one), was prepared in accordance with the general method of example 1 from 3- (5 - ((2S, 6R) -2,6- dimethylmorpholino) pyridin- ;
3- (6- (4-Methylpiperadin-l-yl) pyridin-3-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one;
4- (3H) - (4-fluorophenyl) piperazin-1-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin- On;
3- (6- (4-Methylpiperidin-1-yl) pyrimidin-4-yl) -8- (4 (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one;
3- (2-morpholinoethyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one; And
3- (3- (1H-imidazol-1-yl) propyl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 (3H) -one.
10. A compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof; A pharmaceutical composition for preventing or treating cancer, comprising a pharmaceutically acceptable carrier.
6. The method of claim 5,
The cancer is selected from the group consisting of basal cell carcinoma, hematoblastoma, rhabdomyosarcoma, chondrosarcoma, melanoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, breast cancer, ovarian cancer, gastric cancer, , Cancer of the kidney, cancer of the head, mesothelioma, soft tissue sarcoma, osteosarcoma, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone cancer, acute leukemia, chronic leukemia, glioma, hodgkins disease, skin melanoma, bladder cancer, endocrine cancer, A papillary adenoma, a pituitary adenoma, a uterine cancer, a stomach cancer, and a bile duct cancer, wherein the cancer is selected from the group consisting of papillary thyroid carcinoma, papillary thyroid carcinoma, papillary thyroid carcinoma, cervical cancer, endometrial cancer, ovarian cancer, skin cancer,
6. The method of claim 5,
Wherein said compound inhibits a hedgehog signaling pathway. ≪ RTI ID = 0.0 > 11. < / RTI >
6. The method of claim 5,
Wherein said compound inhibits SMO (Smoothened) activity.
6. The method of claim 5,
Wherein said compound inhibits Gli1 expression.
6. The method of claim 5,
Wherein said compound inhibits a hedgehog signaling pathway to SMO (smoothened) variant (D477H).

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