KR101633722B1

KR101633722B1 - 4-(1-pyrrole-3,4-dicarboxamide)pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient

Info

Publication number: KR101633722B1
Application number: KR1020140135844A
Authority: KR
Inventors: 이광호; 김형래; 조성윤; 하재두; 김필호; 황종연; 윤창수; 정희정; 박지훈; 이정옥; 채종학; 라티프무하마드
Original assignee: 한국화학연구원
Priority date: 2014-10-08
Filing date: 2014-10-08
Publication date: 2016-06-28
Also published as: KR20160042306A

Abstract

TECHNICAL FIELD The present invention relates to a 4- (1-perl-3,4-dicarboxyamide) pyrimidine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. - (1-pero-3,4-dicarboxyamide) pyrimidine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is excellent in the activity of inhibiting reverse transcribed lymphoma kinase (ALK) (ALK) fusion protein, such as ALK, NPM-ALK, and is useful as a pharmaceutical composition for prevention or treatment of cancer since it is expected to be effective in preventing recurrence of cancer Can be used.

Description

A pharmaceutical composition for preventing or treating 4- (1-pyrrole-3,4-dicarboxyamide) pyrimidine derivatives, a process for producing the same, dicarboxamide) pyrimidine derivatives, preparation methods thereof, and pharmaceutical compositions for use in preventing or treating cancer comprising the same as an active ingredient}

TECHNICAL FIELD The present invention relates to a 4- (1-perl-3,4-dicarboxyamide) pyrimidine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Cancer is a mass of cells composed of undifferentiated cells which, unlike normal cells, can regulate and inhibit proliferation and suppression according to the individual's needs, ignoring the necessary conditions in the tissues and is called a tumor. These unlimited, proliferating cancer cells penetrate into surrounding tissues and, in the worse case, become metastasized to other organs of the body, resulting in severe pain and ultimately death.

According to the American Cancer Society data, there are more than 12 million new cases of cancer diagnosed globally in 2007, with 7.6 million deaths and about 20,000 deaths every day. In Korea, according to 2006 National Statistical Office, death from cancer was the leading cause of death. Therefore, the development of a tumor treatment agent having excellent therapeutic effect for the reduction of mental and physical pain caused by cancer and bruising and improvement of the quality of life is urgently required.

However, in many efforts, it has not yet been accurately determined how normal cells are transformed into cancer cells. However, the internal factors such as environmental factors, chemical substances, radiation, and viruses, and external factors such as genetic factors and immunological factors Factors are complexly entangled, resulting in cancer. The genes involved in the development of cancer include oncogenes and tumor suppressor genes. Cancer occurs when the balance between them is destroyed by the internal or external factors described above.

Cancer is largely classified into blood cancer and solid cancer and occurs in almost all parts of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer and skin cancer. Recently, a few targets such as Gleevec or Herceptin Therapeutics are currently being used to treat certain cancers, but until now, chemotherapy with chemotherapeutic agents that inhibit surgery, radiation therapy and cell proliferation is the main method. However, since it is not a target drug, the biggest problem of conventional chemotherapy is cytotoxic side effects and drug resistance, which are the main factors that eventually fail treatment despite successful initial response by anticancer drugs. Therefore, in order to overcome the limitations of these chemotherapeutic agents, it is necessary to develop a targeted therapeutic agent with clear mechanism of action.

Therefore, many studies on specific molecular biologic factors involved in tumorigenesis for developing a target therapeutic agent are under way, and in particular, molecular biological factors are widely used to determine the prognosis of cancer, chemotherapy, and radiation therapy .

Gleevec is the most representative drug that inhibits tyrosine kinase receptors of certain molecular biologic factors. The Gleevec inhibits the action of the Bcr-Abl fusion gene, which is formed by chromosomal translocation in the Philadelphia chromosome observed in chronic myelogenous leukemia, and thus acts as an anticancer agent. As a tyrosine kinase inhibitor, Gleevec exhibits satisfactory results when administered to patients suffering from chronic myelogenous leukemia have. Thereafter, the drugs that exhibit anticancer effects with tyrosine kinase inhibitors include gefitinib and erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, which are used as therapeutic agents for non-small cell lung cancer, and kidney cells Sorafenib and sunitinib have been used to treat cancer, but they have been known to have side effects such as bleeding, heart attack, heart failure, and liver failure.

Recently, anaplastic lymphoma kinase (ALK) has been found in many human tumors and has been studied as a target of target treatment.

The carcinogenic process of inverse lymphoma kinase (ALK) is known to be a study of the fusion gene of ALK-NPM (nucleophosmin, nucleophosphin), which is mainly observed in inverse large cell lymphoma. When the inverse lymphoma kinase (ALK) is activated by gene fusion, the tyrosine kinase of the inverse lymphoma kinase (ALK) acts abnormally and causes cancer. In other words, abnormally activated degenerative lymphoma kinase (ALK) induces cell proliferation, prevents apoptosis, prevents cell death, rearranges the cellular skeleton, and modifies cell morphology. Cancer geneation of inverted lymphoma kinase (ALK) is mediated by interaction with a downstream molecule, the target of reverse forming lymphoma kinase (ALK), which mediates intracellular signaling. Inverse lymphoma kinase (ALK) is linked to other tyrosine kinases that are normal or cancer-genetically modified to interact or activate a variety of other pathways.

In particular, the inverse Lymphoma kinase (ALK) gene in lung cancer cells is fused with EML4 (Echinoderm Microtubule-Associated Protein-Like 4) gene to produce active tyrosine kinase, EML4-ALK, In addition, Mosse et al. Reported that 26% of the 491 neuroblastoma specimens were amplified with the reverse priming lymphoma kinase (ALK) gene amplification, and that EML4-reverse forming lymphoma kinase (ALK) There is one. In addition, the inverse lymphoma kinase (ALK) gene may be useful for the treatment of numerous B-cell lymphomas, systemic breakfast necrosis, inflammatory myoblastic fibrosarcoma, esophageal squamous cell carcinoma, non-small cell lung carcinoma, rhabdomyosarcoma, myoblastoma, melanoma and melanoma cell lines In the rare disease of inflammatory bone marrow fibroblastoma tumor, several types of reverse priming lymphoma kinase (ALK) fusion proteins have been found to be expressed in non-hematopoietic cell tumors, and these fusion proteins are thought to be deeply involved in tumor development have.

Thus, therapeutic agents targeting ALK-NPM for the treatment of cancer are being developed by blocking the activation pathway of inverse lymphoma kinase (ALK). Recently, Crytotinib (PF-02341066), a small molecule tyrosine phosphorylase inhibitor, has been developed as a selective inhibitor of tumorigenic mutation in Pfizer. It has been shown that ATP competitiveness c-Met / HGFR and inverse lymphoma kinase ) Inhibitor, which is known to be effective in the treatment of non-small cell lung cancer. In 2011, the FDA received a new drug approval.

In addition, NVP-TAE684 and LDK-378 from Novartis and CH5424802 from Chugai are known to have the effect of reducing the tumor size in neuroblastoma cell lines in addition to the reverse large-cell lymphoma cell line.

In Patent Documents 1 to 3, therapeutic candidates having various skeletons have been developed to inhibit the activity of conventional inverse lymphoma kinase (ALK), and pyrimidine derivatives selectively inhibit lymphoma kinase (ALK) Can be developed.

Accordingly, the present inventors have made efforts to develop a compound that exhibits an inhibitory effect on ALK (anaplastic lymphoma kinase) activity. In the present invention, 4- (1-perl-3,4-dicarboxyamide ) Pyrimidine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can act as an inhibitor of the activity of inverse-forming lymphoma kinase (ALK), and thus can be used as a preventive or therapeutic agent for cancer.

WO 2009143389 A1 WO 2008051547 A1 WO 2004080980 A1

It is an object of the present invention to provide a 4- (1-pero-3,4-dicarboxyamide) pyrimidine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the 4- (1-perl-3,4-dicarboxyamide) pyrimidine derivative.

It is still another object of the present invention to provide a method for preventing or treating cancer comprising the above-mentioned 4- (1-perro-3,4-dicarboxyamide) pyrimidine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a pharmaceutical composition.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² independently represent -H, C ₁ _-10 linear or branched alkyl, C ₁ _-10 straight or branched alkoxy, unsubstituted or substituted C ₆ _-10 aryl group of C ₁ _-5 straight or branched alkyl is or unsubstituted or substituted straight or branched chain alkoxy of C ₆ _-10 aryl group of C ₁ _-5,

The linear or branched alkoxy-substituted C ₆ _-10 aryl C _1-5 of the C ₆ _-10 straight or branched chain alkyl and substituted aryl C _1-5 of is independently -OH, halogen, C _1-5 straight-chain of or branched alkyl and C ₁ _-5 straight or branched chain alkoxy group of C ₆ _-10 are one or more substituents selected from the group consisting of substituted aryl of C ₁ _-5 straight or branched chain alkyl and C ₆ _-10 aryl C ₁ _-5 straight or branched alkoxy;

X is -H, -OH, halogen, unsubstituted or at least one halogen-substituted C ₁ _-10 straight or branched alkyl, or unsubstituted or substituted by one or more halogens, and is linear or branched alkoxy-substituted C ₁ _-10;

Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from the group consisting of -H, -OH, C ₁ _-10 linear or branched alkyl, C ₁ _-10 linear or branched alkoxy, or N, Unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one heteroatom selected,

Wherein said substituted 5-10 membered heterocycloalkyl is selected from the group consisting of -OH, halogen, C ₁ _-5 straight or branched alkyl, C ₁ _-5 straight or branched alkoxy and -C (= O) OR ³ Wherein one or more substituents are substituted 5-10 membered heterocycloalkyl,

Wherein R ³ is a C ₁ _-5 alkyl;

Z ³ and Z ⁴ may be joined together with the carbon atoms to which they are attached to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S However,

Wherein the substituted cycloalkyl is 5 to 10 membered heteroaryl selected from the group consisting of -OH, halogen, straight or branched chain alkoxy, and -C of C ₁ _-5 straight or branched chain alkyl, C ₁ _-5 of (= O) OR ⁴ Wherein one or more substituents are substituted 5-10 membered heterocycloalkyl,

Wherein R ⁴ is a straight or branched alkyl of C ₁ _-5.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And

Reacting the compound represented by the formula (6) and the compound represented by the formula (7) prepared in the step 2 to prepare a compound represented by the formula (1) (step 3) .

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , X, Z ¹ , Z ² , Z ³ and Z ⁴ are as defined in the above formula (1).

Further, the present invention relates to a process for the preparation of

The compound-Boc (

(1), which comprises reacting a compound represented by the formula (1) with a compound represented by the formula (1).

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ , R ² , X, Z ¹ , Z ² and Z ⁴ are the same as defined in Formula 1,

The compounds represented by the general formulas (1a) and (1b) are included in the compounds represented by the general formula (1).

Also, as shown in the following Reaction Scheme 3,

The compound represented by the formula (1c) -Boc (

[Reaction Scheme 3]

In Scheme 3,

R ¹ , R ² , X, Z ^1, and Z ² are the same as defined in Formula 1,

The compounds represented by the formulas (1c) and (1d) are included in the compound represented by the above formula (1).

Further, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The 4- (1-perl-3,4-dicarboxyamide) pyrimidine derivative according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is excellent in the activity of inhibiting reverse transcribed lymphoma kinase (ALK) , And thus has excellent therapeutic effect on cancer cells having an inverted lymphoma kinase (ALK) fusion protein such as EML4-ALK and NPM-ALK, and is expected to be effective in preventing cancer recurrence. And may be usefully used as an emulsion composition.

Hereinafter, the present invention will be described in detail.

[Chemical Formula 1]

In Formula 1,

Wherein R ³ is a C ₁ _-5 alkyl;

Wherein R ⁴ is a straight or branched alkyl of C ₁ _-5.

Preferably,

R ¹ and R ² are independently selected from the group consisting of -H, C ₁ _-5 straight or branched chain alkyl, C ₁ _-5 straight or branched alkoxy, unsubstituted or substituted C ₆ _-8 aryl C ₁ _-3 straight or branched Alkyl, or unsubstituted or substituted C ₆ _-8 aryl C ₁ _-3 straight or branched alkoxy,

The straight or branched alkyl of substituted C ₆ _-8 aryl C ₁ _-3 and the substituted C ₆ _-8 aryl C _1-3 straight or branched alkoxy are independently halogen, C ₁ _-3 straight or branched alkyl And straight or branched alkyl of C ₆ _-8 aryl C ₁ _-3 substituted with at least one substituent selected from the group consisting of C _1-3 linear or branched alkoxy and C ₆ _-8 aryl C ₁ _-3 Linear or branched alkoxy;

X is -H, halogen, C ₁ _-5 straight or branched chain alkyl, or C ₁ _-5 straight or branched alkoxy;

Z ^1, Z ^2, Z ³ and Z ⁴ are independently -H, straight or branched C ₁ _-5 alkyl, a C ₁ _-5 straight or branched chain alkoxy, or N, O and one selected from the group consisting of S Unsubstituted or substituted 5-8 membered heterocycloalkyl containing more than one heteroatom,

Wherein said substituted 5-8 membered heterocycloalkyl is substituted with at least one member selected from the group consisting of halogen, C ₁ _-5 straight or branched alkyl, C ₁ _-5 straight or branched alkoxy and -C (= O) OR ³ Wherein the substituent is a substituted 5-8 membered heterocycloalkyl,

Wherein R ³ is a C ₁ _-5 alkyl;

Z ³ and Z ⁴ may be joined together with the carbon atoms to which they are attached to form an unsubstituted or substituted 5-8 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S However,

Wherein said substituted 5-8 membered heterocycloalkyl is substituted with at least one member selected from the group consisting of halogen, C ₁ _-5 straight or branched alkyl, C ₁ _-5 straight or branched alkoxy and -C (= O) OR ⁴ Wherein the substituent is a substituted 5-8 membered heterocycloalkyl,

Wherein R ⁴ is a straight or branched alkyl of C ₁ _-5.

More preferably,

R ¹ is n-propyl, or

ego;

R ² is -H;

X is -Cl;

Z ¹ is -H, methoxy, or isopropoxy;

Z ² is -H, or methoxy;

Z < ³ > is methoxy,

, or

ego;

Z ⁴ is -H, methyl, or methoxy;

Z ³ and Z ⁴ are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted piperidine,

The substituted piperidine may be substituted with a -Boc (

) Is a substituted piperidine.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) Synthesis of 1- (5-chloro-2 - ((2,3,4-trimethoxyphenyl) amino) pyrimidin-4-yl) -N3, N4- Dicarboxamide;

(2) Synthesis of 1- (5-chloro-2 - ((3,4,5-trimethoxyphenyl) amino) pyrimidin-4-yl) -N3, N4- Dicarboxamide;

(3) Synthesis of tert-butyl 4- (4 - ((4- (3,4-bis (propylcarbamoyl) -1 H-perrol- 1 -yl) -5- chloropyrimidin- -Isopropoxy-2-methylphenyl) piperidine-1-carboxylate;

(4) Synthesis of 1- (5-chloro-2 - ((2-isopropoxy-5-methyl-4- (piperidin- -Dipropyl-1H-purol-3,4-dicarboxamide;

(5) Synthesis of tert-butyl 6 - ((4- (3,4-bis (propylcarbamoyl) -1 H-peror- 1 -yl) -5- chloropyrimidin-2- yl) amino) -3,4-dihydroisoquinolin-2 (1H) -carboxylate;

(6) Synthesis of 1- (5-chloro-2 - ((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin- Dipropyl-1H-purol-3,4-dicarboxamide;

(7) Synthesis of 1- (5-chloro-2 - ((2,3,4-trimethoxyphenyl) amino) pyrimidin-4-yl) -N3, N4- -3,4-dicarboxamide;

(8) Synthesis of 1- (5-chloro-2 - ((3,4,5-trimethoxyphenyl) amino) pyrimidin-4-yl) -N3, N4- -3,4-dicarboxamide;

(9) Synthesis of tert-butyl 6 - ((4- (3,4-bis ((4-methylbenzyl) carbamoyl) -1 H-perol- 1 -yl) -5- chloropyrimidin- -7-methoxy-3,4-dihydroisoquinolin-2 (1H) -carboxylate;

(10) 1- (5-Chloro-2 - ((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin- Bis (4-methylbenzyl) -1H-peryl-3,4-dicarboxamide;

(11) tert -butyl 4- (4 - ((4- (3,4-bis ((4-methylbenzyl) carbamoyl) ) Amino) -5-methoxy-2-methylphenyl) piperidine-1-carboxylate; And

(12) 1- (5-Chloro-2 - ((2-isopropoxy-5-methyl-4- (piperidin- -Bis (4-methylbenzyl) -1 H-pero-3,4-dicarboxamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. 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, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-carboxylate, benzenesulfonate, Sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, the present invention encompasses not only the compound represented by the formula (1) and pharmaceutically acceptable salts thereof, but also solvates, optical isomers and hydrates thereof which can be prepared therefrom.

Further, the present invention relates to a process for preparing a compound represented by the following formula 1,

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In the process for preparing the compound represented by the formula (1) according to the present invention, the step (1) is a step of reacting the compound represented by the formula (2) with the compound represented by the formula (3) Concretely, the compound represented by the general formula (2) is mixed with the compound represented by the general formula (3), and the compound represented by the general formula (4) is prepared by irradiating with a microwave.

In this case, the reaction is preferably carried out at a temperature of 100-200 ° C, and the irradiation time of the microwave is not particularly limited, but it is preferable to irradiate the reaction solution for 50-150 minutes.

In the process for preparing a compound represented by the formula (1) according to the present invention, the compound represented by the formula (5) is reacted with the compound represented by the formula (5) More specifically, a step of adding a base dissolved in a solvent to a compound represented by the formula (4) and stirring the mixture, adding a compound represented by the formula (5) and stirring to prepare a compound represented by the formula (6) to be.

As the solvent, tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, , Phenylbutyrate, chicrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate , And it is preferable to use dimethylformamide (DMF).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, and it is preferable to use cesium carbonate (Cs ₂ CO ₃ ).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 90 hours.

In the process for preparing a compound represented by the formula (1) according to the present invention, the compound represented by the formula (7) is reacted with the compound represented by the formula (7) More specifically, an acid dissolved in a solvent is added to a compound represented by the formula (6) and stirred, and then the compound represented by the formula (7) is added and stirred to prepare a compound represented by the formula to be.

As the solvent, tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, , Phenylbutyrate, chicrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate And it is preferable to use dioxane.

As the acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid and the like can be used, and toluene sulfonic acid is preferably used.

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but it is preferable to carry out the reaction for 0.5 to 40 hours.

The present invention also relates to a process for producing a compound represented by the formula

The compound-Boc (

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ , R ² , X, Z ¹ , Z ² and Z ⁴ are the same as defined in Formula 1,

Hereinafter, the method for preparing the compound represented by Formula 1b according to the present invention will be described in detail.

In the process for preparing the compound represented by the formula (1b) according to the present invention, the step (1) is a step of reacting the compound represented by the formula (1a) with -Boc

) Group is removed to prepare a compound represented by the formula (1b). More specifically, the compound represented by the formula (1b) is prepared by adding an acid to the compound represented by the formula (1a) and stirring the mixture.

At this time, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid and the like can be used as the acid, and it is preferable to use trifluoroacetic acid.

In addition, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 40 hours.

Further, the present invention relates to a process for the preparation of

The compound represented by the formula (1c) -Boc (

[Reaction Scheme 3]

In Scheme 3,

R ¹ , R ² , X, Z ^1, and Z ² are the same as defined in Formula 1,

Hereinafter, a method for preparing the compound represented by Formula 1d according to the present invention will be described in detail.

In the method for preparing the compound represented by the formula (1d) according to the present invention, the step 1 is a step of reacting the compound represented by the formula (1c) with -Boc

) Group is removed to prepare a compound represented by the formula (1d). More specifically, an acid is added to a compound represented by the formula (1c) and stirred to prepare a compound represented by the formula (1d).

Further, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Herein, the pharmaceutical composition is characterized by inhibiting the activity of ALK (Anaplastic Lymphoma Kinase) to inhibit the expression and growth of cancer cells. Examples of the cancer include non-small cell lung cancer, neuroblastoma, inflammatory bone marrow fibroblast Tumor, rhabdomyosarcoma sarcoma, myoblastoma, breast cancer, gastric cancer, lung cancer, melanoma, and the like.

Reverse transforming lymphoma kinase (ALK) is a gene that induces cell proliferation of cancer cells in cancer cells. The gene fusion process activates reverse transforming lymphoma kinase (ALK), and in turn activates lymphocyte kinase (ALK) Tyrosine kinase acts abnormally to induce cell proliferation, prevents apoptosis, prevents cell death, rearranges cellular skeletons, and modifies cell morphology. In addition, reverse lymphoma kinase (ALK) It interacts with other tyrosine kinases that are differentiated and activates several different pathways.

Thus, experiments were carried out to determine the inverse lymphoma kinase (ALK) activity of the 4- (1-perro-3,4-dicarboxyamide) pyrimidine derivative represented by the formula As a result, the compounds prepared in Examples 2, 4, 6, 8 and 12 according to the present invention effectively decreased the activity of reverse priming lymphoma kinase (ALK) enzyme at low concentration (10 μM) The compound prepared in Example 8 showed a 74% inhibition of the reverse priming lymphoma kinase (ALK) enzyme activity, indicating that it has an excellent inhibitory activity (see Table 2 in Experimental Example 1).

In addition, an experiment was conducted to measure the inverse lymphoma kinase (ALK) inhibitory activity of the 4- (1-perro-3,4-dicarapiamide) pyrimidine derivative represented by the formula As a result, the compounds prepared in Examples 2, 4, 6, and 11 according to the present invention exhibited higher activity than the cells of H3122 CP, a non-small cell lung cancer cell containing low-level (< 10 [mu] M) reverse forming lymphoma kinase (ALK) The activity was reduced to 50% (IC ₅₀ ). In particular, the compound prepared in Example 11 was found to reduce the cellular activity of H3122 CP to 50% at a very low concentration of 2.3 [mu] M (see Table 3 in Experimental Example 2).

Therefore, the 4- (1-perl-3,4-dicarapiamido) pyrimidine derivative represented by the formula (1) according to the present invention is excellent in the effect of inhibiting the inverse lymphoma kinase (ALK) Neuroblastoma, inflammatory myelofibroblastoma, endometrioma sarcoma, myofiber oblastoma, breast cancer, gastric cancer, lung cancer, melanoma, and the like.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. &Lt; / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 / day, based on adult patients weighing 70, and may be administered once to several times per day It may be administered in divided doses.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.

< Example 1 > 1- (5- Chloro -2 - ((2,3,4- Trimethoxyphenyl ) Amino) pyrimidin-4-yl) - N3, N4 - dipropyl-1 H - Perl -3,4- Dicarboxyamide Produce

Step 1: N3 , N4 - Dip profil -1H- Perl -3,4- Dicarboxyamide Produce

Diethyl 1 H -pero-3,4-dicarboxylate (400 mg, 1.89 mmol) and excess n -propylamine were mixed together. The reaction mixture was irradiated with microwave at 180 < 0 > C for 100 minutes. When the reaction was complete, EtOAc and saturated NaHCO ₃ Layer separation was carried out using a solution. The aqueous layer was extracted three times with EtOAc. The collected organic layer was washed with water and brine, dried over anhydrous MgSO _4. The solvent was removed under vacuum. The crude product was purified by Medium Pressure Liquid Chromatography (MPLC) using dichloromethane / acetone (5: 1) and silica gel to obtain the desired compound in 67% yield.

¹ H NMR (300 MHz, CDCl ₃ )? 11.04 (s, 1H), 8.42 (br, 2H), 7.23 (br, 1H), 3.33 (q, J = 6.7 Hz, 4H), 1.87 s, 1 H), 1.62 (sextet, J = .7.3 Hz, 4 H), 0.96 (t, J = 7.9 Hz, 6 H);

¹³ C NMR (125 MHz, CDCl ₃ ), 165.8, 123.7, 118.3, 41.5, 22.8, 11.5;

LC-MS (EI) for C 12 H 19 N 3 O 2 (M + H & lt ^; + & gt ^; ): m / z = 238.12, Exact Mass: 237.1477.

Step 2: 1- (2,5- Dichloropyrimidine Yl) - N3 , N4 - Dip profil -1H- Perl -3,4- Dicarboxyamide Produce

To the reaction flask was added anhydrous Cs ₂ CO ₃ (0.15 g, 0.03 mmol) dissolved in N3 , N4 -dipropyl-1H-perro- 3,4-dicarboxamide (140 mg, 0.59 mmol) 480 mg, 1.5 mmol), and the mixture was stirred for 5 minutes. 2,4,5-trichloropyrimidine (216 mg, 1.18 mmol) was added to the reaction mixture, and the mixture was stirred at 35 占 폚 for 90 hours. The reaction was monitored via LC-MS. After completion of reaction, the layer separation was carried out by using EtOAc and saturated NaHCO ₃ solution. The aqueous layer was extracted three times with EtOAc. The collected organic layer was dried by washing with brine and Na ₂ SO _4, filter, and solvent was removed under vacuum. The crude product was purified by column chromatography using hexane / ethyl acetate (2: 1) and silica gel to give the desired compound as a colorless solid (205 mg, 90%).

^{1 H NMR (300 MHz, acetone-} d 6) δ 9.30 (br, 1 H), 8.95 (s, 1 H), 8.32 (s, 2 H), 3.33 (q, J = 6.0 Hz, 4 H), 2.82 (br, 1H), 1.62 (sextet, J = 7.2 Hz, 4 H), 0.98 (t, J = 7.2 Hz, 6 H);

^{13 C NMR (75 MHz, Acetone-} d 6) δ 163.4, 162.5, 157.7, 153.6, 125.8, 121.7, 119.5, 41.0, 22.5, 10.9;

LC-MS (EI) for C ₁₆ H ₁₉ N ₅ O ₂ (M + H & lt ^; + & gt ^; ): m / z = 384.36, Exact Mass: 383.0915.

Step 3: 1- (5- Chloro -2 - ((2,3,4-trimethoxyphenyl) amino) pyrimidin-4- Work ) - N3, N4 - dipropyl-1 H - Perl -3,4- Dicarboxyamide Produce

To the reaction flask was added 1- (2,5-dichloropyrimidin-4-yl) -N3 , N4 -dipropyl-1H-purrol-3,4-dicarboxamide (2.0 g, 5.20 mmol) And p -toluenesulfonic acid monohydrate (791 mg, 4.16 mmol) dissolved in 1,4-dioxane (15 mL), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 2,3,4-trimethoxyaniline (1.05 g, 5.73 mmol) and heated to 50 < 0 > C for 24 hours. The reaction was monitored via LC-MS. After the reaction was completed, saturated NaHCO ₃ The solution was added to terminate the reaction. After removal of the organic solvents in vacuo, a saturated NaHCO ₃ Solution. The aqueous layer was extracted three times with EtOAc. After the organic layer was collected, washed with brine, dried with Na ₂ SO _4, filter, and concentrated in vacuo. The crude product was purified by column chromatography using hexane / ethyl acetate (4: 1) and silica gel to give the title compound as a colorless solid (2.50 g, 90%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.44 (br, 2H), 8.26 (br, 2H), 7.86 (d, J = 8.9 Hz, 1H) d, J = 9.1 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.40 (q, J = 6.4 Hz, 4 H), 2.70 ( s, 1 H), 1.66 (sextet, J = 9.1 Hz, 4 H), 1.01 (t, J = 7.1 Hz, 6 H);

LC-MS (EI) for C ₂₅ H ₃₁ ClN ₆ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 531.31, Exact Mass: 530.2044.

< Example 2 > 1- (5- Chloro -2 - ((3,4,5-trimethoxyphenyl) amino) pyrimidin-4- Work ) - N3, N4- Dipropyl-1 H - Perl -3,4- Dicarboxyamide Produce

The procedure of Example 1 was repeated except that 3,4,5-trimethoxybenzeneamine was used instead of 2,3,4-trimethoxy aniline to obtain the desired compound as a colorless solid (525 mg, 86%).

¹ H NMR (CDCl ₃ 300 MHz)? 8.44 (br, 2H), 8.26 (br, 2H), 7.88 (d, J = 8.7 Hz, 1H) , J = 9.5 Hz, 1 H ), 3.95 (s, 3 H), 3.86 (s, 6 H), 3.45 (q, J = 6.5 Hz, 4 H), 2.72 (s, 1 H), 1.64 (sextet , J = 9.2 Hz, 4 H), 1.05 (t, J = 7.2 Hz, 6 H);

LC-MS (EI) for C ₂₅ H ₃₁ ClN ₆ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 531.19, Exact Mass: 530.2044.

< Example 3> tert -Butyl 4- (4 - ((4- (3,4- Bis ( Profile carbamoyl )-One H - Perl -1-yl) -5- Loropyrimy Yl) amino) -5- Isopropoxy -2- Methylphenyl ) Piperidin-l- Carboxy Produce

Except that tert-butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate was used instead of 2,3,4-trimethoxy aniline , The objective compound was obtained (24 mg, 55%) in the same manner as in Example 1,

¹ H NMR (300 MHz, CDCl ₃ )? 8.45 (s, 1H), 8.23 (s, 2H), 8.12 , 6.73 (s, 1 H) , 4.58 (quintet, J = 7.5 Hz 1 H), 4.25-4.29 (br, 1 H), 3.59-3.64 (m, 1 H), 3.38 (q, J = 6.6 Hz, 4 H), 2.82 (t, J = 1.9 Hz, 3 H ), 2.35 (s, 3 H) 1.59-1.77 (m, 8 H), 1.49 (s, 9 H), 1.38 (d, J = 5.7 Hz, 6 H) 0.99 (t, J = 7.8 Hz, 6 H);

LC-MS (EI) for C ₃₆ H ₅₀ ClN ₇ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 696.25, Exact Mass: 695.3562.

< Example 4 > 1- (5- Chloro -2 - ((2- Isopropoxy -5- methyl -4- (piperidin-4-yl) Phenyl ) Amino) pyrimidin-4-yl) - N ₃ , N ₄ - Dip profil -One H - Perl -3,4- Dicarboxyamide Produce

A tert prepared in Example 3, dissolved in CH ₂ Cl ₂ - butyl 4- (4 - ((4- (3,4-bis (propyl carbamoyl) -1 H-peorol-1-yl) -5 2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (5 mg, 0.007 mmol) in dichloromethane TFA) (1.0 mL) at O < 0 > C. The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo, and then purified through high-performance liquid chromatography (HPLC) using a _C18 column to give the title compound as a 2-trifluoroacetic acid salt Trifluoroacetic acid salt, TFA salt) (5.3 mg, 90%).

¹ H NMR (300 MHz, CD ₃ OD)? 8.35 (s, 1H), 8.20 (s, 2H), 8.12 ), 6.73 (s, 1 H ), 4.58 (m, 2 H), 4.21-4.34 (br, 1 H), 3.55-3.62 (m, 1 H), 3.40 (q, J = 6.5 Hz, 4 H) , 2.82 (t, J = 2.0 Hz, 3 H ), 2.35 (s, 3 H) 1.59-1.77 (m, 8 H), 1.33 (d, J = 6.5 Hz, 6 H) 0.92 (t, J = 7.5 Hz, 6 H);

LC-MS (EI) for C ₃₁ H ₄₂ ClN ₇ O ₃ (M + H & lt ^; + & gt ^; ): m / z = 596.19, Exact Mass: 595.3038.

< Example 5> tert -Butyl 6 - ((4- (3,4- Bis ( Profile carbamoyl )-One H - Perl -1-yl) -5- Chloropyrimidine Yl) amino) -7- Methoxy -3,4- Dihydroisoquinoline -2 (1 H ) - Carboxy ray Manufacture

Except that tert-butyl 6-amino-7-methoxy-3,4-dihydroisoquinolin-2 (1H) -carboxylate was used instead of 2,3,4-trimethoxy aniline , The procedure of Example 1 was repeated to obtain the desired compound (15 mg, 28%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.43 (s, 1 H), 8.20 (s, 2 H), 8.05 (s, 1 H), 7.79 (s, 1 H), 6.58 (s, 1 H) , 4.51 (s, 2 H) , 3.88 (s, 3 H), 3.59-3.64 (m, 2 H), 3.38 (q, J = 6.7 Hz, 4 H), 2.82 (t, J = 2.0 Hz, 2 H ), 1.59-1.71 (sextet, J = 6.3 Hz, 6 H), 1.49 (s, 9 H), 1.01 (t, J = 7.3 Hz, 6 H);

LC-MS (EI) for C ₃₁ H ₄₀ ClN ₇ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 626.17, Exact Mass: 625.2779.

< Example 6 > 1- (5- Chloro -2 - ((7- Methoxy -1,2,3,4- Tetrahydroisoquinoline Yl) amino) pyrimidin-4-yl) - N3 , N4 - Dip profil -One H - Perl -3,4- Dicarboxyamide Produce

A tert prepared in Example 3-butyl 4- (4 - ((4- (3,4-bis (propyl carbamoyl) -1 H-peorol-yl) -5-chloro-pyrimidin-2-yl ) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-instead of using the carboxy-rate, a tert prepared in example 5-butyl-6 - ((4- (3,4-bis (propyl carbamoyl) -1 H - peorol-yl) -5-chloro-pyrimidin-2-yl) amino) -7-methoxy-3,4-dihydroisoquinoline -2 (1 H) - carboxylic (4.3 mg, 92%) was obtained in the form of a trifluoroacetic acid salt (TFA salt) by carrying out the same procedure as in Example 4,

LC-MS (EI) for C ₂₆ H ₃₂ ClN ₇ O ₃ (M + H & lt ^; + & gt ^; ): m / z = 526.32, Exact Mass: 525.2255.

< Example 7 > 1- (5- Chloro -2 - ((2,3,4- Trimethoxyphenyl ) Amino) pyrimidin-4-yl) - N3, N4 - bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Produce

Step 1: N3 , N4 - Bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Produce

Diethyl 1 H -peroline-3,4-dicarboxylate (400 mg, 1.89 mmol) and excess 4-methylbenzylamine were mixed together. The reaction mixture was irradiated with microwave at 180 < 0 > C for 100 minutes. When the reaction was complete, EtOAc and saturated NaHCO ₃ Layer separation was carried out using a solution. The aqueous layer was extracted three times with EtOAc. The collected organic layer was washed with water and brine, dried over anhydrous MgSO _4. The solvent was removed under vacuum. The crude product was purified by Medium Pressure Liquid Chromatography (MPLC) using dichloromethane / acetone (5: 1) and silica gel to obtain the desired compound in 40% yield.

^{1 H NMR (300 MHz, acetone-} d 6) δ 10.84 (s, 1 H), 9.51 (br, 2 H), 7.55 (d, J = 1.5 Hz, 2 H), 7.21 (d, J = 7.4 Hz , 4 H), 7.09 (d, J = 7.5 Hz, 4 H), 4.47 (d, J = 5.6 Hz, 4 H), 2.27 (s, 6 H);

¹³ C NMR (75 MHz, Acetone- d ₆ ) 205.6, 164.9, 136.9, 136.1, 128.9, 127.5, 124.5, 118.2, 42.4, 20.2;

LC-MS (EI) for C 22 H 23 N 3 O 2 (M + H & lt ^; + & gt ^; ): m / z = 362.16, Exact Mass: 361.1790.

Step 2: 1- (2,5- Dichloropyrimidine Yl) - N3 , N4 - Bis (4- Methylbenzyl )-One H - Perl -3,4- D Preparation of carboxamide

Dissolved in peorol -3,4-carboxamide (100 mg, 0.28 mmol) and dry DMF (4.0 mL) - prepared in Step 1 to a reaction flask N3, N4 - bis (4-methylbenzyl) -1 H Anhydrous Cs ₂ CO ₃ (228 mg, 0.70 mmol) was added and stirred for 5 min. 2,4,5-trichloropyrimidine (102 mg, 0.55 mmol) was added to the reaction mixture, and the mixture was stirred at 35 占 폚 for 90 hours. The reaction was monitored via LC-MS. When the reaction was complete, EtOAc and saturated NaHCO ₃ Layer separation was carried out using a solution. The aqueous layer was extracted three times with EtOAc. The collected organic layer was dried by washing with brine and Na ₂ SO _4, filter, and solvent was removed under vacuum. The crude product was purified by column chromatography using hexane / ethyl acetate (5: 1) and silica gel to give the title compound as a colorless solid (109 mg, 78%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.64 (s, 1H), 8.49-8.40 (m, 2H), 8.27 (s, 2H), 7.25-7.23 (m, 4 H), 4.55 (d, J = 8.5 Hz, 4 H), 2.33 (s, 6 H); ¹³ C NMR (75 MHz, CDCl ₃ ), 163.6, 162.2, 158.5, 152.9, 137.1, 135.1, 129.4, 127.8, 125.4, 121.8, 118.5, 43.6, 21.3;

LC-MS (EI) for C ₂₆ H ₂₃ Cl ₂ N ₅ O ₂ (M + H & lt ^; + & gt ^; ): m / z = 508.19 Exact Mass: 507.1229.

Step 3: 1- (5- Chloro -2 - ((2,3,4- Trimethoxyphenyl ) Amino) pyrimidin-4-yl) - N3, N4 - bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Produce

Prepared in Step 2 to a reaction flask 1- (2,5-dichloro-pyrimidin-4-yl) - N3, N4 - bis (4-methylbenzyl) -1 H - peorol-3,4-carboxamide ( 60 mg, 0.12 mmol) and p -toluenesulfonic acid monohydrate (18 mg, 0.09 mmol) dissolved in 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 2,3,4-trimethoxy aniline (33 mg, 0.18 mmol) and heated to 80 [deg.] C for 24 hours. The reaction was monitored via LC-MS. After the reaction was completed, saturated NaHCO ₃ The solution was added to terminate the reaction. After removal of the organic solvents in vacuo, a saturated NaHCO ₃ Solution. The aqueous layer was extracted three times with EtOAc. After the organic layer was collected, washed with brine, dried with Na ₂ SO _4, filter, and concentrated in vacuo. The crude product was purified by column chromatography using hexane / ethyl acetate (5: 1) and silica gel to give the title compound as a colorless solid (2.50 g, 90%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.42 (s, 1 H), 8.35-8.40 (br, 2 H), 8.20 (s, 2 H), 7.91 (d, J = 9.0 Hz, 1 H), 7.63 (br, 1 H), 7.24-7.25 (m, 4 H), 7.12-7.15 (m, 4 H), 6.65 (d, J = 9.1 Hz, 1 H), 4.57 ( d, J = 5.6 Hz, 4 H), 3.95 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 2.33 (s, 6 H) ;

LC-MS (EI) for C ₃₅ H ₃₅ ClN ₆ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 655.30, Exact Mass: 654.2357.

< Example 8 > 1- (5- Chloro -2 - ((3,4,5- Trimethoxyphenyl ) Amino) pyrimidin-4-yl) - N3, N4 - bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Produce

The target compound was obtained by carrying out the same processes as in the above Example 7 except that 3,4,5-trimethoxybenzeneamine was used instead of 2,3,4-trimethoxy aniline (205 mg, 72%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.45 (s, 1 H), 8.37-8.44 (br, 2 H), 8.22 (s, 2 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.62 (br, 1 H), 7.23-7.26 (m, 4 H), 7.11-7.16 (m, 4 H), 6.66 (d, J = 9.5 Hz, 1 H), 4.56 ( d, J = 6.5 Hz, 4 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 2.35 (s, 6 H) ;

LC-MS (EI) for C ₃₅ H ₃₅ ClN ₆ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 655.27, Exact Mass: 654.2357.

< Example 9> tert -Butyl 6 - ((4- (3,4- Bis ((4- Methylbenzyl ) Carbamoyl )-One H - Perl -1-yl) -5- Chloropyrimidine Yl) amino) -7- Methoxy -3,4- Dihydroisoquinoline -2 (1 H ) -Carboxylate

Except that tert-butyl 6-amino-7-methoxy-3,4-dihydroisoquinolin-2 (1H) -carboxylate was used instead of 2,3,4-trimethoxy aniline , The procedure of Example 7 was repeated to obtain the title compound (18 mg, 32%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.42 (s, 1H), 8.350-8.38 (br, 2H), 8.23 H), 7.24-7.27 (m, 4 H), 7.13-7.15 (m, 4 H), 6.60 (s, 1 H), 4.57 (d, J = 5.9 Hz, 4 H), 3.88 (s, 3 H ), 3.59-3.63 (m, 4H), 2.75 (t, J = 5.5 Hz, 2H), 2.33 (s, 6H), 1.49 (s, 9H);

LC-MS (EI) for C ₄₁ H ₄₄ ClN ₇ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 750.15, Exact Mass: 749.3092.

< Example 10> 1- (5- Chloro -2 - ((7- Methoxy -1,2,3,4- Tetrahydroisoquinoline Yl) amino) pyrimidin-4-yl) - N3 , N4 - Bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Manufacture of de

A tert prepared in Example 3-butyl 4- (4 - ((4- (3,4-bis (propyl carbamoyl) -1 H-peorol-yl) -5-chloro-pyrimidin-2-yl ) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-instead of using the carboxy-rate, a tert prepared in example 9-butyl-6 - ((4- (3,4-bis ((4-methylbenzyl) carbamoyl) -1 H - peorol-yl) -5-chloro-pyrimidin-2-yl) amino) -7-methoxy-3,4-dihydroisoquinoline-2 ( 1 H ) -carboxylate, the target compound was obtained in the form of a trifluoroacetic acid salt (TFA salt) (6.1 mg, 87%) in the same manner as in Example 4, .

LC-MS (EI) for C ₃₆ H ₃₆ ClN ₇ O ₃ (M + H & lt ^; + & gt ^; ): m / z = 650.15, Exact Mass: 650.2568.

< Example 11> tert -Butyl 4- (4 - ((4- (3,4-bis ((4-methylbenzyl) carbamoyl) -1 H Yl) -5-chloropyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidine-1-carboxylate

Except that tert-butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate was used instead of 2,3,4-trimethoxy aniline , The procedure of Example 7 was repeated to obtain the desired compound (37 mg, 49%).

¹ H NMR (300 MHz, CDCl ₃ )? 8.44 (s, 1H), 8.33 (br, 1H), 8.31 , 7.71 (s, 1H), 7.24-7.25 (m, 4H), 7.12-7.15 (m, 2H), 6.71 3H), 1.64-1.71 (m, 8 H), 2.34 (s, 6H ) , 1.49 (s, 9 H), 1.25 (m, 6 H);

LC-MS (EI) for C ₄₆ H ₅₄ ClN ₇ O ₅ (M + H & lt ^; + & gt ^; ): m / z = 820.35, Exact Mass: 819.3875.

< Example 12> 1- (5- Chloro -2 - ((2- Isopropoxy -5- methyl -4- (piperidin-4-yl) Phenyl ) Amino) pyrimidin-4-yl) - N3 , N4 - Bis (4- Methylbenzyl )-One H - Perl -3,4- Dicarboxyamide Manufacturing

A tert prepared in Example 3-butyl 4- (4 - ((4- (3,4-bis (propyl carbamoyl) -1 H-peorol-yl) -5-chloro-pyrimidin-2-yl ) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-instead of using the carboxy-rate, a tert prepared in example 11, tert-butyl 4- (4 - ((4- (3, 4-bis ((4-methylbenzyl) carbamoyl) -1 H-peorol-yl) -5-chloro-pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidine- (7.2 mg, 78%) was obtained in the form of a 2-trifluoroacetic acid salt (TFA salt) by carrying out the same processes as in the above Example 4, except that 1-carboxy-1-carboxylate was used.

The chemical structures of the compounds prepared in Examples 1-12 are summarized in Table 1 below.

Example Chemical structural formula Example Chemical structural formula One

7

2

8

3

9

4

10

5

11

6

12

< Experimental Example 1> Inverse formation Lymphoma Kinase ( ALK ) Inhibitory activity evaluation 1

In order to measure the inhibitory activity of the 4- (1-pero-3,4-dicarboxylic amide) pyrimidine derivative represented by the formula (1) according to the present invention in the enzyme-inhibiting activity of Anaplastic Lymphoma Kinase Was performed.

Specifically, in order to measure the inhibitory activity against the inverse lymphoma kinase (ALK), the compound prepared in Example 1-12 was added to a Grayer 96 well round bottom plate at a concentration of 10 μM, and inverse lymphoma kinase (ALK) Enzyme (1 占 퐇) and biotin-adhered peptide substrate (2 占 퐇) were mixed for 15 minutes and cultured. ATP solution (5 ㎕) was added thereto and the kinase reaction was carried out at room temperature for 30 minutes. An anti-phosphotyrosine antibody (5 μl) with streptavidin-conjugated XL (XL 665) (5 μl) and europium (Eu ³ ⁺ ) dissolved in ethylenediaminetetraacetic acid solution was added to the reaction solution The reaction was stopped and incubated for 1 hour and then analyzed using homogeneous time-resolved fluorescence (HTRF, Cisbio). And read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument. The results are shown in Table 2 below.

Example ALK
wt. % inh @
10 μM One 8.1 2 29 3 0 4 29 5 14 6 32 7 0 8 74 9 4.4 10 17 11 10 12 47

As shown in Table 2 above, the compounds prepared in Examples 2, 4, 6, 8 and 12 according to the present invention effectively reduce (at 10 μM) reverse priming lymphoma kinase (ALK) enzyme activity . In particular, the compound prepared in Example 8 showed a 74% inhibition of the reverse priming lymphoma kinase (ALK) enzyme activity, thus confirming that it has an excellent inhibitory activity.

Therefore, the 4- (1-perl-3,4-dicarapiamido) pyrimidine derivative represented by the formula (1) according to the present invention is excellent in the effect of inhibiting the inverse lymphoma kinase (ALK) Can be effectively used as a pharmaceutical composition for the prophylaxis or treatment of cancers such as neuroblastoma, inflammatory myelofibroblastoma tumor, rhabdomyosarcoma sarcoma, myofiber oblastoma, breast cancer, gastric cancer, lung cancer and melanoma.

< Experimental Example 2> Inverse formation Lymphoma Kinase ( ALK ) Inhibitory activity evaluation 2

In order to measure the inhibitory activity of an anaplastic lymphoma kinase (ALK) inhibitor of the 4- (1-pero-3,4-dicarapiamide) pyrimidine derivative represented by the formula (1) Was performed.

Specifically, 4,000 non-small-cell lung cancer cells, H3122, were dispensed into each well of a 96-well plate with 100 μl of DMEM (Dulbecco's Modified Eagle's Medium) medium. After one day, each compound was added to each well containing cells at 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.0016 μM, and 0.00032 μM. DMSO (dimethyl sulfoxide) was added to the compound-free well by the same amount as the compound. After 3 days, the cells were fixed by adding 10% TCA (trichloroacetic acid), and the wells were washed three times in flowing water. The SRB solution (1 × Sulforhodamine B) was added to stain live cells, and the amount of living cells was calculated by measuring the absorbance. The IC ₅₀ of the test compound subjected to the above experiments was implemented using prism (version 5.01, GraphPad) software. The IC ₅₀ of the compound, which reduces the cellular activity of H3122 CP, a non-small cell lung cancer cell containing the inverse lymphoma kinase (ALK) enzyme, to 50% is shown in Table 3 below.

Example H3122 CP
IC ₅₀ ([mu] M) One > 10 2 3.2 3 > 10 4 4.4 5 > 10 6 5.2 7 > 10 8 > 10 9 > 10 10 > 10 11 2.3 12 > 10

As shown in Table 3 above, the compounds prepared in Examples 2, 4, 6, and 11 according to the present invention exhibited a low level of (<10 μM) non-small cell lung cancer cells containing an inverted lymphoma kinase (ALK) (IC ₅₀ ) of H3122 CP. In particular, the compound prepared in Example 11 was found to reduce the cellular activity of H3122 CP to 50% at a very low concentration of 2.3 μM.

< Formulation example 1> Preparation of pharmaceutical preparations

1-1. Manufacture of Powder

2 g of the compound of formula 1 according to the invention

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

1-2. Manufacture of tablets

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

1-3. Preparation of capsules

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

1-4. Manufacture of granules

The compound of formula 1 according to the present invention, 150 mg

Soybean extract 50 mg

Glucose 200 mg

Starch 600 mg

After mixing the above components, 100 μl of 30% ethanol was added and the mixture was dried at 60 ° C to form granules, which were filled in a capsule.

Claims

Wherein the compound is any one selected from the group consisting of the following compounds, its optical isomers, or a pharmaceutically acceptable salt thereof:
(2) Synthesis of 1- (5-chloro-2 - ((3,4,5-trimethoxyphenyl) amino) pyrimidin-4-yl) -N3, N4- Dicarboxamide;
(4) Synthesis of 1- (5-chloro-2 - ((2-isopropoxy-5-methyl-4- (piperidin- - dipropyl-lH-pyrrole-3,4-dicarboxamide;
(6) Synthesis of 1- (5-chloro-2 - ((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin- Dipropyl-lH-pyrrole-3,4-dicarboxamide; And
(11) Synthesis of tert -butyl 4- (4 - ((4- (3,4-bis ((4-methylbenzyl) carbamoyl) -1 H- pyrrol- 1 -yl) -5-chloropyrimidin- ) Amino) -5-methoxy-2-methylphenyl) piperidine-1-carboxylate.

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As shown in Scheme 1 below,
Reacting a compound represented by formula (2) with a compound represented by formula (3) to prepare a compound represented by formula (4) (step 1);
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And
A step of reacting the compound represented by the formula (6) and the compound represented by the formula (7) prepared in the step 2 to prepare a compound represented by the formula (1) (step 3) Lt; RTI ID = 0.0 > of: < / RTI &
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ , R ² , X, Z ¹ , Z ² , Z ³ and Z ⁴ are as defined in the name of the compound of claim 1).

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A pharmaceutical composition for the prophylaxis or treatment of non-small cell lung cancer, which comprises as an active ingredient a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group of compounds of claim 1.

9. The method of claim 8,
Wherein said pharmaceutical composition inhibits the activity of anaplastic lymphoma kinase (ALK) to inhibit the expression and growth of non-small cell lung cancer cells.

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