KR101154539B1 - Novel aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for the prevention or treatment of abnormal cell growth diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing and treating abnormal cell growth diseases containing the same as an active ingredient. Prevention of abnormal cell growth disorders by showing excellent inhibitory effects against various protein kinases causing abnormal cell growth disorders such as ABL1, B-RAF, c-Kit, FMS, LCK, LYN, P38α and C-RAF And useful for treatment.

Description

Novel Aminopyrazole arylamide derivatives or acceptable acceptable salts according to novel aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and methods for preparing the same and preparations for the prevention and treatment of abnormal cell growth diseases method particular and pharmaceutical composition for the prevention or treatment of abnormal cell growth diseases containing the same as an active ingredient}

The present invention relates to a novel aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating abnormal cell growth disease containing the same as an active ingredient.

Among the cell signaling networks involved in cell growth, the "Erk pathway" is responsible for determining the fate of cells, such as growth, differentiation, aging, or necrosis, from extracellular stimuli in almost all types of human cells. it is known that (Wellbrock et al., Nat. Rev. Mol. Cell Biol . 11: 875-885 (2004)). Ras GTPase, an important component of this signaling system, activates Raf protein kinase by receiving a signal from a cell membrane receptor (eg EGFR), and Raf protein kinase activates by phosphorylating Mek protein kinase, and the Mek protein kinase is activated by Erk. Activates protein kinase A series of activation processes determine the fate of various cells by the transcriptional factors in the nucleus or cytoplasm undergoing phosphorylation of the activated Erk protein kinase. The biological importance of Raf in the "Erk path" began to attract attention as the mutation turned out to be high in human tumor cells (Monia et al., Nature) . Medicine 2: 668-675 (1996); Davies et al., Nature 417: 949-954 (2002)), of the three genes expressing Raf protein (a-, b-, C-RAF), abnormally activated mutant B-RAF is 66% of melanoma. It was found in the above and in other cancers. B-RAF mutants, such as V600E, whose point mutations are important for Akt-mediated B-RAF phosphorylation, are also involved in the activation of the MAP kinase pathway commonly found in non small cell lung carcinomas (NSCLCs). Disturbance of induced B-RAF suggests that disruption is an important point in the transition to malignant tumor cells. More than 90% of B-RAF mutations in melanoma are associated with codon 600, but more than 89% of B-RAF mutations have been found in other sites in NSCLC, which may predict different responses when lung cancer and melanoma are treated with Raf inhibitors. do.

Recent studies have shown that the inhibition of mutant B-RAF with siRNA in human melanoma cells inhibited both Mek and Erk, which stopped tumor cell growth and ultimately promoted cell death (Sharma, et al. Cancer Res . 65: 2412-2421 (2005); Wellbrock et al., Cancer Res . 64: 2338-2342 (2004). In addition, short-hairpin RNA xenograft model experiments targeting B-RAF mutations have shown that inhibition of B-RAF can induce and reversibly regulate tumor inhibition (Hoeflich et al., Cancer Res . 66: 999-1006 (2006). Taken together, it can be seen that the signal transduction system in bv cells is deeply involved in tumor development, and B-RAF is an important target of anticancer drugs.

Tumor cells often rely on one or two major signaling systems for their survival (Jonkers et al., Cancer Cell . 6: 535-538 (2004)), the Erk pathway not only has great appeal as a target for anticancer drugs, but also consists of protein kinases that are advantageous for drug design as small molecule inhibitors. Mek protein kinase inhibitors show bright promise in clinical trials, but Raf signaling, which does not depend on Mek, also contributes to tumorigenesis or spread (Wellbrock et al., Nat . Rev. Mol . Cell) . Biol . 11: 875-885 (2004)) The development of inhibitors targeting Raf is of sufficient significance as a therapeutic agent for tumors caused by mutations in the Ras or Raf genes.

Accordingly, the inventors of the present invention, while conducting research to develop protein kinase inhibitor, aminopyrazole arylamide derivative compounds having excellent inhibitory activity against protein kinase cause various protein kinase such as ABL1. , V600E, B-RAF, C-RAF, FMS, JNK, Lck, Lyn, p38α and so on, showing excellent inhibitory effect, it can be useful in the prevention and treatment of abnormal cell growth diseases, completed the present invention It was.

It is an object of the present invention to provide novel aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention to provide a novel aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating abnormal cell growth disease, which contains a novel aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a novel aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same and a pharmaceutical composition for preventing and treating abnormal cell growth diseases containing the same as an active ingredient. do.

The novel aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity against protein kinase and are therefore characterized by various protein kinases, such as ABL1, B-RAF, which cause abnormal cell growth diseases. Since it shows an excellent inhibitory effect on c-Kit, FMS, LCK, LYN, P38α and C-RAF, it can be usefully used for the prevention and treatment of abnormal cell growth diseases.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention provides an aminopyrazole arylamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula 1,

R ¹ is hydrogen; C ₁ -C ₄ straight or branched alkyl; C ₅ -C ₁₂ aryl C ₁ -C ₄ alkyl, C ₅ -C ₁₂ heteroaryl C ₁ -C ₄ alkyl, C ₅ unsubstituted or substituted with one or more C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy ˜C ₁₂ cycloalkyl or C ₅ ˜C ₁₂ heterocycloalkyl,

R ² Is hydrogen; Or C ₁ -C ₄ straight or branched alkyl,

L is -NRC (O)-; -NRC (O) NR-; -NRC (S) NR-; -C (O) NR-; -C (O) NRC (O) R-; Or -NRS (O) _0-2 - and, wherein R is hydrogen, a C ₁ ~ C ₄ straight or branched chain alkyl, or straight or branched chain alkyl amine of the C ₁ ~ C _4,

R ³ is X or XY, wherein X and Y are each independently unsubstituted or 1 or more halogen, C ₁ ~ C ₄ linear or branched alkyl, C ₁ ~ alkoxy, trifluoromethyl, and morpholino furnace of C ₄ C ₅ to C ₁₂ aryl, C ₅ to C ₁₂ heteroaryl, C ₅ to C ₁₂ aryl C ₁ to C ₄ alkyl, C ₅ to C ₁₂ heteroaryl C ₁ to C ₄ alkyl substituted with a substituent selected from the group consisting of: , C ₅ -C ₁₂ cycloalkyl or C ₅ -C ₁₂ heterocycloalkyl.)

Preferably

R ¹ is hydrogen, methyl, ethyl, phenyl, phenylmethyl, phenylethyl or 3-methoxyphenylmethyl,

R ² is hydrogen, methyl or ethyl,

L is -NHC (O)-, -NHC (O) NH- or -NHC (S) NH-,

R ³ is X or XY, wherein X and Y are each independently unsubstituted or substituted with one or more of fluoro, chloro, methyl, ethyl, trifluoromethyl, morpholino, phenyl, thiazolyl, isoxazolyl, pyri Dinyne, pyrimidinyl, piperazinyl, furanyl, benzofuranyl, benzothiophenyl or piperazinylmethyl.

More preferably,

R ¹ is phenylmethyl or 3-methoxyphenylmethyl,

R ² is methyl,

L is -NHC (O)-, -NHC (O) NH- or -NHC (S) NH-,

R ³ is (3,4-di-methoxyphenyl) methyl, 2,4-dimethylphenyl, 2,3-dichlorophenyl, 3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoro Methyl) phenyl, 3- (4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) phenyl, 4-((4-ethylpiperazin-1-yl) methyl) -3- ( Trifluoromethyl) phenyl, 3- (3-morpholino-5- (trifluoromethyl) phenyl, 4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl , 3- (4-methyl-1H-imitazol-1-yl) -5- (trifluoromethyl) phenyl, 4- (1-methylpiperidin-4-yloxy) -3- (trifluoro Methyl) phenyl, 5-bromothiopin, naphthyl, benzothiopinyl, furanyl, isoxazolyl, pyrazolyl, pyridazinyl, thiazolyl, pyrazinyl, thienyl, pyrimidinyl, imidazolyl, pyrroyl , Dihydropyrroyl, oxazolyl, triazolyl, thiadiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, benzothiazolyl, benzothiazophenyl, benzodioxolyl, amino Pyrazole arylamide, indolyl, indilyl, dihydroindilyl or dihydrobenzofuranyl.

Specific compounds of the aminopyrazole arylamide derivative represented by Formula 1 of the present invention are as follows.

1) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-chloro-3- (trifluoromethyl) phenyl) urea Fig. 2--2-benzamide;

2) N- (5-amino-1-benzyl-1H-pyrazol-4-yl) -5- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -2-methyl Benzamide;

3) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5 (3- (2,4,5-trichlorophenyl) ureido Benzamide;

4) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5 (3- (2,3,6-trichlorophenyl) ureido Benzamide;

5) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-chlorophenyl) thioureido) -2-methylbenz Amides;

6) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-trifluoromethyl) phenylureido) Benzamide;

7) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3-cyclohexylureido) benzamide;

8) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (3-chlorophenyl) ureido) -2-methylbenzamide;

9) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (2,4-bis (trifluoromethyl) phenyl) ureido ) -2-methylbenzamide;

10) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (3- (3-methylisoxazole-5 -Yl) ureido) benzamide;

11) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-((4-ethylpiperazin-1-yl) methyl -3- (trifluoromethyl) phenyl) ureido) -2-methylbenzamide;

12) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl4- (3- (3- (trifluoromethyl) phenyl) ureido Benzamide;

13) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3-cyclohexylureido) -2-methylbenzamide;

14) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (4-chloro-3- (trifluoromethyl) phenyl) urea Fig. 2--2-benzamide;

15) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl4- (3- (2-morpholino-5- (trifluoro Methyl) phenyl) ureido) benzamide;

16) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (4-trifluoromethyl) pyrimidine-2 -Yl) ureido) benzamide;

17) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (3,4-dichlorophenyl) ureido) -2-methyl Benzamide;

18) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (3-chlorophenyl) ureido) -2-methylbenzamide;

19) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (4-chlorophenyl) thioureido) -2-methylbenz Amides;

20) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (3- (4-methyl-1H-imidazole -1-yl) -5- (trifluoromethyl) phenyl) ureido) benzamide;

21) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (3-morpholino-5- (trifluoro Rhomethyl) phenyl) ureido) benzamide;

22) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (trifluoromethyl) benzamido) benzamide ;

23) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-methylpiperazin-1-yl)- 5- (trifluoromethyl) benzamido) benzamide;

24) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-methyl-1H-imidazole-1- Yl) -5- (trifluoromethyl) benzamido) benzamide;

25) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -1-phenyl-5- (trifluoromethyl ) -1H-pyrazole-4-carboxamide;

26) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -5- (2-chloro-5- (tri Fluoromethyl) phenyl) furan-2-carboxamide;

27) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -5- (4-chlorophenyl) isoxazole- 3-carboxamide;

28) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -1- (4-methoxyphenyl) -5 -(Trifluoromethyl) -1H-pyrazole-4-carboxamide;

29) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -2- (pyridin-4-yl) thiazole -4-carboxamide;

30) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (4-nitro-3- (trifluoromethyl ) Benzamido) benzamide;

31) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -2-chloroisonicotinamide;

32) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5- (2-chloro-5- (tri Fluoromethyl) phenyl) furan-2-carboxamide;

33) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -1-phenyl-5- (trifluoromethyl ) -1H-pyrazole-4-carboxamide;

34) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5-methylisoxazole-3-carbox Amides;

35) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -2- (pyridin-4-yl) thiazole -4-carboxamide;

36) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) pyrazine-2-carboxamide;

37) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) benzo [b] thiophene-2-carboxamide ;

38) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) benzofuran-2-carboxamide;

39) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -2-chloroisonicotinamide; And

40) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5- (4-chlorophenyl) isoxazole- 3-carboxamide.

The aminopyrazole arylamide derivative represented by Chemical Formula 1 of the present invention may 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. . The expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient, and any organic or inorganic addition of the compound of formula 1 in which the side effects caused by the salt do not compromise the beneficial efficacy of the compound of formula 1 Salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, succinic acid, tartaric acid, galacturonic acid, embic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, disylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, tosylate, trifluoroacete , Aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Heavy hydrochloride or trifluoroacetate are preferred.

In addition, the aminopyrazole arylamide derivative represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

The present invention also provides a method for preparing an aminopyrazole arylamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

The compound of Formula 1 according to the present invention may be prepared by the method as shown in the following schemes 1-2.

Hereinafter, the above production method will be described using the reaction scheme.

Manufacturing Method 1

As represented by the following Scheme 1, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

Preparing a compound of Chemical Formula 4 by cyclizing and nitrosing the compound of Chemical Formula 2 and the compound of Chemical Formula 3 as starting materials (Step 1);

Preparing a compound of formula 5 by reducing the compound of formula 4 prepared in step 1 (step 2);

Preparing a compound of formula 7 by condensing the compound of formula 5 prepared in step 2 with a carboxylic acid compound of formula 6 (step 3);

Preparing a compound of formula 8 by reducing the compound of formula 7 prepared in step 3 (step 4); And

The compound of formula 8 prepared in step 4 may be prepared by a method comprising the step of coupling the amine compound or isocyanate compound of formula 9 with the compound of formula 1a (step 5).

Scheme 1

(In Scheme 1, R ¹ To R ³ is as defined in Formula 1, wherein the compound of Formula 1a is included in the compound of Formula 1.)

Specifically, in step 1, it can be carried out using a nitrosation reaction that is commonly used, for example, the compound of Formula 2 and the amine compound of Formula ₃ are added to ethanol, NaNO ₃ is added as a base, and then 50 ° C. The cyclization and nitrosification reaction at can be carried out to obtain the compound of formula 4.

Next, in step 2, it can be carried out using a reduction reaction that is commonly used, for example, by putting the compound of formula 4 in ethanol and reducing the reaction at 80 ℃ using tin chloride hydrate, -NO substituent is -NH A compound of formula 5 reduced to ₂ can be obtained.

Next, in step 3, the compound of Formula 5 and the compound of Formula 6, HPBt, EDCI and triethylamine (TEA) are added under a dimethylformamide (DMF) solvent to reflux and stir at 80 ° C. to obtain a compound of Formula 7. Can be.

Next, in Step 4, the compound of Formula 7 may be reduced in the same manner as in Step 2 to obtain a compound of Formula 8 in which -NO substituent is reduced to -NH ₂ .

Next, in Step 5, the compound of Formula 8 and the R ³ -NCO compound of Formula 9 may be added to tetrahydrofuran (THF) as a reaction solvent, and a coupling reaction may be performed at room temperature to obtain a compound of Formula 1a.

Manufacturing Method 2

As represented by Scheme 2 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

The compound of Formula 8 may be prepared by a method for preparing the compound of Formula 1b by coupling reaction with a carboxylic acid compound of Formula 10 (step 5 ′).

Scheme 2

(In Scheme 2, R ¹ To R ³ is as defined in Formula 1, wherein the compound of Formula 1b is included in the compound of Formula 1.)

Specifically, in step 5 ', the compound of Formula 8, triethylamine, R ³ -COOH, EDCI, and HOBt coupling agent are added to dimethylformamide (DMF) as a reaction solvent, and the coupling reaction is performed at room temperature. The compound of can be obtained.

The present invention also provides a pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the aminopyrazole arylamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

At this time, examples of the abnormal cell growth diseases include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer , Kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia and hematologic cancers such as multiple myeloma and myelodysplastic syndrome, lymphomas such as Hodgkin's disease and non-Hodgkin's lymphoma, psoriasis and fibroadenoma.

The Raf protein has been recognized as an important source and promoter of malignant tumors by the discovery that mutant species of B-RAF have a high frequency in human tumors (Davies, H. et al. Nature 417: 949-954 (2002)).

In the case of B-RAF, approximately 7% of the mutant species are found in relation to tumors, respectively, of melanoma (50-70%), ovarian cancer (35%), thyroid cancer (50%) and rectal cancer (10%). It is known to show frequency (Tuveson, et al., Cancer Cell . 4: 95-98 (2003); Xing, Endocrine-Related Cancer : 12: 245-262 (2005)). In particular, the mutant V600E B-RAF has a 500-fold increase in its phosphorylation capacity, which in turn results in overactivation of MEK and ERK, leading to abnormal growth of tumor cells.

Recent studies have shown that the inhibition of mutant B-RAF with siRNA in human melanoma cells results in inhibition of both MEK and ERK, leading to the inhibition of tumor cell growth and ultimately to cell death (Sharma). , et al., Cancer Res. 65: 2412-2421 (2005); Wellbrock et a1., Cancer Res . 64: 2338-2342 (2004). In addition, short-hairpin RNA xenograft model experiments targeting B-RAF mutations have shown that inhibition of B-RAF can induce and reversibly regulate tumor inhibition (Hoeflich et al., Cancer Res . 66: 999-1006 (2006). Taken together, B-RAF confirms that intracellular signal transduction system is deeply involved in tumor development and is an important target for anticancer drugs.

The aminopyrazole arylamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof showed an excellent inhibitory effect on B-RAF, ALK, C-RAF, EGFR, Flt3, Fms, Tie2, TrkB and the like.

Specifically, the compound of the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof showed the result that the IC ₅₀ has a B-RAF kinase inhibitory activity of 10 μM or less in the B-RAF kinase inhibitory activity experiment (Table 1). Reference).

In addition, the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof is ABL1, B-RAF, c-Kit, FMS, LCK, LYN, P38α and C-RAF in experiments of inhibitory activity against various kinase The results with inhibitory activity were shown (see Table 2).

Therefore, the pharmaceutical composition containing the aminopyrazole arylamide derivative or the pharmaceutical salt thereof as an active ingredient is ABL1, V600E, B-RAF, C-RAF, FMS, JNK, Lck, Lyn, p38α, etc. It can be usefully used to treat the various cancers described above derived from expression.

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. 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, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized 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 the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

Example  1: N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- (4- Chloro -3- (t Rifluorome Teal) Phenyl ) Eureido )-2- Methylbenzamide  Produce

Step 1: 1- (4-methoxybenzyl) -4- Nitroso -1H- Pyrazole -5- Amine  Produce

After cooling 36% HCl solution (3.4 ml, 39.96 mmol) to -15 ° C., MeOH (2.8) in 3-methoxyacrylonitrile (738 mg, 8.88 mmol), 30% NaNO ₂ aqueous solution (1.84 g, 8.88 mmol) ml) The mixed solution was slowly added dropwise at -15 ~ -5 ° C, and stirred for 1 hour at the same temperature. After flushing with nitrogen for 5 minutes, p-methoxy (PMB) hydrazine hydrochloride (2 g, 8.88 mmol) and a mixture of water (1.5 ml) and MeOH (1.5 ml) were added and stirred at 50 ° C. for 1 hour. It was. After cooling to 10 ℃ water (1 ml) was added and neutralized with NH ₄ OH. The reaction solution was cooled to 5 ° C. and stirred for 30 minutes. The resulting red solid was filtered and washed with water and MeOH mixture (3/1) to obtain the target compound (950 mg, 46%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.57 (1H, s), 7.13 (2H, d, J = 16.75 MHz), 6.90 (2H, d, J = 6.71 MHz), 6.19 (2H, br, s , J = 23.54 MHz), 5.06 (2H, s), 3.80 (3H, s).

Step 2: 1- (4-methoxybenzyl) -1 H- Pyrazole -4,5- Diamine  Produce

32% of a solution of 1- (4-methoxybenzyl) -4-nitroso-1H-pyrazol-5-amine (100 mg, 0.49 mmol) prepared in step 1 in EtOH (1 ml) After acidification with HCl (0.2 ml, 2.45 mmol), a solution of EtOH (0.25 ml) of SnCl ₂ -2H ₂ O (243 mg) was added dropwise for 15 minutes with stirring at 60-70 ° C. After 1 hour it was cooled and poured on ice, and then adjusted to pH 7-8 using 5% NaHCO ₃ solution. Then extracted with EtOAc (3 times re-extracted with CHCl ₃ / MeOH), the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to give the target compound (90 mg, 97%).

¹ H-NMR (400 MHz, DMSO) δ 7.16 (1H, s), 7.12 (2H, d, J = 8.55 MHz), 6.85 (2H, d, J = 8.64 MHz), 5.11 (2H, s), 3.76 (3H, s)

Step 3: N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- Nitrobenzamide  Produce

1- (4-methoxybenzyl) -1H-pyrazole-4,5-diamine (348 mg, 1.59 mmol) and 2-methyl-4-nitrobenzoic acid (289 mg, 1.59 mmol) prepared in step 2 , HOBt (323 mg, 2.39 mmol), EDCI (397 mg, 2.07 mmol) and triethylamine (0.26 mL, 1.91 mmol) were dissolved in dimethylformamide (5 mL), stirred and heated to 80 ° C. for 8 hours. Was stirred. The reaction solution was cooled, diluted with ethyl acetate dropwise, and then washed with saturated sodium bicarbonate solution. The organic solvent layer was separated and dried over Na ₂ SO ₄ , volatiles were removed by distillation under reduced pressure to obtain a mixture in the form of a solid, and then purified by column chromatography (silica gel, hexane / ethyl acetate = 1/1) to obtain a white solid. Obtained (520 mg, 85.7%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (1H, s), 8.16 (1H, s), 7.45 (1H, d, J = 7.43 Hz), 7.346 (1H, s), 7.33 (1H , d, J = 9.748 Hz), 7.31 (2H, d, J = 7.11 Hz), 6.88 (2H, d, J = 17.96 Hz), 4.78 (2H, s), 3.66 (3H, s), 2.26 (3H , s)

Step 4: 5-amino-N- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4-yl) -2- Methylbenzamide  Produce

N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5-nitrobenzamide (1.36 mmol) prepared in step 3 was added EtOH ( a solution obtained by dissolving _{SnCl 2? 2H 2 O (0.95} mmol) in EtOH (0.25 ml) was dissolved the solution was added dropwise over 15 minutes to 5 ml). Stir for 30 minutes until a clear solution, then for 1 hour at room temperature. After the reaction was completed, the mixture was adjusted to pH 7-8 by dropwise addition of 5% NaHCO ₃ solution, extracted with EtOAc (3 times reextracted with CHCl ₃ / MeOH), and the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a mixture state. Was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (1H, s), 7.14 (1H, d, J = 2.5 Hz), 7.45 (1H, d, J = 7.432 Hz), 7.346 (1H, s ), 7.33 (1H, d, J = 9.748 Hz), 7.31 (2H, d, J = 7.11 Hz), 6.88 (2H, d, J = 17.96 Hz), 4.78 (2H, s), 3.66 (3H, s ), 2.26 (3H, s)

Step 5: N- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4-yl) -5- (3- (4- Chloro -3- (t Refluoromethyl ) Phenyl ) Eureido )-2- Methylbenzamide  Produce

5-amino-N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methylbenzamide (22 mg) and 4-chloro- obtained in step 4 above. 3- (trifluoromethyl) phenyl isocyanate (15 mg) was dissolved in tetrahydrofuran solvent and stirred at room temperature for 12 hours. After the reaction was completed, methylene chloride was added and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and filtered, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel) with methylene chloride and methanol to obtain a target compound (28 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (1H, s), 9.19 (1H, s), 8.89 (1H, s), 8.10 (1H, d, J = 2.38 Hz), 7.65-7.59 (3H, m), 7.54 (1H, d, J = 2.26 Hz), 7.44 (1H, s), 7.41 (1H, d, J = 2.132 Hz), 7.19 (2H, d, J = 8.492 Hz), 7.15 (2H, d, J = 8.67 Hz), 6.87 (2H, d, J = 8.67 Hz), 5.12 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s)

In the same manner as in Example 1, the compound of Examples 2 to 21 was obtained.

< Example  2> N- (5-amino-1-benzyl-1H- Pyrazole -4-yl) -5- (3- (4- Chloro -3- ( Trifluoromethyl ) Phenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (1H, s), 9.22 (1H, s), 8.93 (1H, s), 8.10 (1H, d, J = 2.31 Hz), 7.63-7.61 (2H, m), 7.55 (1H, d, J = 2.26 Hz), 7.47 (1H, s), 7.43 (1H, dd, J = 2.22 Hz, 9.8 Hz), 7.31 (2H, d, J = 7.74 Hz ), 7.26 (1H, d, J = 6.88 Hz), 7.20 (1H, s), 7.17 (2H, d, J = 6.8 Hz), 5.16 (2H, s), 5.12 (2H, s), 2.32 (3H , s)

<Example 3> N- (5- amino-1- (4-methoxybenzyl) -1H- pyrazol-4-yl) -2-methyl-5 (4- (2,4,5-bit Recliner Lophenyl ) ureido ) benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (1H, s), 9.55 (1H, s), 8.53 (1H, s), 7.90 (1H, s), 7.77 (1H, s), 7.68 -7.62 (3H, m), 7.54 (1H, s), 7.43 (1H, s), 7.35 (1H, d, J = 5.89 Hz), 7.21 (2H, d, J = 8.86 Hz), 7.15 (2H, d, J = 8.42 Hz), 7.10 (1H, s), 6.88 (2H, d, J = 8.7 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.44 ( 3H, s)

< Example  4> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5 (3- (2,6-da Dichloro Phenyl) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (1H, s), 9.55 (1H, s), 8.53 (1H, s), 7.77 (1H, s), 7.53 (2H, d, J = 5.69 Hz), 7.43 (1H, s), 7.35 (1H, d, J = 5.89 Hz), 7.22 (1H, s), 7.15 (2H, d, J = 8.42 Hz), 7.11 (1H, s), 6.88 (2H, d, J = 8.7 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.44 (3H, s)

< Example  5> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- (4- Chlorophenyl ) Sioyureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (1H, s), 10.04 (1H, s), 8.89 (1H, s), 8.10 (1H, d, J = 2.38 Hz), 7.54 (1H , d, J = 2.26 Hz), 7.44 (1H, s), 7.41 (1H, d, J = 2.132 Hz), 7.17 (2H, d, J = 9.21 Hz), 7.15 (2H, d, J = 8.67 Hz ), 6.87 (2H, d, J = 8.67 Hz), 6.44 (2H, d, J = 9.24 Hz), 5.12 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H , s)

< Example  6> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- (3- (4-trifluoromethyl) Phenylureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (1H, s), 9.14 (1H, s), 8.92 (1H, s), 8.01 (1H, s), 7.55 (2H, s), 7.52 (1H, s), 7.44 (1H, s) 7.30 (1H, d, J = 8.05 Hz), 7.18 (1H, d, J = 8.06 Hz), 7.15 (2H, d, J = 8.22 Hz), 6.88 ( 2H, d, J = 8.588 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.34 (3H, s)

< Example  7> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- Cyclonuclear oil raid ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (1H, s), 8.47 (1H, s), 7.39 (1H, s), 7.35 (1H, d, J = 2.6 Hz), 7.34 (1H , s), 7.29-7.27 (1H, m), 7.22 (1H, s), 7.14 (2H, d, J = 8.57 Hz), 6.87 (2H, d, J = 8.56 Hz), 5.10 (2H, s) , 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s), 1.81-1.64 (4 H, m), 1.28-1.14 (6 H, m)

< Example  8> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- (3- Chlorophenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (1H, s), 9.54 (1H, s), 8.45 (1H, s), 7.65-7.55 (2H, m), 7.39 (1H, m) , 7.35 (1H, d, J = 2.6 Hz), 7.34 (1H, s), 7.31 (1H, s), 7.29-7.27 (1H, m), 7.22 (1H, s), 7.14 (2H, d, J = 8.52 Hz), 6.87 (2H, d, J = 8.50 Hz), 5.10 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s)

< Example  9> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- (2,4-bis (t) Refluoromethyl ) Phenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (1H, s), 9.17 (1H, s), 8.89 (1H, s), 8.10 (1H, d, J = 2.38 Hz), 7.69-7.61 (4 H, m), 7.54 (1H, d, J = 2.26 Hz), 7.47 (1H, s), 7.43 (1H, d, J = 2.56 Hz), 7.31 (1H, d, J = 9.23 Hz), 7.15 (2H, d, J = 8.67 Hz), 6.87 (2H, d, J = 8.67 Hz), 5.12 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s )

< Example  10> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- (3- (3- (3-meth Till Soxazole-5-day) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (1H, s), 9.26 (1H, s), 7.65-7.56 (3H, m), 7.40 (1H, s) 7.22 (1H, d, J = 6.6 Hz), 7.16 (2H, d, J = 8.75 Hz), 6.89 (2H, d, J = 8.64 Hz), 6.61 (1H, s), 5.13 (2H, s), 5.07 (2H, s), 3.72 (3H, s), 2.35 (3H, d, J = 5.58 Hz), 2.34 (3H, s),

< Example  11> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -5- (3- (4-((4- Ethyl piperazine -1 day) methyl -3- ( Trifluoromethyl ) Phenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (1H, s), 9.26 (1H, s), 9.02 (1H, s), 7.65-7.56 (4 H, m), 7.40 (1H, dd , J = 2.33 Hz, 8.32 Hz) 7.22 (1H, d, J = 6.6 Hz), 7.16 (2H, d, J = 8.75 Hz), 6.89 (2H, d, J = 8.67 Hz), 5.13 (2H, s ), 5.08 (2H, s), 3.72 (3H, s), 3.16 (2H, s), 3.14 (3H, m), 2.93 (4 H, t, J = 12.4 Hz), 2.40 (4 H, t, J = 12.3 Hz), 2.34 (3H, s), 2.29 (3H, s), 1.18 (3H, t, J = 7.24 Hz)

< Example  12> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- Methyl4 -(3- (3- (t Refluoromethyl ) Phenyl ) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (1H, s), 7.55 (2H, m), 7.38 (1H, s), 7.21 (1H, d, J = 8.55 Hz), 7.14 (2H , d, J = 8.44 Hz), 6.89 (2H, s), 6.39 (2H, s), 5.37 (2H, s), 5.15 (2H, s), 5.05 (2H, s), 3.72 (3H, s) , 2.32 (3H, s)

< Example  13> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -4- (3- Cyclonuclear oil raid )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (1H, s), 8.47 (1H, s), 7.39 (1H, s), 7.35 (1H, d, J = 2.6 Hz), 7.34 (1H , s), 7.29-7.27 (1H, m), 7.22 (1H, s), 7.14 (2H, d, J = 8.57 Hz), 6.87 (2H, d, J = 8.56 Hz), 5.10 (2H, s) , 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s), 1.81-1.64 (4 H, m), 1.28-1.14 (6 H, m)

< Example  14> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -4- (3- (4- Chloro -3- (t Refluoro methyl) Phenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (1H, s), 7.40 (1H, m), 7.21 (1H, d, J = 8.688 Hz), 7.14 (2H, d, J = 8.44 Hz ), 6.89 (2H, s), 6.39 (2H, s), 5.37 (2H, s), 5.15 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.32 (3H, s)

< Example  15> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- Methyl4 -(3- (2-morpholino-5- ( Trifluoromethyl ) Phenyl ) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (1H, s), 9.43 (1H, s), 8.47 (1H, s), 8.35 (1H, s), 7.49-7.30 (6 H, m ), 7.15 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 5.15 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 3.88 (4 H, s), 2.86 (4 H, s), 2.41 (3H, s)

< Example  16> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -4- (3- (4-t Rifluorome Thi) pyrimidin-2-yl) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (1H, s), 9.11 (1H, s), 8.12 (1H, d, J = 4.56 Hz), 7.21 (1H, d, J = 8.12 Hz ), 7.14 (2H, d, J = 8.44 Hz), 6.89 (2H, d, J = 8.50 Hz), 6.39 (1H, d), 5.37 (2H, s), 5.15 (2H, s), 5.05 (2H , s), 3.72 (3H, s), 2.32 (3H, s)

< Example  17> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -4- (3- (3,4- Dichlorophenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (1H, s), 9.05 (1H, s), 8.93 (1H, s), 7.89 (1H, d, J = 2.51 Hz), 7.50 (2H , d, J = 5.7 Hz), 7.40 (2H, s), 7.35-7.31 (2H, m), 7.14 (2H, d, J = 8.62 Hz), 6.87 (2H, d, J = 8.62 Hz), 5.12 (2H, s), 5.04 (2H, s), 3.72 (3H, s), 2.36 (3H, s)

< Example  18> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -4- (3- (3- Chlorophenyl ) Eureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (1H, s), 9.45 (1H, s), 8.55 (1H, s), 7.77 (1H, d, J = 3.34 Hz), 7.48 (2H , d, J = 4.88 Hz), 7.31 (2H, m), 7.14 (2H, d, J = 8.62 Hz), 6.87 (2H, d, J = 8.62 Hz), 5.12 (2H, s), 5.04 (2H , s), 3.72 (3H, s), 2.36 (3H, s)

< Example  19> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -4- (3- (4- Chloro Phenyl) Sioyureido )-2- Methylbenzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (1H, s) 10.03 (1H, s), 8.92 (1H, s), 8.11 (1H, d, J = 2.22 Hz), 7.19 (1H, s), 7.14 (2H, d, J = 8.62 Hz), 6.87 (2H, d, J = 8.62 Hz), 6..74 (2H, d, J = 9.31 Hz), 5.12 (2H, s), 5.04 (2H, s), 3.72 (3H, s), 2.36 (3H, s)

< Example  20> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -4- (3- (3- (4-methyl-1H-) Imidazole -1-yl) -5- ( Trifluoromethyl ) Phenyl ) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (1H, s), 9.26 (1H, s), 9.12 (1H, s), 8.95 (1H, s), 8.87 (1H, s), 7.40 (1H, s), 7.35 (2H, s), 7.32 (1H, s), 7.20 (1H, m), 7.16-7.13 (2H, m), 6.88-6.84 (2H, m), 6.39 (1H, s ), 5.42 (1H, s), 5.12 (1H, s), 5.05 (2H, t, J = 7.88 Hz), 3.74 (4H, t, J = 4.78 Hz) 3.72 (3H, d, J = 1.62 Hz ), 3.16 (4 H, t, J = 4.78 Hz), 2.36 (3H, s)

< Example  21> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -4- (3- (3-Mo Lepoli No-5- ( Trifluoromethyl ) Phenyl ) Eureido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (1H, s), 9.11 (1H, d, J = 9.24 Hz), 8.95 (1H, s), 8.87 (1H, s), 7.40 (1H , s), 7.35 (2H, s), 7.32 (1H, s), 7.20 (1H, m), 7.16-7.13 (2H, m), 6.88-6.84 (2H, m), 6.39 (1H, s), 5.42 (1H, s), 5.12 (1H, s), 5.05 (2H, t, J = 7.88 Hz), 3.74 (4H, t, J = 4.78 Hz) 3.72 (3H, d, J = 1.62 Hz), 3.16 (4H, t, J = 4.78 Hz), 2.36 (3H, s)

< Example  22> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- (3- (t Refluoromethyl ) Benzamido ) Benzamide

N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5-nitrobenzamide (10 mg) prepared in step 3 of Example 1 above , 0.028 mmol), 3-trifluoromethyl-benzoic acid (5.4 mg), EDCI (8.05 mg), HOBt (6.8 mg), triethylamine (10 μl) in N, N-dimethylformamide solvent (0.5 ml) After melt | dissolving in, it stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfite, filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (tri Fluoromethyl) benzamido) benzamide (8 mg, 0.014 mmol, 53%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (1H, s), 9.14 (1H, s), 8.92 (1H, s), 8.01 (1H, s), 7.55 (2H, s), 7.52 (1H, s), 7.44 (1H, s) 7.30 (1H, d, J = 8.05 Hz), 7.18 (1H, d, J = 8.06 Hz), 7.15 (2H, d, J = 8.22 Hz), 6.88 ( 2H, d, J = 8.588 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.34 (3H, s)

In the same manner as in Example 22, the compound of Examples 23 to 40 was obtained.

< Example  23> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- (3- (4-meth Tilpipera Jin-1-yl) -5- ( Trifluoromethyl ) Benzamido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (1H, s), 9.59 (1H, s), 7.81 (1H, s), 7.79 (1H, s), 7.72 (1H, s), 7.62 (1H, s), 7.44 (1H, s) 7.37 (1H, s), 7.27 (1H, d, J = 8.096 Hz), 7.15 (2H, d, J = 8.83 Hz), 6.88 (2H, d, J = 8.448 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 3.5 (4 H, m), 2.5 (4 H, m), 2.34 (3H, s), 2.23 (3H, s)

< Example  24> N- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) -2- methyl -5- (3- (4-methyl-1H- Imidazole -1-yl) -5- ( Trifluoromethyl ) Benzamido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (1H, s), 9.52 (1H, s), 8.1 (1H, s), 7.90 (1H, s), 7.81 (1H, s), 7.79 (1H, s), 7.77 (1H, s), 7.64 (1H, s), 7.44 (1H, s), 7.27 (1H, d, J = 8.12 Hz), 7.15 (2H, d, J = 8.83 Hz) , 6.88 (2H, d, J = 8.50 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.34 (3H, s), 2.27 (3H, s)

< Example  25> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -1- Phenyl -5- ( Trifluoromethyl ) -1H- Pyrazole -4- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (1H, s), 9.65 (1H, s), 8.30 (1H, s), 7.78 (1H, d), 7.67 (1H, dd, J = 1.69 Hz), 7.62-7.60 (3H, m), 7.58-7.52 (2H, m), 7.44 (1H, s), 7.27 (1H, d, J = 8.28 Hz), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  26> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -5- (2- Chloro -5- ( Trifluoromethyl ) Phenyl ) Furan -2- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (1H, s), 9.60 (1H, s), 8.47 (1H, s), 7.78 (1H, d), 7.67 (1H, dd, J = 1.69 Hz), 7.62-7.60 (3H, m), 7.58-7.52 (2H, m), 7.44 (1H, s), 7.27 (1H, d, J = 8.28 Hz), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  27> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -5- (4- Chlorophenyl ) Isoxazole -3- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (1H, s), 9.58 (1H, s), 8.09 (2H, d, J = 7.98 Hz), 7.93 (1H, d, J = 9.93 Hz ) 7.71 (2H, s) 7.66 (2H, d, J = 8.58 Hz), 7.48 (2H, d, J = 8.11 Hz), 7.29 (1H, d, J = 8.11 Hz), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  28> N- (3- (5-amino-1- (4-methoxybenzyl) -1H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -1- (4- Methoxyphenyl ) -5- ( Trifluoromethyl ) -1H- Pyrazole -4- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (1H, s), 9.55 (1H, s), 8.23 (1H, s), 7.76 (1H, d), 7.43 (2H, d, J = 6.3 Hz), 7.29 (1H, d, J = 8.11 Hz), 7.14-7.05 (4 H, m), 6.86 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s ), 3.83 (3H, S), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  29> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -2- (pyridin-4-yl) Thiazole -4- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (1H, s), 9.61 (1H, s), 8.78 (2H, m), 8.63 (1H, s), 8.12 (2H, m), 7.93 (1H, d, J = 9.93 Hz) 7.91 (1H, dd, J = 8.36 Hz) 7.46 (1H, s), 7.29 (1H, d, J = 8.11 Hz), 7.15 (2H, d, J = 8.57 Hz ), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s).

< Example  30> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4-yl) -2- methyl -5- (4-nitro-3- ( Trifluoromethyl ) Benzamido ) Benzamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.47 (1H, s), 9.54 (1H, s), 8.32 (2H, m), 8.16 (1H, d, J = 9.01 Hz), 8.01 (1H , s), 7.55 (2H, s), 7.52 (1H, s), 7.44 (1H, s), 7.15 (2H, d, J = 8.22 Hz), 6.88 (2H, d, J = 8.588 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.34 (3H, s)

< Example  31> N- (3- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -4-methylphenyl) -2- Chloroisonicotinamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (1H, s), 9.60 (1H, s), 8.62 (1H, d, J = 5.04 Hz), 8.00 (1H, s), 7.88-7.87 (1H, m), 7.83 (1H, d, J = 2.21 Hz), 7.44 (1H, d, J = 4.05 Hz), 7.30 (1H, d, J = 8.17 Hz), 7.15 (2H, d, J = 8.72 Hz), 6.88 (2H, d, J = 8.60 Hz), 5.13 (2H, s), 5.05 (2H, s), 3.71 (3H, s), 2.34 (3H, s)

< Example  32> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -5- (2- Chloro -5- ( Trifluoromethyl ) Phenyl ) Furan -2- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (1H, s), 9.48 (1H, s), 8.47 (1H, s), 7.88 (1H, d, J = 8.5 Hz), 7.80 (1H , d, J = 8.5 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.54-7.49 (2H, m), 7.42 (1H, s), 7.15 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 5.15 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.41 (3H, s)

< Example  33> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -1- Phenyl -5- ( Trifluoromethyl ) -1H- Pyrazole -4- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (1H, s), 9.45 (1H, s), 8.33 (1H, s), 7.63-7.53 (5 H, m), 7.49 (1H, d , J = 8.9 Hz), 7.41 (1H, s), 7.15 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 5.14 (2H, s), 5.05 (2H, s ), 3.72 (3H, s), 2.39 (3H, s)

< Example  34> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -5- Methylisoxazole -3- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (1H, s), 7.68 (1H, s), 7.67 (1H, d, J = 7.83 Hz), 7.46 (1H, d, J = 8.07 Hz ), 7.41 (1H, s), 7.15 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.66 (1H, s), 5.14 (2H, s), 5.05 (2H , s), 3.72 (3H, s), 2.37 (3H, s)

< Example  35> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -2- (pyridin-4-yl) Thiazole -4- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (1H, s), 9.47 (1H, s), 8.80-8.78 (2H, m), 8.66 (1H, s), 8.13 (2H, m) , 7.84-7.72 (2H, m), 7.51 (1H, d, J = 8.41 Hz), 7.42 (1H, s), 7.15 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.66 (1H, s), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.37 (3H, s)

< Example  36> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) pyrazine-2- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (1H, s), 9.47 (1H, s), 8.87 (1H, s), 8.77 (1H, s), 8.66 (1H, s), 7.87 -7.80 (2H, m), 7.51 (1H, d, J = 8.12 Hz), 7.48 (1H, s), 7.15 (2H, d, J = 8.54 Hz), 6.88 (2H, d, J = 8.59 Hz) , 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, s), 2.37 (3H, s)

< Example  37> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) Benzo [b] Thiophene -2- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (1H, s), 9.47 (1H, s), 8.39 (1H, s), 8.07 (1H, d, J = 8.09 Hz), 8.02 (1H , d, J = 8.09 Hz), 7.7 (1H, m), 7.67 (2H, m), 7.50 (2H, d, J = 7.23 Hz), 7.42 (1H, s), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.41 (3H, s)

< Example  38> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) Benzofuran -2- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (1H, s), 9.46 (1H, s), 7.84 (1H, d, J = 7.66 Hz), 7.79 (1H, d, J = 0.65 Hz ) 7.74 (1H, s), 7.72 (2H, s), 7.54-7.48 (2H, m), 7.42 (1H, s), 7.39-7.36 (1H, m) 7.15 (2H, d, J = 8.57 Hz) , 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  39> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -2- Chloroisonicotinamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (1H, s), 9.47 (1H, s), 8.63 (1H, d, J = 5.08 Hz), 8.01 (1H, s), 7.87 (1H , dd), 7.68-7.65 (2H, m), 7.50 (1H, d, J = 8.32 Hz), 7.41 (1H, s), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H, d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Example  40> N- (4- (5-amino-1- (4-methoxybenzyl) -1 H- Pyrazole -4- Ilkaba Mole ) -3-methylphenyl) -5- (4- Chlorophenyl ) Isoxazole -3- Carboxamide

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (1H, s), 9.50 (1H, s), 8.01 (2H, d, J = 8.28 Hz), 7.71 (2H, s), 7.66 (2H , d, J = 8.58 Hz), 7.56 (1H, s), 7.49 (1H, d, J = 8.07 Hz), 7.42 (1H, s), 7.15 (2H, d, J = 8.57 Hz), 6.88 (2H , d, J = 8.57 Hz), 5.14 (2H, s), 5.05 (2H, s), 3.72 (3H, d, J = 1.62 Hz), 2.40 (3H, s)

< Experimental Example  1> Protein Kinase  Enzyme Activity Measurement

In order to measure the proliferation inhibitory activity of abnormal cells of the aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof according to the present invention, the following experiment was performed.

(1) B- RAF Kinase  Enzyme Activity Measurement

Reagents include base reaction buffer solution (20 mM Hepes, pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO Was used.

10 nM B-RAF (V600E) was used as the enzyme. The B-RAF is the 416-terminal portion of a human B-RAF residue that is GST-labeled and recombined with an N-terminus comprising a V599E mutation. The molecular weight is 67.3 kDa and GenBank NM_004333.

1 M MEK1 (K97R) was used as the substrate. The MEK1 was a kinase-dead mutant (GenBank Accession No. NM_002755) and used a full length having a His6 tag at the C-terminus. The molecular weight is 44.3 kDa and was expressed in E. coli.

First, the enzyme was added to the prepared substrate solution by mixing the substrate in the prepared reaction buffer solution and mixed. Next, the compound of Example 1, 14, 22 or 23 dissolved in 100% DMSO was added to the enzyme reaction mixture and incubated at room temperature for 30 minutes. Then ³³ P-ATP was added to the reaction mixture and the reaction was initiated. Incubated at room temperature for 2 hours. Thereafter, enzyme activity was detected by the P81 filter-binding method.

Specifically, 25 μl of P81 was slowly spotted and placed in a scintillation vial, which was washed four times for 10 minutes with 0.75% phosphoric acid and once for 5 minutes with acetone. 5 ml of a scintillation cocktail (scintillation cocktail) was placed in the scintillator container and the signal was read by a scintillation counter.

The IC ₅₀ of the test compound which carried out the experiment was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.

The IC ₅₀ of this compound which reduces B-RAF kinase enzyme activity by 50% is shown in Table 1 below.

(2) C- RAF Kinase  Enzyme Activity Measurement

The method of (1) above except that RAF-1 (306-terminal portion of the N-terminal GST-labeled and recombined human RAF-1 residue, including modifications of Y340D and Y341D), is used as the enzyme. Experiments were carried out in the same manner to measure C-RAF activity and the results are shown in Table 1 below.

Example IC ₅₀ ([mu] M) B-RAF-V600E C-RAF One <1.0 <1.0 14 <1.0 <1.0 22 <1.0 <1.0 23 <1.0 <1.0

As shown in Table 1, the IC ₅₀ of the compounds according to the invention (Examples 1, 14, 22 or 23) was determined to be 1.0 μM or less, from which the aminopyrazole arylamide derivatives according to the invention or pharmaceuticals thereof It can be seen that the acceptable salt has an excellent inhibitory effect on B-RAF and C-RAF kinase.

(3) various Kinase  Measurement of inhibitory activity

Inhibition activity of various kinases at 10 μM concentration of the compound prepared in Example 22 was measured using Reaction Biology Kinase Profiling Service (IC ₅₀ profiler express), and the results are shown in Table 2 below. .

Kinase Inhibitory Activity (%) ABL1 67.8 AKT1 (dPH, S473D) 3.69 ALK 7.65 Aurora A 0 B-RAF (V599E) 96.9 c-Kit 62.8 c-MET 12.7 c-Src 16.1 CDK1 / cyclin B 0 CDK2 / cyclin E 0 EGFR / ERBB1 15.8 ERK2 / MAPK1 / P42MAPK 0 FAK / PTK2 1.5 FGFR3 0.05 FLT3 12.9 FMS 90.2 GSK3B 1.43 1GF-1R 0.70 JAK3 0 JNK1a1 7.05 JNK3 / MAPK10 12.8 KDR / VEGRF2 0.02 LCK 95.3 LYN / LYN A 94.6 MEK1 0 mTOR / FRAP1 1.20 P38α / MAPK14 94.6 p70S6K 0.02 PKA 0 PLK1 6.26 RAF1 (C-RAF) 100 RON / MST1R 0 ROS / ROS1 0 SYK 0 TRKB / NTRK2 6.64

As shown in Table 2, the aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof according to the invention are excellent for ABL1, B-RAF, c-Kit, FMS, LCK, LYN, P38α and C-RAF. It can be seen that there is an inhibitory effect.

< Experimental Example  2> Determination of A375P cell line (melanoma) proliferation inhibitory activity

A375P cell line purchased from ATCC was treated with DMEM culture [10% FBS, 1% penicillin / streptomycin] 5% CO ₂ Incubated at 37 ° C. in the presence. Cultured A375P cell lines were taken with 0.05% trypsin-0.02% EDTA and 5 × 10 ³ cells per well were placed in 96-well plates. To measure cell viability, MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] activity screening method (CellTiter 96 Assay, Promega) was used as follows. 15 μl dye per well was added and incubated for 2 hours, and then 100 μl of the stop solution was treated and absorbance was measured 24 hours later. After plating, the compound was treated one day later. When the compound is treated, a 10 mM stock is prepared, and diluted sequentially in 1/3 of dimethyl sulfoxide (DMSO) to prepare a test compound plate at 12 points, and 0.5 μl is added (final concentration DMSO). 0.5%). The values were read at 590 nm wavelength using EnVision 2103 and GI ₅₀ values were calculated using GraphPad Prism 4.0 software.

Representative results are shown in Table 3 below.

Example A375P Cell Line Proliferation
Inhibitory activity (GI ₅₀ , μM) Example A375P Cell Line Proliferation
Inhibitory activity (GI ₅₀ , μM) Example 1 <10 Example 18 <10 Example 2 <10 Example 19 <10 Example 3 <10 Example 20 <10 Example 7 <10 Example 21 <10 Example 8 <10 Example 22 <10 Example 14 <10 Example 23 <10 Example 17 <10 Example 27 <10

As shown in Table 3, the GI ₅₀ of the compounds according to the invention was determined to be 10 μM or less, from which the aminopyrazole arylamide derivatives or pharmaceutically acceptable salts thereof according to the invention exhibited excellent inhibition against melanoma. It can be seen that there is an effect.

Examples of formulations for the composition of the present invention are illustrated below.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Preparation of powders

2 g of aminopyrazole arylamide derivatives of Formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of aminopyrazole arylamide derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

<1-3> Preparation of Capsule

100 mg of aminopyrazole arylamide derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml aminopyrazole arylamide derivative of Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the aminopyrazole arylamide derivative according to the invention in a suitable volume of injectable sodium chloride BP, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and adjust the volume with injectable sodium chloride BP And mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (10)

Aminopyrazole arylamide derivatives represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

.
(In Formula 1,
R ¹ is C ₅ -C ₁₂ aryl C ₁ -C ₄ alkyl which is unsubstituted or substituted with one or more C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,
R ² is hydrogen; Or C ₁ -C ₄ straight or branched alkyl,
L is -NRC (O)-; -NRC (O) NR- or -NRC (S) NR-, wherein R is hydrogen or C ₁ -C ₄ straight or branched alkyl,
R ³ is X or XY, wherein X and Y are each independently C ₅ -C ₁₂ aryl, C ₅ -C ₁₂ heteroaryl, C ₅ -C ₁₂ aryl C ₁ -C ₄ alkyl, C ₅ -C ₁₂ hetero Aryl C ₁ to C ₄ alkyl, C ₅ to C ₁₂ cycloalkyl or C ₅ to C ₁₂ heterocycloalkyl, C ₅ to C ₁₂ aryl, C ₅ to C ₁₂ heteroaryl, C ₅ to C ₁₂ aryl C ₁ ˜C ₄ alkyl, C ₅ to C ₁₂ heteroaryl C ₁ to C ₄ alkyl, C ₅ to C ₁₂ cycloalkyl or C ₅ to C ₁₂ heterocycloalkyl are unsubstituted or at least one halogen, C ₁ to C ₄ straight chain Or a substituent selected from the group consisting of branched alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl and morpholino.)
The method of claim 1,
R ¹ is 4-methoxybenzyl,
R ² is hydrogen, methyl or ethyl,
L is -NHC (O)-, -NHC (O) NH- or -NHC (S) NH-,
R ³ is X or XY, wherein X and Y are each independently unsubstituted or substituted with one or more of fluoro, chloro, methyl, ethyl, trifluoromethyl, morpholino, phenyl, thiazolyl, isoxazolyl, pyri An aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof, characterized in that it is diyl, pyrimidinyl, piperazinyl, furanyl, benzofuranyl, benzothiophenyl or piperazinylmethyl.
The method of claim 1,
R ¹ is 4-methoxybenzyl,
R ² is methyl,
L is -NHC (O)-, -NHC (O) NH- or -NHC (S) NH-,
R ³ is (3,4-di-methoxyphenyl) methyl, 2,4-dimethylphenyl, 2,3-dichlorophenyl, 3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoro Methyl) phenyl, 3- (4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) phenyl, 4-((4-ethylpiperazin-1-yl) methyl) -3- ( Trifluoromethyl) phenyl, 3- (3-morpholino-5- (trifluoromethyl) phenyl, 4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl , 3- (4-methyl-1H-imitazol-1-yl) -5- (trifluoromethyl) phenyl, 4- (1-methylpiperidin-4-yloxy) -3- (trifluoro Methyl) phenyl, 5-bromothiopin, naphthyl, benzothiopinyl, furanyl, isoxazolyl, pyrazolyl, pyridazinyl, thiazolyl, pyrazinyl, thienyl, pyrimidinyl, imidazolyl, pyrroyl , Dihydropyrroyl, oxazolyl, triazolyl, thiadiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, benzothiazolyl, benzothiazophenyl, benzodioxolyl, amino An aminopyrazole arylamide derivative, or a pharmaceutically acceptable salt thereof, characterized in that it is pyrazole arylamideyl, indolyl, indilyl, dihydroindilyl or dihydrobenzofuranyl.
According to claim 1, wherein the compound represented by Formula 1
1) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-chloro-3- (trifluoromethyl) phenyl) urea Fig. 2--2-benzamide;
2) N- (5-amino-1-benzyl-1H-pyrazol-4-yl) -5- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -2-methyl Benzamide;
3) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5 (3- (2,4,5-trichlorophenyl) ureido Benzamide;
4) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5 (3- (2,3,6-trichlorophenyl) ureido Benzamide;
5) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-chlorophenyl) thioureido) -2-methylbenz Amides;
6) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-trifluoromethyl) phenylureido) Benzamide;
7) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3-cyclohexylureido) benzamide;
8) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (3-chlorophenyl) ureido) -2-methylbenzamide;
9) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (2,4-bis (trifluoromethyl) phenyl) ureido ) -2-methylbenzamide;
10) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (3- (3-methylisoxazole-5 -Yl) ureido) benzamide;
11) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -5- (3- (4-((4-ethylpiperazin-1-yl) methyl -3- (trifluoromethyl) phenyl) ureido) -2-methylbenzamide;
12) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl4- (3- (3- (trifluoromethyl) phenyl) ureido Benzamide;
13) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3-cyclohexylureido) -2-methylbenzamide;
14) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (4-chloro-3- (trifluoromethyl) phenyl) urea Fig. 2--2-benzamide;
15) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl4- (3- (2-morpholino-5- (trifluoro Methyl) phenyl) ureido) benzamide;
16) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (4-trifluoromethyl) pyrimidine-2 -Yl) ureido) benzamide;
17) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (3,4-dichlorophenyl) ureido) -2-methyl Benzamide;
18) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (3-chlorophenyl) ureido) -2-methylbenzamide;
19) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -4- (3- (4-chlorophenyl) thioureido) -2-methylbenz Amides;
20) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (3- (4-methyl-1H-imidazole -1-yl) -5- (trifluoromethyl) phenyl) ureido) benzamide;
21) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-4- (3- (3-morpholino-5- (trifluoro Rhomethyl) phenyl) ureido) benzamide;
22) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (trifluoromethyl) benzamido) benzamide ;
23) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-methylpiperazin-1-yl)- 5- (trifluoromethyl) benzamido) benzamide;
24) N- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (3- (4-methyl-1H-imidazole-1- Yl) -5- (trifluoromethyl) benzamido) benzamide;
25) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -1-phenyl-5- (trifluoromethyl ) -1H-pyrazole-4-carboxamide;
26) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -5- (2-chloro-5- (tri Fluoromethyl) phenyl) furan-2-carboxamide;
27) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -5- (4-chlorophenyl) isoxazole- 3-carboxamide;
28) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -1- (4-methoxyphenyl) -5 -(Trifluoromethyl) -1H-pyrazole-4-carboxamide;
29) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -2- (pyridin-4-yl) thiazole -4-carboxamide;
30) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-yl) -2-methyl-5- (4-nitro-3- (trifluoromethyl ) Benzamido) benzamide;
31) N- (3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -4-methylphenyl) -2-chloroisonicotinamide;
32) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5- (2-chloro-5- (tri Fluoromethyl) phenyl) furan-2-carboxamide;
33) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -1-phenyl-5- (trifluoromethyl ) -1H-pyrazole-4-carboxamide;
34) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5-methylisoxazole-3-carbox Amides;
35) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -2- (pyridin-4-yl) thiazole -4-carboxamide;
36) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) pyrazine-2-carboxamide;
37) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) benzo [b] thiophene-2-carboxamide ;
38) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) benzofuran-2-carboxamide;
39) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -2-chloroisonicotinamide; And
40) N- (4- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-4-ylcarbamoyl) -3-methylphenyl) -5- (4-chlorophenyl) isoxazole- An aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of 3-carboxamides.
As represented by Scheme 1 below,
Preparing a compound of Chemical Formula 4 by cyclizing and nitrosing the compound of Chemical Formula 2 and the compound of Chemical Formula 3 as starting materials (Step 1);
Preparing a compound of formula 5 by reducing the compound of formula 4 prepared in step 1 (step 2);
Preparing a compound of formula 7 by condensing the compound of formula 5 prepared in step 2 with a carboxylic acid compound of formula 6 (step 3);
Preparing a compound of formula 8 by reducing the compound of formula 7 prepared in step 3 (step 4); And
The aminopyrazole arylamide derivative of claim 1 comprising the step of coupling the compound of formula 8 prepared in step 4 with an amine compound or isocyanate compound of formula 9 to prepare a compound of formula 1a (step 5) Manufacturing Method:
[Reaction Scheme 1]

.
(In Scheme 1, R ¹ To R ³ is as defined in formula 1 of claim 1, wherein the compound of formula 1a is included in the compound of formula 1 of claim 1.
As represented by Scheme 2 below,
Preparing a compound of Chemical Formula 4 by cyclizing and nitrosing the compound of Chemical Formula 2 and the compound of Chemical Formula 3 as starting materials (Step 1);
Preparing a compound of formula 5 by reducing the compound of formula 4 prepared in step 1 (step 2);
Preparing a compound of formula 7 by condensing the compound of formula 5 prepared in step 2 with a carboxylic acid compound of formula 6 (step 3);
Preparing a compound of formula 8 by reducing the compound of formula 7 prepared in step 3 (step 4); And
A method for preparing the aminopyrazole arylamide derivative of claim 1 comprising the step of coupling a compound of Formula 8 with a carboxylic acid compound of Formula 10 to prepare a compound of Formula 1b (step 5 ′):
Scheme 2

.
(In Scheme 2, R ¹ To R ³ is the same as defined in Formula 1 of claim 1, wherein the compound of Formula 1b is included in the compound of Formula 1 of claim 1.
A pharmaceutical composition for preventing and treating cancer or a tumor containing the aminopyrazole arylamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
According to claim 7, wherein the aminopyrazole arylamide derivative or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for the prevention and treatment of cancer or tumors by inhibiting protein kinase to inhibit the proliferation of abnormal cells.
The method of claim 8, wherein the protein kinase is selected from the group consisting of ABL1, B-RAF, c-Kit, FMS, LCK, LYN, P38α, and C-RAF. Composition.
The method of claim 8, wherein the cancer or tumor is gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis adenocarcinoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and paraparous cancer. Pharmaceutical composition for the prevention and treatment of cancer or tumors, characterized in that selected from the group consisting of thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematologic cancer, lymphoma, psoriasis and fibroadenomas.