KR20240055676A - Novel Altiratinib derivatives, preparation method thereof, and Composition for preventing, improving or treating skin pigmentation comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel altiratinib derivative, a method for producing the same, and a composition for preventing, improving, or treating skin pigmentation containing the same as an active ingredient. The altiratinib derivative according to the present invention is compared with altiratinib. Therefore, although the toxicity to melanocytes was significantly low, the effect of inhibiting melanin production was confirmed to be similar or improved. Therefore, the composition containing the altiratinib derivative or its salt according to the present invention as an active ingredient can not only be used for the prevention or treatment of pigmentation, but can also be used in various fields of skin care, such as skin whitening by improving pigmentation, etc. It is expected that it can be put to good use.

Description

Novel Altiratinib derivatives, preparation method thereof, and Composition for preventing, improving or treating skin pigmentation comprising the same as an active ingredient same as an active ingredient}

The present invention relates to a novel altiratinib derivative, a method for producing the same, and a composition for preventing, improving, or treating skin pigmentation containing the same as an active ingredient.

Human skin color is influenced by environmental or physiological conditions such as solar ultraviolet rays, fatigue, and stress, but is fundamentally determined by the composition and distribution of various chromophores such as melanin, hemoglobin, and carotenoid in the skin. Melanin is a black-brown polymer pigment synthesized by melanocytes. The tyrosinase enzyme converts tyrosine into DOPA and then undergoes a series of oxidation processes to synthesize melanin. Melanosomes containing melanin transfer melanin from melanocytes to keratinocytes such as keratinoids through dendrites and distribute melanin throughout the epidermis. Skin color is determined by the amount of melanin, and the greater the amount of melanin, the darker the skin color.

Melanin absorbs ultraviolet rays and plays a role in blocking ultraviolet rays from penetrating the skin, but excessive melanin accumulation causes hyperpigmented skin diseases such as hyperpigmentation. Pigmentation or hyperpigmentation is a condition in which melanin increases in the skin, nails, and mucous membranes surrounding the mouth or nasal cavity, causing the skin to turn black. It can be caused by genetic diseases, drugs, inflammation, trauma, etc. It can be caused by various causes, such as exposure to ultraviolet rays and hyperpigmented skin diseases such as melasma. Pigmentation is considered a socially important disease because it can cause mental stress and reduce quality of life.

Conventional methods for treating pigmentation include various approaches such as chemical peeling, laser surgery, drug therapy, and cosmetic procedures, but they have side effects and cost issues, and tyrosine such as kojic acid, arbutin, etc. Substances that inhibit tyrosinase enzyme activity are used as drugs, but they have safety problems such as skin irritation and cell death. In particular, hydroquinone is commonly used alone or in combination with other drugs for diseases related to skin pigmentation, but is known to cause side effects such as allergies and cancer. Therefore, there is a need for the development of substances that can effectively prevent, improve, and treat pigmentation without causing side effects in the human body.

Republic of Korea Patent Publication No. 10-2008-0069177

The present inventors conducted research to discover a substance that can effectively suppress skin pigmentation without causing side effects to the human body. As a result, a derivative of Altiratinib has a melanin production inhibition effect similar to that of Altiratinib. The present invention was completed by confirming that it was similar and had significantly low cytotoxicity.

Accordingly, the object of the present invention is to provide altiratinib derivatives or salts thereof.

Another object of the present invention is to provide a method for producing altiratinib derivatives according to the present invention.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Another object of the present invention is to provide a cosmetic composition for preventing or improving pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Another object of the present invention is to provide a skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to the present invention to the skin of an individual in need thereof.

Another object of the present invention is to provide a topically applied preparation for preventing or improving pigmentation containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Another object of the present invention is to provide a food composition for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Another object of the present invention is to provide a health functional food for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Another object of the present invention is to provide a quasi-drug composition for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art to which the present invention belongs from the description below. There will be.

In order to achieve the above object, the present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):

[Formula 1]

In Formula 1,

R ₁ is a halogen element, or ego,

R ₂ is , , , , or ego,

n is 0, 1, or 2,

Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),

A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,

A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,

A ₇ to A ₁₀ is each independently C=O, or NH,

The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.

In one embodiment of the present invention, the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto.

[Formula 2a]

(In Formula 2a,

n is 0, 1, or 2,

R ₃ and R ₄ are each independently a halogen element, hydrogen (H), hydroxyl group (OH), methoxy (OCH ₃ ), methyl (CH ₃ ), ethyl (CH ₂ CH ₃ ), trifluoromethyl (CF ₃ ), or nitro group (NO ₂ ),

Wherein A ₁ is N, CH, CMe, or CPh,

The A ₂ is O, S, NH, NMe, NEt, or CH _2. )

[Formula 2b]

(In Formula 2b,

n is 1 or 2,

R ₅ and R ₆ are each independently a halogen element, hydrogen (H), methoxy (OCH ₃ ), or methyl (CH ₃ ),

A ₃ is N, CH, or CMe,

where A ₄ is O, S, NH, or NMe.)

[Formula 2c]

(In Formula 2c,

Wherein A ₅ is O, S, or NH,

A ₆ is N, or CH.)

[Formula 2d]

(In Formula 2d above,

R ₁ is a halogen element, or ego,

A ₇ and A ₈ are each independently C=O, or NH.)

[Formula 2e]

(In Formula 2e above,

A ₉ and A ₁₀ are each independently C=O, or NH.)

In another embodiment of the present invention, the altiratinib derivative has the formula (1):

The R ₁ is ego,

i) When n is 0,

The R ₂ is , or ego,

ii) When n is 1,

The R ₂ is , or It may be, but is not limited to this.

In another embodiment of the present invention, the altiratinib derivative may be any one selected from the group consisting of the following compounds, but is not limited thereto:

(1) N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);

(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);

(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);

(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);

(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT- 005);

(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-006);

(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] (ALT-007);

(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-008);

(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);

(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);

(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);

(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);

(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] (ALT-013);

(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);

(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indene-3-carboxamide] (ALT-015);

(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);

(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indole-6-carboxamide] (ALT-017);

(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Vaxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);

(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] (ALT-019);

(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);

(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);

(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);

(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);

(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] (ALT-024) ;

(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ( ALT-025);

(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);

(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N- (4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); and

(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide] (ALT-028).

In addition, the present invention relates to a compound selected from the following Formula 3 or the following Formula 4 and a compound represented by the following Formula 5, in the presence of an organic solvent, using a coupling reagent, through amide coupling. A method for producing an altiratinib derivative according to claim 1, characterized in that it undergoes a coupling reaction,

A manufacturing method is provided wherein the coupling reagent is at least one selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC.

[Formula 3]

[Formula 4]

[Formula 5]

In Formula 5 above,

R is , , , , or ego,

n is 0, 1, or 2,

Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),

A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,

A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,

A ₇ to A ₁₀ is each independently C=O, or NH,

The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.

In one embodiment of the present invention, the organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide. , DMF), dimethyl sulfoxide (DMSO), and dichloroethylene (DCE), but is not limited thereto.

Additionally, the present invention provides a pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.

Additionally, the present invention provides a method for preventing or treating pigmentation, comprising administering a pharmaceutical composition containing an altiratinib derivative or a salt thereof as an active ingredient to an individual in need thereof.

In addition, the present invention provides uses of altiratinib derivatives or salts thereof for preventing, improving or treating pigmentation, and/or for skin whitening.

In addition, the present invention provides the use of an altiratinib derivative or a salt thereof for manufacturing a medicament for treating pigmentation.

In one embodiment of the present invention, the pigmentation includes freckles, freckles, lentigines, age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, and gravidic chlorasma. ), post-inflammatory hyperpigmentation due to wounds or dermatitis, senile pigmented spots, and solar lentigines, but is not limited thereto.

Additionally, the present invention provides a cosmetic composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.

In one embodiment of the present invention, the cosmetic composition includes serum, lotion, paste, patch, gel, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutritional lotion, cream, massage cream, nutrition. Cream, mist, moisture cream, hand cream, hand lotion, foundation, essence, nutritional essence, pack, soap, oil, foundation, makeup base, wax, spray, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, It may be a body lotion or body cleanser formulation, but is not limited thereto.

Additionally, the present invention provides a skin care method for preventing or improving pigmentation, comprising the step of applying the composition according to the present invention to the skin of an individual in need thereof.

Additionally, the present invention provides a topically applied preparation for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.

In one embodiment of the present invention, the topical application preparation may be in the form of a cream, gel, lotion, powder, powder spray, oil, roll-on formulation, ointment, foam, spray, stick, or tincture, but is limited thereto. It doesn't work.

Additionally, the present invention provides a food composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient. The food composition includes a health functional food composition.

In addition, the present invention provides a health functional food for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.

Additionally, the present invention provides a quasi-drug composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.

Additionally, the present invention provides a kit for preventing or improving pigmentation, comprising a pharmaceutical composition, cosmetic composition, topical application preparation, food composition, or quasi-drug composition according to the present invention.

It was confirmed that the altiratinib derivative according to the present invention had a similar or superior melanin production inhibition effect to altiratinib and had significantly low cytotoxicity. Therefore, the composition containing altiratinib derivatives or their salts according to the present invention as an active ingredient can not only be used for the prevention or treatment of pigmentation, but can also be used in various fields of skin care, such as skin whitening by improving pigmentation, etc. It is expected that it can be put to good use.

Figure 1 is a diagram showing the results of measuring the skin permeability of altiratinib derivative compounds ALT-002 and ALT-003 using PAMPA.
Figure 2 is a diagram showing the results of measuring melanin content after treatment of altiratinib derivative compounds ALT-001 to ALT-003, ALT-006, and ALT-013 on Mel-Ab, a mouse melanin cell line treated with FSK.
Figure 3 shows melanin content after treatment of altiratinib derivative compounds ALT-015 to ALT-017, ALT-019 to ALT-021, ALT-026, and ALT-028 on Mel-Ab, a mouse melanocyte cell line treated with FSK. This is a drawing showing the measurement results.
Figure 4 shows the melanin content measured after treatment of altiratinib derivative compounds ALT-001 to ALT-003, ALT-006, and ALT-013 to Mel-Ab, a mouse melanocyte cell line treated with FSK, compared to the control group of cells treated with FSK only. This is a drawing expressed as a percentage.
Figure 5 is a diagram showing the results of measuring melanin content after treatment of altiratinib derivative compounds ALT-002, ALT-003, ALT-006, and ALT-009 on B16F10, a mouse melanocyte cell line treated with FSK.
Figure 6 is a diagram showing the results of measuring melanin content after treating the altiratinib derivative compound ALT-022 to B16F10, a mouse melanocyte cell line treated with FSK.
Figure 7 is a diagram showing the results of measuring melanin content after treating human melanocytes with altiratinib derivative compounds ALT-002 and ALT-003.
Figure 8 is a diagram showing the results of measuring melanin content after treating human melanocytes with altiratinib derivative compounds ALT-024 and ALT-028.
Figure 9 is a diagram showing the results of treating altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations to Mel-Ab, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
Figure 10 is a diagram showing the results of treating altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations to Mel-Ab, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
Figure 11 is a diagram showing the results of treating altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations to B16F10, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
Figure 12 is a diagram showing the results of treating altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations to B16F10, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
Figure 13 is a diagram showing the results of treating human melanocytes with altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations and then confirming the degree of cell activity through apoptosis analysis.
Figure 14 is a diagram showing the results of treating human melanocytes with altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations and then confirming the degree of cell activity through apoptosis analysis.

The present inventors completed the present invention by confirming that the altiratinib derivative has significantly lower toxicity to melanocytes compared to altiratinib and effectively inhibits melanin production in melanocytes similar to altiratinib. .

Hereinafter, the present invention will be described in detail.

The present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):

[Formula 1]

In Formula 1,

R ₁ is a halogen element, or ego,

R ₂ is , , , , or ego,

n is 0, 1, or 2,

Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),

A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,

A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,

A ₇ to A ₁₀ is each independently C=O, or NH,

The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.

In the present invention, the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto:

[Formula 2a]

(In Formula 2a,

n is 0, 1, or 2,

R ₃ and R ₄ are each independently a halogen element, hydrogen (H), hydroxyl group (OH), methoxy (OCH ₃ ), methyl (CH ₃ ), ethyl (CH ₂ CH ₃ ), trifluoromethyl (CF ₃ ), or nitro group (NO ₂ ),

Wherein A ₁ is N, CH, CMe, or CPh,

The A ₂ is O, S, NH, NMe, NEt, or CH _2. )

[Formula 2b]

(In Formula 2b,

n is 1 or 2,

R ₅ and R ₆ are each independently a halogen element, hydrogen (H), methoxy (OCH ₃ ), or methyl (CH ₃ ),

A ₃ is N, CH, or CMe,

where A ₄ is O, S, NH, or NMe.)

[Formula 2c]

(In Formula 2c,

A ₅ is O, S, or NH,

A ₆ is N, or CH.)

[Formula 2d]

(In Formula 2d above,

R ₁ is a halogen element, or ego,

A ₇ and A ₈ are each independently C=O, or NH.)

[Formula 2e]

(In Formula 2e,

A ₉ and A ₁₀ are each independently C=O, or NH.)

In the present invention, the altiratinib derivative is more preferably, in Formula 1,

The R ₁ is ego,

i) When n is 0,

The R ₂ is , or ego,

ii) When n is 1,

The R ₂ is , or It may be, and according to one embodiment of the present invention, the altiratinib derivative is preferably ALT-002 (Compound 7a), ALT-003 (Compound 6a), ALT-006 (Compound 9a), or ALT-013. (Compound 8c).

The term “C ₁ -C ₅ alkyl group” used in the present invention refers to a monovalent alkyl group having 1 to 5 carbon atoms. Examples of this term include functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl, etc. The alkyl and other alkyl moiety-containing substituents described in the present invention include both straight-chain and branched forms. Substituted C ₁ -C ₅ alkyl means that one or more hydrogen atoms are substituted with another substituent. The substituent is not limited, but may include a halogen element, N, O, S, nitrile group, nitro group, hydroxy Includes groups, carbonyl groups, ester groups, imide groups, substituted or unsubstituted aryl groups, etc.

The term “halogen element” used in the present invention may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).

As used herein, the term “C ₁ -C ₅ alkoxy group” means the group -OR, where R means “C ₁ -C ₅ alkyl”. Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, etc.

Preferred embodiments of the altiratinib derivative represented by Formula 1 according to the present invention are as follows:

(1) N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);

(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);

(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);

(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);

(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT- 005);

(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-006);

(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] (ALT-007);

(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-008);

(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);

(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);

(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);

(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);

(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] (ALT-013);

(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);

(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indene-3-carboxamide] (ALT-015);

(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);

(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indole-6-carboxamide] (ALT-017);

(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Vaxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);

(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] (ALT-019);

(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);

(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);

(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);

(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);

(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] (ALT-024) ;

(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ( ALT-025);

(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);

(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N- (4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); and

(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide] (ALT-028).

The altiratinib derivative of the present invention can be used in the form of a pharmaceutically acceptable salt.

As used in the present invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases, and acids formed by pharmaceutically acceptable free acids. Addition salts are useful.

The acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodine. Ide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methylbenzoate Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycol Includes sulfonate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, trifluoroacetate, or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone or acetonitrile. It can be manufactured by ordering. It can also be prepared by evaporating the solvent or excess acid from this mixture and drying it, or by suction-filtering the precipitated salt.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. The corresponding silver salts are obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g. silver nitrate).

In addition, the compound of the present invention may include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods.

In addition, in another aspect of the present invention, in the presence of an organic solvent, any one compound selected from the compound of formula 3 or the compound of formula 4 below and the compound of formula 5 below are used as a coupling reagent. A method for producing the altiratinib derivative, characterized in that it undergoes an amide coupling reaction with,

The coupling reagent is one or more selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC.

[Formula 3]

[Formula 4]

[Formula 5]

In Formula 5 above,

R is , , , , or ego,

n is 0, 1, or 2,

Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),

A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,

A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,

A ₇ to A ₁₀ is each independently C=O, or NH,

The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.

In the present invention, the method for producing the altiratinib derivative may be an amide coupling reaction at room temperature for 15 to 90 hours, but is not limited thereto.

According to one embodiment of the present invention, the altiratinib derivative according to the present invention may be synthesized through a reaction according to Scheme 1 below, and more preferably in “steps d to f: Amide Coupling”. It may be synthesized through a reaction that follows.

In the present invention, the organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide (DMF). , dimethyl sulfoxide (DMSO), and dichloroethylene (DCE), and preferably dimethylformamide, but is not limited thereto.

In addition, the present invention provides, in another aspect of the present invention, a pharmaceutical composition for preventing or treating pigmentation, comprising the Altiratinib derivative or a salt thereof according to the present invention as an active ingredient, In the present invention, the salt may preferably be a pharmaceutically acceptable salt of the altiratinib derivative.

In the present invention, “Altiratinib (ALT)” is a known drug known to have anticancer effects, and is registered as ID54576299 in PubChem, a chemical molecule database. The structural formula of altiratinib disclosed in the database is shown in Chemical Formula 6 below.

[Formula 6]

In the present invention, “pigmentation” refers to any disease or disease of the skin caused by discoloration of the skin (pigmentation) or proliferation of abnormally pigmented cells, and includes “hyperpigmentation” and Can be used interchangeably. Skin pigmentation includes excessive or unwanted pigmentation. Factors such as aging, environmental stress, and UV exposure can be potential causes of skin pigmentation. Skin pigmentation of the present invention may be due to an increase in one or more various types of melanin biosynthesized in the skin and/or hair follicles and deposited on the hair or skin compared to the patient's basic pigmentation, and specific examples include spots, freckles, and lentigo. , age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, gravidic chloasma, hyperpigmentation after inflammation due to wounds or dermatitis, senile pigmentation spots, and solar lentigines, but is not limited thereto.

In one embodiment of the present invention, the altiratinib derivative or a pharmaceutically acceptable salt thereof can inhibit melanin production by satisfying one or more of the following characteristics: (a) of CRTC3 (CREB Regulated Transcription Coactivator 3) Inhibits transcriptional activation function; (b) inhibiting the expression of Microphthalmia-associated transcription factor (MITF); (c) inhibiting the expression of tyrosinase, Dopachrome tautomerase (DCT), or tyrosinase related protein 1 (TRP1); or (d) inhibiting the activity of tyrosinase.

As used herein, “melanin” refers to a general term for black or brown pigments present in tissues such as skin or eyes of animals. In particular, melanin is an important factor in determining a person's skin color. The melanin expression gene is different depending on the race, and the amount and distribution of melanocytes are adjusted accordingly to determine skin color. Melanin plays a role in protecting the skin by blocking ultraviolet rays, but excessive melanin production causes skin pigmentation such as spots, freckles, and skin spots, and further participates in the etiology of skin aging and skin cancer.

In the present specification, “CRTC3 (CREB Regulated Transcription Coactivator 3)” is a transcriptional coactivator of CREB. When dephosphorylated, it moves into the nucleus and binds to CREB to activate the expression of target genes. Therefore, inhibiting the transcriptional activation function of CRTC3 means inhibiting the expression of CRTC3 itself, inhibiting dephosphorylation of CRTC3 (i.e., promoting phosphorylation of CRTC3), and inhibiting the movement of CRTC3 into the nucleus. , a concept that includes both inhibiting the binding of CTRC3 to CREB and/or inhibiting the transcriptional promotion function of CRTC3's target genes.

In the present specification, “MITF (Microphthalmia-associated transcription factor)” is a transcription factor that promotes gene expression of factors that induce melanin synthesis in melanocytes. In other words, as the expression of MITF increases or its function is activated, the expression of melanin synthesis-inducing factors is promoted to induce melanin production. Conversely, as the expression of MTIF decreases or its function is suppressed, melanin production is suppressed.

In the present specification, tyrosinase, DCT (Dopachrome tautomerase), and TRP1 (tyrosinase related protein 1) are proteins whose expression is promoted by MITF and are involved in melanin synthesis in melanocytes. In particular, tyrosinase is an enzyme that induces melanin synthesis by oxidizing tyrosine, and increasing the expression or activity of tyrosinase further promotes melanin production.

Therefore, the pharmaceutical composition according to the present invention is used for the treatment of patients suffering from pigmentation accompanied by mutations in one or more factors involved in melanin synthesis selected from the group consisting of CRTC3, MITF, tyrosinase, DCT, and TRP1. You can. In other words, the pharmaceutical composition according to the present invention may inhibit melanin production particularly effectively in patients suffering from pigmentation accompanied by the above mutation. Here, “mutation” includes increased activity or increased expression of the factors involved in melanin synthesis.

The content of the altiratinib derivative or a pharmaceutically acceptable salt thereof in the composition according to the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the patient's condition, etc., for example, 0.0001 to 0.0001 based on the total weight of the composition. It may be 99.9% by weight, or 0.001 to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount with the solvent removed.

The pharmaceutical composition according to the present invention may further include appropriate carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

The pharmaceutical composition according to the present invention can be prepared as powder, granules, sustained-release granules, enteric-coated granules, solutions, eye drops, ellipsis, emulsions, suspensions, spirits, troches, perfumes, and limonadese according to conventional methods. , tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, pills, tinctures, soft extracts, dry extracts, liquid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta preparations, sprays, inhalants, patches, sterilized injection solutions, or aerosols, and the external preparations include creams, gels, patches, sprays, ointments, and warning agents. , it may have a dosage form such as lotion, liniment, pasta, or cataplasma.

Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, and calcium. These include phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Additives to tablets, powders, granules, capsules, pills, and troches according to the present invention include corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, and phosphoric acid. Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl. Excipients such as cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin. , hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. binders can be used, Hydroxypropyl methyl cellulose, corn starch, agar powder, methyl cellulose, bentonite, hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose, calcium citrate, sodium lauryl sulfate, silicic anhydride, 1-hydroxy Propylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, Disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol solution, light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium, kaolin, petrolatum, sodium stearate, cacao fat, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogen. Added soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, Macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acids, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, Lubricants such as starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

Additives to the liquid according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc. can be used.

A solution of white sugar, other sugars, or sweeteners, etc. may be used in the syrup according to the present invention, and if necessary, flavoring agents, colorants, preservatives, stabilizers, suspending agents, emulsifiers, thickening agents, etc. may be used.

Purified water can be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. can be used as needed.

Suspensions according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Topics may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV solution, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV solution, ethanol, propylene glycol, non-volatile oil - sesame oil. solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristic acid, and benzene benzoate; Solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, Tween, nicotinic acid amide, hexamine, and dimethylacetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and buffering agents such as gums; Isotonic agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO ₃ ) carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), and ethylenediaminetetraacetic acid; Sulfurizing agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and acetone sodium bisulfite; Analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; It may contain suspending agents such as CM sodium, sodium alginate, Tween 80, and aluminum monostearate.

Suppositories according to the present invention include cacao oil, lanolin, witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, lecithin, Lanet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydrocote SP, S-70-XXA, S-70-XX75(S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Massaupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppositories type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecobi (W, R, S, M, Fs), Tegestor triglyceride base (TG-95, MA, 57) and The same mechanism can be used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the extract with at least one excipient, such as starch, calcium carbonate, and sucrose. ) or prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.

In addition, the present invention provides a method for preventing or treating pigmentation, which involves administering a pharmaceutical composition containing an Altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof. to provide.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of patient's disease. It can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains.

The pharmaceutical composition of the present invention can be administered to an individual through various routes. All modes of administration are contemplated, including oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal injection, vaginal injection. It can be administered by internal insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, etc.

The pharmaceutical composition of the present invention is determined depending on the type of drug as the active ingredient along with various related factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and severity of the disease.

In the present invention, “individual” refers to a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cows, etc. refers to mammals of

In the present invention, “administration” means providing a given composition of the present invention to an individual by any suitable method. Accordingly, in the present invention, “administration” is a concept that includes not only injection or ingestion into an individual, but also application.

In the present invention, “prevention” refers to any action that suppresses or delays the onset of the desired disease, and “treatment” refers to the improvement or improvement of the desired disease and its associated metabolic abnormalities by administration of the pharmaceutical composition according to the present invention. It refers to all actions that are beneficially changed, and “improvement” refers to all actions that reduce parameters related to the target disease, such as the degree of symptoms, by administering the composition according to the present invention.

In addition, in another aspect of the present invention, the present invention provides a composition for inhibiting CRTC3 in melanocytes, comprising the altiratinib derivative or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. Preferably, the composition for inhibiting CRTC3 according to the present invention may be a composition for in vivo, ex vivo, and/or in vitro, but is not limited thereto. Preferably, the composition for inhibiting CRTC3 may be a composition for in vitro and/or ex vivo use. That is, the composition for inhibiting CRTC3 according to the present invention may be a composition used to inhibit CRTC3 in melanocytes in vitro and/or ex vivo.

In the present invention, “CRTC3 inhibition” is a concept that includes suppressing the expression and transcriptional activation function of CRTC3, and the meaning of suppressing the transcriptional activation function of CRTC3 is as described above. That is, the altiratinib or a pharmaceutically acceptable salt thereof may inhibit the transcriptional activation function of CRTC3 by satisfying one or more of the following characteristics: (a) promoting CRTC3 phosphorylation; or (b) inhibiting the movement of CRTC3 into the nucleus.

In addition, the present invention provides, in another aspect of the present invention, a cosmetic composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof according to the present invention as an active ingredient, wherein the salt is the altiratinib derivative. It may be a cosmetically acceptable salt.

As used herein, “cosmetically acceptable salt” includes salts derived from cosmetically acceptable inorganic acids, organic acids, or bases. Specific examples include examples of the salts described above, including hadrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate ( Mesylate) and p-toluenesulfonate (tosylate) salts can be further mentioned.

The formulation of the cosmetic composition according to the present invention includes serum, lotion, paste, patch, gel, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutritional lotion, cream, massage cream, nutritional cream, and mist. , moisture cream, hand cream, hand lotion, foundation, essence, nutritional essence, pack, soap, oil, foundation, makeup base, wax, spray, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion or It may be a body cleanser formulation.

The cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, and sphingolipids.

Water-soluble vitamins may be any that can be mixed into cosmetics, but examples include vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine hydrochloride, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, and vitamin H. and their salts (thiamine hydrochloride, sodium ascorbate, etc.) or derivatives (sodium ascorbic acid-2-phosphate, magnesium ascorbic acid-2-phosphate, etc.) are also water-soluble vitamins that can be used in the present invention. Included. Water-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microbial cultures, enzymatic methods, or chemical synthesis.

Oil-soluble vitamins may be any that can be mixed into cosmetics, but examples include vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), etc. , their derivatives (ascorbic palmitate, ascorbic stearate, ascorbic acid dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherol nicotinic acid, vitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenyl ethyl ether, etc.) are also included in the oil-soluble vitamins used in the present invention. Oil-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microbial cultures, enzymatic or chemical synthesis.

Any polymer peptide that can be blended into cosmetics may be used, and examples include collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, and keratin. High molecular weight peptides can be purified and obtained by conventional methods such as purification from microbial culture media, enzymatic methods, or chemical synthesis, or they can usually be purified and used from natural products such as dermis of pigs or cows or silk fiber of silkworms.

The high molecular weight polysaccharide may be anything that can be blended into cosmetics, but examples include hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate, or its salts (sodium salt, etc.). For example, chondroitin sulfate or its salt can usually be purified and used from mammals or fish.

The sphingolipid may be any one that can be blended into cosmetics, and examples include ceramide, phytosphingosine, and sphingolipid. Sphingolipids can usually be purified by conventional methods from mammals, fish, shellfish, yeast, or plants, or obtained by chemical synthesis.

In addition to the above-mentioned essential ingredients, the cosmetic composition of the present invention may contain other ingredients usually blended in cosmetics as needed.

Other ingredients that may be added include oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohol, colorants, fragrances, Examples include blood circulation promoters, cooling agents, antiperspirants, and purified water.

Examples of oil and fat components include ester-based fats and oils, hydrocarbon-based fats and oils, silicone-based fats and oils, fluorine-based fats and oils, animal fats and oils, and vegetable fats and oils.

Ester-based oils include glyceryl tri2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, and stearic acid. Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine. Diisopropyl acid, isoalkyl neopentanoate, tri(caprylic, capric acid)glyceryl, trimethylolpropane tri2-ethylhexanoate, trimethylolpropane triisostearate, pentaelislitol tetra2-ethylhexanoate , cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinooleate, isostear laurate. Reyl, isotridecyl myristate, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, cetoester 2-ethylhexanoate Aryl, 2-ethylhexanoate stearyl, hexyl isostearate, ethylene glycol dioctanate, ethylene glycol dioleate, propylene glycol dicapric acid, di(capryl, capric acid) propylene glycol, propylene glycol dicaprylate, dicapric acid Neopentyl glycol prinate, neopentyl glycol dioctanate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate. , octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerol oleic acid ester, polyglycerol isostearic acid ester, Triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, trioctyl citrate, dimalate Isostearyl, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, Cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytsteryl isostearate, phytsteryl oleate, 12-stealoyl hydroxystearate isocetyl, 12-stealoyl hydride. Ester systems such as stearyl hydroxystearate and isostearyl 12-stealoylhydroxystearate can be mentioned.

Hydrocarbon-based fats and oils include squalene, liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybudene, microcrystalline wax, and petroleum jelly.

Silicone oils include polymethyl silicone, methylphenyl silicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane/methylcetyloxysiloxane copolymer, dimethylsiloxane/methylstealoxysiloxane copolymer, and alkyl. Modified silicone oil, amino-modified silicone oil, etc. can be mentioned.

Examples of fluorine-based fats and oils include perfluoropolyether.

Animal or plant oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, birdflower oil, soybean oil, corn oil, rapeseed oil, apricot oil, palm kernel oil, palm oil, castor oil, sunflower oil, and grape seed oil. , cottonseed oil, palm oil, cucumber nut oil, wheat germ oil, rice germ oil, shea butter, walnut colostrum oil, marker damia nut oil, meadow oil, egg yolk oil, beef tallow, horse oil, mink oil, orange rape oil, jojoba oil. , animal or plant oils such as candelier wax, carnaba wax, liquid lanolin, and hydrogenated castor oil.

Moisturizers include water-soluble low-molecular-weight moisturizers, oil-soluble molecular moisturizers, water-soluble polymers, and fat-soluble polymers.

Water-soluble low-molecular-weight moisturizers include serine, glutamine, sorbitol, mannitol, sodium pyrrolidone-carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (degree of polymerization n = 2 or more), and polypropylene. Examples include glycol (degree of polymerization n = 2 or more), polyglycerin B (degree of polymerization n = 2 or more), lactic acid, lactate, etc.

Examples of fat-soluble low-molecular-weight moisturizers include cholesterol and cholesterol esters.

Water-soluble polymers include carboxyvinyl polymer, polyaspartate, tragacanth, xanthan gum, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, water-soluble chitin, chitosan, and dextrin. You can.

Examples of oil-soluble polymers include polyvinylpyrrolidone/eicosene copolymer, polyvinylpyrrolidone/hexadecene copolymer, nitrocellulose, dextrin fatty acid ester, and polymer silicone.

Examples of emollients include long-chain acyl glutamic acid cholesteryl ester, hydroxystearic acid cholesteryl, 12-hydroxystearic acid, stearic acid, rosin acid, and lanolin fatty acid cholesteryl ester.

Examples of surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.

Nonionic surfactants include self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE (polyoxyethylene) sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE. Glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hydrogenated castor oil, POE castor oil, POEㆍPOP (polyoxyethyleneㆍpolyoxypropylene) copolymer, POEㆍPOP alkyl ether, polyether modified silicone, lauric acid Examples include alkanolamide, alkylamine oxide, and hydrogenated soybean phospholipid.

Anionic surfactants include fatty acid soap, alpha-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate, alkyl amide sulfate, alkyl phosphate, POE alkyl phosphate, and alkyl amide phosphate. , alkyloyl alkyl taurine salt, N-acylamino acid salt, POE alkyl ether carboxylate, alkyl sulfosuccinate, sodium alkyl sulfoacetate, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate ester, etc. .

Cationic surfactants include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, and chloride. Examples include benzalkonium, diethylaminoethylamide stearate, dimethylaminopropylamide stearate, and quaternary ammonium salts of lanolin derivatives.

Amphoteric surfactants include carboxy beta type, amide beta type, sulfo beta type, hydroxy sulfo beta type, amide sulfo beta type, phosphobeta type, aminocarboxylate type, imidazoline derivative type, and amide amine type. Amphoteric surfactants, etc. can be mentioned.

Organic and inorganic pigments include silicic acid, anhydrous silicic acid, magnesium silicate, talc, sericite, mica, kaolin, bengala, clay, bentonite, titanium-coated mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, and aluminum oxide. Inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, ultramarine blue, chromium oxide, chromium hydroxide, calamine and complexes thereof; Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenol resin, fluorine resin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene/styrene copolymer, Examples include organic pigments such as silk powder, cellulose, CI pigment yellow, and CI pigment orange, and complex pigments of these inorganic pigments and organic pigments.

Examples of organic powder include metal soaps such as calcium stearate; Alkyl phosphate metal salts such as sodium zinc cetilate, zinc laurylate, and calcium laurylate; Acyl amino acid polyvalent metal salts such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroyl glycine calcium; Amidesulfonic acid polyvalent metal salts such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N such as N-epsilon-lauroyl-L-lysine, N-epsilon-palmitoylizine, N-alpha-paritoylolnithine, N-alpha-lauroylarginine, N-alpha-hydrogenated beef tallow fatty acid acylarginine, etc. -Acyl basic amino acid; N-acyl polypeptides such as N-lauroylglycylglycine; Alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid; Examples include polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, divinylbenzene/styrene copolymer, and ethylene tetrafluoride.

UV absorbers include para-aminobenzoic acid, ethyl para-aminobenzoate, amyl para-aminobenzoate, octyl para-aminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomenthyl salicylate, and benzyl cinnamate. , paramethoxycinnamic acid-2-ethoxyethyl, paramethoxycinnamic acid octyl, diparamethoxycinnamic acid mono-2-ethylhexane glyceryl, paramethoxycinnamic acid isopropyl, diisopropylㆍdiisopropylcinnamic acid ester mixture, uro Kaninic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone disulfonate sodium, dihydroxybenzophenone , tetrahydroxybenzophenone, 4-tert-butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxy)-1 , 3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, etc.

Disinfectants include hinokitiol, triclosan, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zincphyllithione, benzalkonium chloride, and photosensitive. Sub-No. 301, mononitroguaiacol sodium, undecirenic acid, etc. can be mentioned.

Antioxidants include butylhydroxyanisole, propyl gallate, and elisorbic acid. Examples of pH adjusters include citric acid, sodium citrate, malic acid, sodium malate, fumal acid, sodium fumalate, succinic acid, sodium succinate, sodium hydroxide, and sodium monohydrogen phosphate. Examples of alcohol include higher alcohols such as cetyl alcohol.

In addition, the mixing ingredients that may be added are not limited to this, and any of the above ingredients can be mixed within the range that does not impair the purpose and effect of the present invention, but in an amount of 0.01-5% by weight or 0.01-3% based on the total weight. Can be formulated in % weight percentages.

When the formulation of the present invention is a lotion, paste, cream or gel, the carrier ingredients include animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. It can be used.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used as the carrier ingredient. In particular, when the formulation is a spray, chlorofluorohydrocarbon and propane may be used as carrier ingredients. /May contain propellants such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solvating agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 , 3-butyl glycol oil, fatty esters of glycerol, fatty acid esters of polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, the carrier ingredients include water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, and microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used.

When the formulation of the present invention is a surfactant-containing cleansing agent, the carrier ingredients include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, and fatty acid amide. Ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linoline derivative, or ethoxylated glycerol fatty acid ester can be used.

Additionally, the present invention provides a skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to the present invention to the skin of an individual in need thereof. In this specification, “application” includes all means of providing a cosmetic composition to the skin, such as administration, injection, or application.

In addition, in another aspect of the present invention, the present invention provides a topically applied preparation for preventing or improving pigmentation, comprising an altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The topical application preparations may be in the form of creams, gels, lotions, powders, powder sprays, oils, roll-on formulations, ointments, foams, sprays, sticks or tinctures.

In addition, the present invention provides, in another aspect of the present invention, a food composition and health functional food for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient, wherein the salt is foodologically acceptable. It may be salt.

As used herein, the term “foodologically acceptable salt” includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.

When using the altiratinib derivative or its salt of the present invention as a food additive, the altiratinib derivative or its salt can be added as is or used with other foods or food ingredients, and can be used appropriately according to conventional methods. . The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). In general, when manufacturing food or beverages, the altiratinib derivative of the present invention or its salt may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

There are no special restrictions on the types of foods above. Examples of foods to which the above substances can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, These include alcoholic beverages and vitamin complexes, and include all health functional foods in the conventional sense.

The health drink composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional drinks. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame can be used. The proportion of natural carbohydrates is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.

In addition to the above, the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may contain carbonating agents used in carbonated drinks. In addition, the composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients can be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.

In this specification, “health functional food” is the same term as food for special health use (FoSHU), and refers to food with high medical and medical effects that has been processed to efficiently exhibit bioregulatory functions in addition to supplying nutrients. This means that the food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to achieve useful effects in preventing or improving obesity.

The health functional food of the present invention can be manufactured by a method commonly used in the industry, and can be manufactured by adding raw materials and components commonly added in the industry. In addition, unlike general drugs, it is made from food, so it has the advantage of not having any side effects that may occur when taking the drug for a long time, and it can be highly portable.

The health functional food has the advantage of having better effects when consumed in the form of inner beauty food. The inner beauty is a food referred to as 'edible cosmetics or beauty food'. It refers to foods that change the skin constitution to a healthy one by absorbing various ingredients that are good for the skin into the body. It refers to foods that change the skin constitution to a healthy one by selecting cosmetics that suit your skin type. You can select and consume inner beauty foods that suit each individual, considering their skin condition and lifestyle. For example, when cosmetics containing the above cosmetic composition are mixed with inner beauty food containing altilatinib derivatives or salts thereof, the effect is significantly higher compared to using only cosmetics or drugs, resulting in a more effective pigmentation prevention or improvement effect. Of course, it can have the advantage of seeing a whitening effect.

In addition, the present invention provides, in another aspect of the present invention, a quasi-drug composition for preventing or improving pigmentation, comprising an altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The term "quasi-drug" as used in the present invention refers to products that have a milder effect than pharmaceuticals among products used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases in humans or animals. For example, the Pharmaceutical Affairs Act According to the Act, quasi-drugs exclude products used for medicinal purposes and include products used to treat or prevent diseases in humans and animals, and products that have a mild or no direct effect on the human body.

When using the altiratinib derivative of the present invention or a pharmaceutically acceptable salt thereof as a quasi-drug additive, it can be added as is or used together with other quasi-drugs or quasi-drug components, and can be used appropriately according to conventional methods. The mixing ratio with other ingredients used together can be appropriately determined depending on the purpose of use (eg, prevention, improvement or therapeutic treatment).

Examples of the quasi-drug composition of the present invention include, but are not limited to, scalp and hair care compositions such as masks, ointments, creams, lotions, essences, sprays, shampoos, and rinses, body cleansers, foams, and soaps.

The content of the altiratinib derivative of the present invention or a pharmaceutically acceptable salt thereof is not limited to the total weight of the quasi-drug composition, but is 0.001% by weight to 0.1% by weight, more preferably 0.0001% by weight to 1% by weight. may be included.

In addition, the present invention provides a kit for preventing or improving pigmentation, comprising a pharmaceutical composition, a composition for inhibiting CRTC3, a cosmetic composition, a topical application preparation, a food composition, or a quasi-drug composition according to the present invention.

“Kit” according to the present invention is intended to achieve the object of the present invention, namely, preventing, improving, or treating pigmentation; skin whitening; Alternatively, tools and/or reagents known in the art necessary for achieving skin care, etc. may be additionally included. For example, the kit further includes instructions describing a skin care method for preventing or improving pigmentation according to the present invention, or an instrument necessary for administering, applying, or absorbing the composition according to the present invention, such as a syringe. , cotton, cotton swabs, sheets, puffs, etc. may be further included.

The term "active ingredient" used in this specification refers to an ingredient that can exhibit the desired activity alone or in combination with a carrier that is inactive on its own.

Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.

[Experimental method]

1. Cell culture

Mel-Ab cells, a mouse melanocyte cell line, were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS, 1% P/S, 100 nM TPA, and 1 nM CT. For the experiment, 7 × 10 ⁵ cells were seeded in a 100 mm dish and cultured at 37°C and 5% CO ₂ for 6 days, and the old medium was replaced with new medium every 48 to 72 hours during the culture period. It was replaced with . B16F10, another mouse melanocyte cell line, was cultured in DMEM medium containing 10% FBS and 1% P/S under the same conditions as above.

Human primary melanocytes (hMC, normal human melanocytes; NHM) were cultured in Medium 254 (Gibco) supplemented with human melanocyte growth supplement (Gibco). Cultured at 37°C and 5% CO ₂ conditions, the medium was replaced every 2 to 3 days. The experiment was performed when the cell confluency reached 70% or more.

2. Measurement of melanin content

Mel-Ab, B16F10, and hMC treated with or without 10 μM FSK (Forskolin) for 1 hour were treated with altiratinib or altiratinib derivative compounds, and cultured for 72 hours. Before measuring the melanin content, check the cell condition by checking the cells under a microscope (Olympus, Tokyo, Japan). After removing the cell culture medium, the cells washed with PBS were dissolved in 550 μl of 1N NaOH and incubated at 100°C for 30 minutes. Heated. After cooling for a while at room temperature, it was centrifuged at 13,000 rpm for 5 minutes. The absorbance of the supernatant was measured at 405 nm using a microplate reader. The intracellular melanin content was expressed as a percentage relative to the cell control group that was not treated with altiratinib or altiratinib derivative compound and FSK.

3. Cytotoxicity assay

B16F10 cells were seeded in a 6-well cell culture plate at 1.2×10 ⁵ cells/well. After 24 hours, the medium was replaced with DMEM containing 10% FSB and 1% AA (antibiotic antimycotic), and the drug was treated 1 hour later. Mel-ab cells were seeded at 3×10 ⁵ cells/well in a 6 well cell culture plate. After washing with 1×PBS, the medium was replaced with DMEM medium containing 10% FBS and 1% AA without CT (Cefixime Tellurite) and TPA (Tissue type plasminogen activator), and treated with drugs 1 hour later. hMC cells were seeded in a 6-well cell culture plate at 6.0×10 ⁵ cells/well.

After 24 hours, the medium was replaced with Media 254 containing HMGS (Human Melanocyte Growth Supplement) and 1% A.A., and the drug was treated 1 hour later. After drug treatment, the cells were cultured for 72 hours.

Cell viability was measured using the MTT assay. After 72 hours of drug treatment, the medium was removed and washed with PBS. Afterwards, the MTT solution dissolved in PBS was added to the medium to a concentration of 2.5 mg/ml, and cultured for 2 hours in an environment of 37°C and 5% CO ₂ . The generated formazan crystals were dissolved in DMSO. Absorbance was measured at 565 nm using a microplate reader (Molecular Devices, Sunnyvale, CA, USA). Cell viability was expressed as a percentage relative to control cells without drug treatment.

4. Parallel artificial membrane permeability assay (PAMPA)

To measure the skin permeability of altiratinib derivatives, the SKIN PAMPA Explorer Test system (Pion Inc.) was used according to the manufacturer's instructions. Incubate the membrane of the acceptor plate with hydration buffer (Pion Inc., #120706) at room temperature for 15-18 hours, dispense PRISMA HT buffer (Pion Inc., #110151) at pH 7.4 to the deep well plate, and prepare by mixing the test substances. did. After dispensing 150 μl of PRISMA HT buffer per well into a UV plate, the absorbance was measured to obtain a blank value, and the mixture in the deep well plate was dispensed into a UV plate at 150 μl per well, and then the absorbance was measured to obtain an initial value. 200 μl of the mixture from the Accetor plate was dispensed onto the donor plate of Stirwell PAMPA sandwich (Pion Inc., #120657), and 200 μl of PRISMA HT buffer was dispensed into each well of the Acceptor plate. After combining the acceptor plate and donor plate and incubating at 25°C for 5 hours, the acceptor plate and donor plate were separated, 150 μl of each was transferred to a UV plate, and the absorbance was measured to obtain the donor and acceptor values. After measuring the absorbance of each sample through a microplate reader, the transmittance value (P _e , 10 ^-6 cm/sec) was analyzed using the PAMPA explorer program, and the average and standard of replicates (n=3) were calculated using the Microsoft Excel program. The deviation was calculated.

[Example]

Example 1. Synthesis of altiratinib derivatives

[Scheme 1]

Reagents and conditions: (a) NaH, DMF, 57%; (b) cyclopropanecarboxamide, Pd ₂ (dba) ₃ , rac -BINAP, K ₃ PO ₄ , 1,4-dioxane, 100°C, 37%; (c) Zn, NH ₄ Cl, MeOH, THF, 0°C, 83%; (d) acids, TBTU, i Pr ₂ NEt, DMF, 6-61%; (e) acids, HATU, i Pr ₂ NEt, DMF, 5-60%; (f) acids, DCC, HOBt, THF, 60°C, 8-17%; (g) 4M HCl in 1,4-dioxane, CH ₂ Cl ₂ , 2% (2-step yield).

The synthesis of Altiratinib began with nucleophilic aromatic substitution of phenol (Compound 1) and aryl fluoride (Compound 2). Compound 4 was produced by Pd-catalyzed Suzuki coupling of aryl chloride (compound 3) and cyclopropanecarboxamide, and aniline (compound 5) was produced by nitro reduction using zinc and ammonium chloride. Altiratinib derivatives were produced through amide coupling reaction between acids containing various bicyclic heterocycles and aniline (compound 5). The specific synthetic route is as follows (however, compound ALT-005 is an intermediate and its synthesis is described separately below):

step a: O-Arylation

A solution of 2-chloropyridin-4-ol (100.0 mg, 0.77 mmol) in DMF (1000.0 μL) was added to a suspension of sodium hydride (60% in dispersion, 40.1 mg, 1.00 mmol) in DMF (430.0 μL) at 0°C. . The mixture was stirred for 30 min, and a solution of 1,2,4-trifluoro-5-nitrobenzene (150.0 mg, 0.85 mmol) in DMF (500.0 μL) was added at the same temperature. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to remove most of the DMF in the mixture, and then partitioned between ethyl acetate and 10% aqueous lithium chloride. The formed precipitate was removed through suction filtration and the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (×2), saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25% EtOAc/ n -hexane) to obtain 125.8 mg (57%) of yellow solid 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (Compound 3). Obtained; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 9.3, 6.8 Hz, 1H), 7.14 (dd, J = 10.3, 6.4 Hz, 1H) , 6.96 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 5.7, 2.2 Hz, 1H); LCMS (ESI), m/z = 328.07 [M+1+CH ₃ CN] ⁺ .

step b: Buchwald-Hartwig amination

2 in 1,4-dioxane (3720.0 μL) in a mixture of Pd ₂ (dba) ₃ (61.3 mg, 0.07 mmol), rac -BINAP (83.0 mg, 0.13 mmol), and K ₃ PO ₄ (592.0 mg, 2.79 mmol). -chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (compound 3, 320.0 mg, 1.12 mmol) and cyclopropanecarboxamide (380.0 mg, 4.47 mmol) were added to 1,4-dioxane (3720.0 μL). The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (25% to 30% EtOAc/ n -hexane) to yield 150.1 mg (37%) of yellow solid N-(4-(2,5-difluoro-4). -nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide (Compound 4) was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26-8.22 (m, 2H), 8.02 (dd, J = 9.5, 6.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 10.7, 6.5 Hz, 1H), 6.73 (dd, J = 5.7, 2.4 Hz, 1H), 1.57-1.51 (m, 1H), 1.10-1.06 (m, 2H), 0.94-0.89 (m, 2H) ; LCMS (ESI), m/z = 336.08 [M+1] ⁺ .

step c: Nitro Reduction

NH ₄ in a solution of N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide (Compound 4, 150.0 mg, 0.45 mmol) in methanol (2237.0 μL) and THF (2237.0 μL). Cl (239.0 mg, 4.47 mmol) and zinc dust (293.0 mg, 4.47 mmol) were added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through a pad of Celite washed well with methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with additional water and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by NH ₂ silica gel chromatography (30% EtOAc/ n -hexane) to obtain 113.0 mg (83%) of a white solid, N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl. )cyclopropanecarboxamide (compound 5) was obtained; ^1H NMR (400 MHz, DMSO -d6 ) δ 10.83 (s, _1H ), 8.17 (d, J = 5.7 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 11.2, 7.5 Hz, 1H), 6.75-6.67 (m, 2H), 5.51 (s, 2H), 2.00-1.94 (m, 1H), 0.79-0.77 (m, 4H); LCMS (ESI), m/z = 306.11 [M+1] ⁺ .

step d or e: Amide Coupling-A

Acid (1.2 equiv), N,N -diisopropylethylamine as a coupling reagent in a solution of N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (compound 5, 1.0 equiv) in DMF. (DIPEA, 5.0 equiv) and TBTU ( O -(benzotriazol-1-yl)- N,N,N',N' -tetramethyluronium tetrafluoroborate, step d) (1.2 equiv) or HATU (1-[Bis(dimethylamino)methylene ]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxid hexafluorophosphate, step e) (1.2 equiv) was added. The reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (×3) and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure.

step f: Amide Coupling-B

A solution of N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (compound 5, 1.0 equiv) in THF with acid (1.2 equiv) and 1-hydroxybenzotriazole (1.1 equiv) as coupling reagents. equiv) and DCC ( N , N' -dicyclohexylcarbodiimide) (1.1 equiv) were added. The reaction mixture was stirred at 60°C. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (×3) and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure.

1-1. N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-001, Compound 6d)

[Compound 6d]

After the amide coupling reaction of 2-(benzo[ d ]isoxazol-3-yl)acetic acid (17.4 mg, 0.10 mmol) using TBTU for 22 hours through step d, NH ₂ silica gel chromatography (30% EtOAc/ n - hexane) of 12.6 mg (32%) of pale yellow solid N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 95%, compound 6d) was obtained; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.36-8.30 (m, 2H), 8.12 (d, J = 5.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H) , 7.75 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.42-7.38 (m, 1H), 6.96 (dd, J = 10.5, 6.9 Hz, 1H), 6.59 (dd, J = 5.8, 2.3 Hz, 1H), 4.20 (s, 2H), 1.54-1.48 (m, 1H), 1.07-1.03 (m, 2H), 0.91-0.84 (m, 2H); LCMS (ESI), m/z = 465.22 [M+1] ⁺ .

1-2. N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-002, Compound 7a)

[Compound 7a]

After the amide coupling reaction of 2-(benzo[ d ]oxazol-2-yl)acetic acid (17.4 mg, 0.10 mmol) using TBTU for 76 hours through step d, NH ₂ silica gel chromatography (30% to 50% EtOAc) / n -hexane) of 8.5 mg (27%) of an ivory solid N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2 -yl)cyclopropanecarboxamide (purity 98%, compound 7a) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.90 (s, 1H), 10.57 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.3, 7.2 Hz, 1H), 7.76-7.73 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.9, 7.4 Hz, 1H), 7.44-7.37 (m, 2H), 6.77 (dd , J = 5.7, 2.4 Hz, 1H), 4.31 (s, 2H), 2.01-1.91 (m, 1H), 0.86-0.77 (m, 4H); LCMS (ESI), m/z = 465.16 [M+1] ⁺ .

1-3. N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-003, Compound 6a)

[Compound 6a]

Through step e, amide coupling reaction of 2-(1 H -indazol-3-yl)acetic acid (17.3 mg, 0.10 mmol) was performed using HATU for 42 hours, followed by NH ₂ silica gel chromatography (60% EtOAc/ n -hexane). ) as 1.4 mg (5%) of white solid N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 99%, compound 6a) was obtained; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19-8.12 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.44-7.40 (m, 1H), 7.25-7.16 (m, 2H), 6.70 (dd, J = 5.8, 2.4 Hz, 1H), 4.21 (s, 2H), 1.89-1.83 ( m, 1H), 0.96-0.85 (m, 4H); LCMS (ESI), m/z = 464.23 [M+1] ⁺ .

1-4. N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (TFA salt, ALT-004, Compound 6b)

[Compound 6b]

2-(5-fluoro-1 H -indazol-3-yl)acetic acid (2-(benzo[ d ]oxazol-2-yl)acetic acid (19.0 mg, 0.10 mmol) using TBTU for 76 hours through step d 2.4 mg (6%) of colorless oil N -(4-(2,5-difluoro-4-( 2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 96%, compound 6b) was obtained; ¹ H NMR (400 MHz, CD ₃ OD); δ 8.26-8.21 (m, 2H), 7.55-7.48 (m, 2H), 7.38 (dd, J = 10.5, 7.1 Hz, 1H), 7.24 (td, J = 9.1, 2.4 Hz, 1H), 7.08-7.06 (m, 2H), 4.19 (s, 2H), 1.86-1.80 (m, 1H), 1.11-1.00 (m, 4H); LCMS (ESI), m/z = 482.08 [M+1] ⁺ .

1-5. N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (ALT-005)

2-oxo-1,2,3 as a coupling reagent to a solution of 4-((2-chloropyridin-4-yl)oxy)-2,5-difluoroaniline (20.0 mg, 0.08 mmol) in DMF (520.0 μL). 4-tetrahydroquinoline-3-carboxylic acid (22.4 mg, 0.12 mmol), N,N -diisopropylethylamine (67.9 μL, 0.39 mmol), and TBTU (50.0 mg, 0.16 mmol) were added. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (×3) and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The crude mixture was recrystallized from dichloromethane (5.0 mL) to obtain 27.0 mg (79%) of a yellow solid N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)- 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (purity 98%, ALT-005) was obtained; ^1H NMR (400 MHz, DMSO -d ₆ ) δ 10.49 (s, 1H), 10.37 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 8.26 (dd, J = 12.5, 7.2 Hz, 1H), 7.62 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 3H), 7.07 (dd, J = 5.8, 2.3 Hz, 1H), 6.99-6.95 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.93 (dd, J = 12.1, 6.6 Hz, 1H), 3.22 (dd, J = 16.2, 12.3 Hz, 1H), 3.12 (dd, J = 16.1, 6.6 Hz, 1H); LCMS (ESI), m/z = 430.10 [M+1] ⁺ .

1-6. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (TFA salt, ALT- 006, compound 9a)

[Compound 9a]

Through step d, amide coupling reaction of 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (18.8 mg, 0.1 mmol) using TBTU for 19 hours was followed by prep-HPLC (with 0.1% TFA). 24.0 mg (61%) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2- from 20% to 100% water/acetonitrile) oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (purity 99%, compound 9a) was obtained. Compound 9a is the TFA salt of ALT-008; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.94 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.25-8.20 (m, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H) ), 6.78 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd, J = 15.6, 12.5 Hz, 1H), 3.13 (dd, J = 16.0, 6.6 Hz, 1H), 2.01-1.95 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1] ⁺ .

1-7. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (TFA salt, ALT- 007, compound 9b)

[Compound 9b]

Through step d, amide coupling reaction of 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (18.8 mg, 0.1 mmol) using TBTU for 88 hours was followed by prep-HPLC (with 0.1% TFA). 2.6 mg (7%) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1- from 20% to 100% water/acetonitrile) oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (purity 97%, compound 9b) was obtained; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (d, J = 6.6 Hz, 1H), 8.08 (dd, J = 12.0, 7.1 Hz, 1H), 8.00 (dd, J = 7.7, 0.9 Hz, 1H) ), 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.42-7.30 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 6.6, 2.5 Hz, 1H) , 4.62 (t, J = 5.9 Hz, 1H), 3.51 (dd, J = 16.2, 6.1 Hz, 1H), 3.38-3.34 (m, 1H), 1.87-1.81 (m, 1H), 1.10-0.99 (m , 4H); LCMS (ESI), m/z = 479.10 [M+1] ⁺ .

1-8. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (ALT-008)

[ALT-008]

5.0 mg (0.01 mmol) of N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- with sat Tetrahydroquinoline-3-carboxamide TFA salt (ALT-006) was treated. An aqueous NaHCO ₃ solution gave the residue partitioned between ethyl acetate and water. The organic layer was washed with additional water, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 3.4 mg (85%) of a pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)- 2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (99% purity, ALT-008) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.92 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.24-8.20 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.97 (td, J = 7.5 , 0.9 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd , J = 15.8, 12.3 Hz, 1H), 3.13 (dd, J = 16.1, 6.6 Hz, 1H), 2.01-1.92 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1] ⁺ .

1-9. N -(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-009, Compound 6f)

[Compound 6f]

After the amide coupling reaction of 2-(1 H -indol-3-yl)acetic acid (27.5 mg, 0.16 mmol) using HATU for 17 hours through step e, NH ₂ silica gel chromatography (60% EtOAc/ n -hexane ) as 4 mg (6%) of pale yellow solid N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 6f) was obtained, purity 96%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 - 8.31 (m, 3H), 8.09 (d, J = 5.8 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 - 7.18 (m, 1H), 6.82 (dd, J = 10.6, 6.9 Hz, 1H), 6.56 (dd , J = 5.8, 2.4 Hz, 1H), 3.95 (s, 2H), 1.54 - 1.47 (m, 1H), 1.07 - 1.02 (m, 2H), 0.89 - 0.83 (m, 2H); LCMS (ESI), m/z = 463.14 [M+1] ⁺ .

1-10. N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-010, Compound 7c)

[Compound 7c]

After the amide coupling reaction of 2-(1 H -indol-2-yl)acetic acid (27.5 mg, 0.16 mmol) using HATU for 30 hours through step e, NH ₂ silica gel chromatography (85% EtOAc/ n -hexane ) as 22.3 mg (36%) of a pale brown solid N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 7c) was obtained with a purity of 97%; ^1H NMR (400 MHz, DMSO _- d6 ) δ 11.00 (s, 1H), 10.90 (s, 1H), 10.25 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 ( d, J = 8.6 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.97 - 6.91 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 6.30 (s, 1H), 3.96 (s, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 463.13 [M+1] ⁺ .

1-11. N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-011, Compound 6e)

[Compound 6e]

After the amide coupling reaction of 2-(benzo[ d ]isothiazol-3-yl)acetic acid (30.4 mg, 0.16 mmol) using HATU for 48 hours through step e, NH ₂ silica gel chromatography (40% EtOAc/ n - hexane) of 16 mg (25%) of pale yellow solid N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 97%, compound 6e) was obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, 1H), 10.51 (s, 1H), 8.23 - 8.19 (m, 3H), 8.11 (dd, J = 12.4, 7.2 Hz, 1H), 7.67 - 7.51 (m, 4H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.41 (s, 2H), 2.01 - 1.93 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 481.12 [M+1] ⁺ .

1-12. N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-012, Compound 7f)

[Compound 7f]

After the amide coupling reaction of 3-(benzo[ d ]oxazol-2-yl)propanoic acid (30.1 mg, 0.16 mmol) using HATU for 17 hours through step e, NH ₂ silica gel chromatography (45% EtOAc/ n - hexane) as a pale yellow solid, N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 98%, compound 7f) was obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, 1H), 10.21 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.09 (dd, J = 12.4, 7.2 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 10.9, 7.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.74 (dd , J = 5.7, 2.4 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.08 - 3.05 (m, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 5.7 Hz, 4H); LCMS (ESI), m/z = 479.13 [M+1] ⁺ .

1-13. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide (ALT-013, Compound 8c)

[Compound 8c]

After the amide coupling reaction of benzo[ d ]thiazole-6-carboxylic acid (28.2 mg, 0.16 mmol) using HATU for 21 hours through step e, 6.2 mg was obtained by NH ₂ silica gel chromatography (35% EtOAc/ n -hexane). (10%) of yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide (purity 96%, Compound 8c ) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.94 (s, 1H), 10.50 (s, 1H), 9.59 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.25 - 8.23 ( m, 2H), 8.13 (dd, J = 8.6, 1.7 Hz, 1H), 7.90 (dd, J = 11.6, 7.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 467.06 [M+1] ⁺ .

1-14. N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-014, Compound 6i)

[Compound 6i]

Through step e, amide coupling reaction of 3-(1 H -indol-3-yl)propanoic acid (29.8 mg, 0.16 mmol) was performed using HATU for 18 hours, followed by NH ₂ silica gel chromatography (50% EtOAc/ n -hexane). ) to obtain 27.1 mg (42%) of pale yellow solid N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 6i) was obtained with a purity of 96%; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.92 (s, 1H), 10.79 (s, 1H), 10.03 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.13 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.01 - 6.96 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.04 - 3.00 (m, 2H), 2.83 - 2.79 ( m, 2H), 2.00 - 1.94 (m, 1H), 0.80 - 0.75 (m, 4H); LCMS (ESI), m/z = 477.16 [M+1] ⁺ .

1-15. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indene-3-carboxamide (ALT-015, Compound 9c)

[Compound 9c]

After the amide coupling reaction of 1 H -indene-3-carboxylic acid (25.2 mg, 0.16 mmol) using HATU for 50 hours through step e, 5.2 mg (9%) was obtained by silica gel chromatography (50% EtOAc/ n -hexane). ) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indene-3-carboxamide (purity 96%, compound 9c) Obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H), 10.23 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H) , 7.89 (dd, J = 11.7, 7.1 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.33 (t, J = 7.0 Hz, 1H), 7.27 ( td, J = 7.4, 1.1 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 3.66 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 6.1 Hz) , 4H); LCMS (ESI), m/z = 448.13 [M+1] ⁺ .

1-16. N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-016, Compound 6j)

[Compound 6j]

Amide coupling reaction of 2-(3-oxoisoindolin-1-yl)acetic acid (22.6 mg, 0.12 mmol) using DCC for 72 hours through step f, followed by NH ₂ silica gel chromatography (3% MeOH/CH ₂ Cl ₂ ) as 8 mg (17%) of pale yellow solid N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide( Compound 6j) was obtained with a purity of 98%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.94 (s, 1H), 10.16 (s, 1H), 8.75 (s, 1H), 8.26 - 8.16 (m, 2H), 7.70 - 7.59 (m, 4H) ), 7.59 - 7.48 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 5.04 - 4.97 (m, 1H), 3.02 (dd, J = 15.2, 5.5 Hz, 1H), 2.70 ( dd, J = 15.2, 8.3 Hz, 1H), 2.00 - 1.94 (m, 1H), 0.77 (d, J = 5.4 Hz, 4H); LCMS (ESI), m/z = 479.10 [M+1] ⁺ .

1-17. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide (ALT-017, compound 8g)

[Compound 8g]

Amide coupling reaction of 1-( tert -butoxycarbonyl)-1 H -indole-6-carboxylic acid (82.0 mg, 0.31 mmol) using DCC for 72 hours through step f, followed by prep-HPLC (20% with 0.1% TFA) 10.5 mg (7%) of tert -butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl as a mixture in 100% water/acetonitrile) )-1 H -indole-1-carboxylate (Compound 8d, Compound 8d is a Boc protected intermediate) was obtained. tert -butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl)-1 H -indole- dissolved in CH ₂ Cl ₂ (736.0μL) 4M HCl dissolved in 1,4-dioxane (190 μl, 0.76 mmol) was added to the 1-carboxylate mixture (10.5 mg) at room temperature, and the mixture was stirred for 19 hours. The solvent was evaporated under reduced pressure. The residue was purified by NH ₂ silica gel chromatography (100% EtOAc/n-hexane) to yield 2.9 mg (2%, 2-step yield) of beige solid N -(4-((2-(cyclopropanecarboxamido) pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide (purity 98%, compound 8g) was obtained; ^1H NMR (400 MHz, acetone- d ₆ ) δ 10.73 (s, 1H), 9.83 (s, 1H), 9.31 (s, 1H), 8.32 (dd, J = 12.4, 7.2 Hz, 1H), 8.23 - 8.15 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.57 (t, J = 2.8 Hz, 1H), 7.36 (dd, J = 10.7, 7.3 Hz) , 1H), 6.72 (dd, J = 5.7, 2.4 Hz, 1H), 6.61 - 6.57 (m, 1H), 1.98 - 1.94 (m, 1H), 0.91 - 0.86 (m, 2H), 0.86 - 0.79 (m , 2H); LCMS (ESI), m/z = 490.45 [M+ ACN +1] ⁺ .

1-18. N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-018, compound 6h)

[Compound 6h]

After the amide coupling reaction of 2-(benzo[ b ]thiophen-3-yl)acetic acid (30.2 mg, 0.16 mmol) using HATU for 31 hours through step e, NH ₂ silica gel chromatography (25% EtOAc/ n - hexane) of 14.3 mg (22%) of white solid N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 97%, compound 6h) was obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.93 (s, 1H), 10.40 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.4, 7.2 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 10.9, 7.4 Hz, 1H), 7.46 - 7.37 (m, 2H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.08 (s, 2H), 2.00 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 480.00 [M+1] ⁺ .

1-19. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide (ALT-019, Compound 8f)

[Compound 8f]

After the amide coupling reaction of benzo[ b ]thiophene-6-carboxylic acid (28.0 mg, 0.16 mmol) using HATU for 30 hours through step e, 4.5 mg was obtained by NH ₂ silica gel chromatography (20% EtOAc/ n -hexane). (7%) of white solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide (purity 95%, compound 8f) ) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.93 (s, 1H), 10.39 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 - 7.97 ( m, 3H), 7.89 (dd, J = 11.7, 7.0 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 6.80 (dd, J = 5.7, 2.4 Hz) , 1H), 2.00 - 1.96 (m, 1H), 0.79 (d, J = 5.6 Hz, 4H); LCMS (ESI), m/z = 466.00 [M+1] ⁺ .

1-20. N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-020, Compound 6k)

[Compound 6k]

Amide coupling reaction of 32-(2-oxoindolin-3-yl)acetic acid (22.6 mg, 0.12 mmol) using DCC for 22 hours through step f, followed by NH ₂ silica gel chromatography (95% EtOAc/ n -hexane) 4 mg (8%) of white solid N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 98) %, compound 6k) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.89 (s, 1H), 10.42 (s, 1H), 10.16 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.07 (dd, J = 12.3, 7.2 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 10.8, 7.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.11 (dd, J = 16.1, 4.9 Hz, 1H), 2.86 (dd, J = 16.1, 7.9 Hz, 1H), 1.97 - 1.94 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 479.00 [M+1] ⁺ .

1-21. N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-021, compound 6g)

[6g of compound]

After the amide coupling reaction of 2-(benzofuran-3-yl)acetic acid (27.7 mg, 0.16 mmol) using HATU for 30 hours through step e, 8.8 was obtained by NH ₂ silica gel chromatography (45% EtOAc/ n -hexane). mg (14%) of white solid N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (98% purity, 6 g of compound) was obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, 1H), 10.34 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.10 (dd, J = 12.3, 7.2 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.36 - 7.25 (m, 2H) ), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.91 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 5.5 Hz, 4H); LCMS (ESI), m/z = 464.00 [M+1] ⁺ .

1-22 N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-022, Compound 7d)

[Compound 7d]

Through step e, amide coupling reaction of 2-(benzofuran-2-yl)acetic acid (27.7 mg, 0.16 mmol) using HATU for 30 hours was followed by NH ₂ silica gel chromatography (35% EtOAc/ n -hexane) for 6.5 mg (11%) of pale yellow solid N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 99%, compound 7d) ) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.90 (s, 1H), 10.38 (s, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.3, 7.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.30 - 7.20 (m, 2H), 6.81 (s, 1H), 6.76 (dd, J = 5.7, 2.4 Hz) , 1H), 4.09 (s, 2H), 2.00 - 1.96 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 464.00 [M+1] ⁺ .

1-23. N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-023, Compound 7e)

[Compound 7e]

After the amide coupling reaction of 2-(benzo[ b ]thiophen-2-yl)acetic acid (30.2 mg, 0.16 mmol) using HATU for 21 hours through step e, NH ₂ silica gel chromatography (35% EtOAc/ n - hexane) of 5.5 mg (8%) of yellow solid N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 96%, compound 7e) was obtained; ^1H NMR (400 MHz, acetone- d ₆ ) δ 9.78 (s, 1H), 9.52 (s, 1H), 8.37 (dd, J = 12.6, 7.3 Hz, 1H), 8.17 (d, J = 5.7 Hz, 1H), 7.87 (dd, J = 13.7, 4.8 Hz, 2H), 7.83 - 7.76 (m, 1H), 7.40 - 7.27 (m, 4H), 6.69 (dd, J = 5.7, 2.4 Hz, 1H), 4.22 (s, 2H), 1.98 - 1.97 (m, 1H), 0.91 - 0.87 (m, 2H), 0.85 - 0.80 (m, 2H); LCMS (ESI), m/z = 480.00 [M+1] ⁺ .

1-24. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide (ALT-024, Compound 8a)

[Compound 8a]

Through step f, amide coupling reaction of 1 H -benzo[ d ]imidazole-6-carboxylic acid (25.5 mg, 0.16 mmol) was performed using DCC for 18 hours, followed by silica gel chromatography (5% MeOH/CH ₂ Cl ₂ ). 3.8 mg (6%) of white solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide( Compound 8a) was obtained with a purity of 96%; ^1H NMR (400 MHz, DMSO _- d6 ) δ 12.80 (s, 1H), 10.93 (s, 1H), 10.30 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.25 ( d, J = 5.7 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.74 - 7.68 (m, 2H), 7.58 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.01 - 1.97 (m, 1H), 0.82 - 0.76 (m, 4H); LCMS (ESI), m/z = 450.00 [M+1] ⁺ .

1-25. N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-025, Compound 6c)

[Compound 6c]

After the amide coupling reaction of 2-(5-methoxy-1 H -indazol-3-yl)acetic acid (32.4 mg, 0.16 mmol) using HATU for 21 hours through step e, silica gel chromatography (75% EtOAc/ n -hexane), 12.8 mg (19%) of dark orange (da is orange) solid N -(4-(2,5-difluoro-4-(2-(5-methoxy- 1H- indazol-3-yl)) acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 97%, compound 6c) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 12.73 (s, 1H), 10.90 (s, 1H), 10.36 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.11 (dd, J = 12.4, 7.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 ( d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 2.3 Hz, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.12 (s, 2H), 3.78 (s, 3H) ), 2.00 - 1.94 (m, 1H), 0.81 - 0.72 (m, 4H); LCMS (ESI), m/z = 493.90 [M+1] ⁺ .

1-26. N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-026, Compound 7b)

[Compound 7b]

Amide coupling reaction of 2-(benzo[ d ]thiazol-2-yl)acetic acid (30.4 mg, 0.16 mmol) using HATU for 30 hours through step e, followed by silica gel chromatography (75% EtOAc/ n -hexane) 5.7 mg (9%) of yellow solid N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 98%, compound 7b) was obtained; ^1H NMR (400 MHz, acetone- d ₆ ) δ 10.12 (s, 1H), 9.80 (s, 1H), 8.40 (dd, J = 12.5, 7.3 Hz, 1H), 8.18 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.50 - 7.44 (m, 1H), 7.35 (dd, J = 10.9, 7.2 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 4.48 (s, 2H), 2.02 - 1.98 (m, 1H) , 0.91 - 0.87 (m, 2H), 0.86 - 0.80 (m, 2H); LCMS (ESI), m/z = 481.20 [M+1] ⁺ .

1-27. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide (ALT-027, Compound 8e)

[Compound 8e]

After the amide coupling reaction of benzofuran-6-carboxylic acid (25.5 mg, 0.16 mmol) using HATU for 18 hours through step e, 8 mg (13%) of white was obtained by silica gel chromatography (35% EtOAc/ n -hexane). Solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide (purity 95%, compound 8e) was obtained; ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.93 (s, 1H), 10.34 (s, 1H), 8.29 - 8.23 (m, 2H), 8.21 (d, J = 2.2 Hz, 1H), 7.94 - 7.81 (m, 3H), 7.71 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.3, 7.4 Hz, 1H), 7.10 (dd, J = 2.1, 0.8 Hz, 1H), 6.80 (dd , J = 5.7, 2.4 Hz, 1H), 2.03 - 1.95 (m, 1H), 0.79 (d, J = 5.8 Hz, 4H); LCMS (ESI), m/z = 450.00 [M+1] ⁺ .

1-28. N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide (ALT-028, Compound 8b)

[Compound 8b]

After the amide coupling reaction of benzo[ d ]oxazole-6-carboxylic acid (25.6 mg, 0.16 mmol) using HATU for 30 hours through step e, 27.8 mg (47 mg) was obtained by silica gel chromatography (50% EtOAc/ n -hexane). %) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide (purity 99%, compound 8b) was obtained; ^1H NMR (400 MHz, DMSO _- d6 ) δ 10.95 (s, 1H), 10.47 (s, 1H), 8.96 (s, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 11.5, 7.1 Hz, 1H), 7.70 ( d, J = 2.3 Hz, 1H), 7.62 (dd, J = 10.3, 7.4 Hz, 1H), 6.81 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.95 (m, 1H), 0.79 (d , J = 6.2 Hz, 4H); LCMS (ESI), m/z = 451.16 [M+1] ⁺ .

Example 2. Confirmation of the skin permeability improvement effect of altiratinib derivatives

As shown in Table 1, the SKIN-PAMPA assay to measure the skin permeability of altiratinib derivatives was performed under pH 8.5 conditions at 25uM, the maximum concentration at which the compound does not form a precipitate.

As a result, as shown in Table 2 and Figure 1, ALT-002 (Compound 7a) and ALT-003 (Compound 6a) were expected to have significantly improved skin permeability compared to altiratinib at pH 8.5.

Example 3. Confirmation of melanin production inhibition effect of altiratinib derivatives

Hyperpigmentation of the skin is a phenomenon caused by excessive accumulation of melanin as melanin production by melanocytes in skin tissue increases. Therefore, it was confirmed whether altiratinib derivative compounds inhibit melanin synthesis in melanocytes. did.

In addition, Forskolin (FSK) activates adenyl cyclase to induce cAMP production, and cAMP increases the expression of melanin-producing enzymes, ultimately leading to melanin production. Therefore, not only the melanin production inhibition effect of altiratinib derivative compounds in a state without stimulation of cells (without FSK treatment), but also the melanin production inhibition effect induced by FSK treatment of altiratinib derivative compounds was confirmed.

The results of confirming the melanin production inhibitory effect of altiratinib derivative compounds in Mel-Ab cells, a mouse melanocyte cell line, are shown in Table 3 and Figures 2 and 3. The melanin production inhibitory effect of altiratinib derivatives from ALT-001 to ALT-014. The results expressed as a percentage relative to the cell control group that was not treated with FSK are shown in Table 4 and Figure 4. As shown in Tables 3 to 4 and Figures 2 to 4, among Altiratinib (ALT) derivative compounds, ALT-002 (Compound 7a), ALT-003 (Compound 6a), and ALT-013 (Compound 8c) ) was confirmed to have an equal or improved melanin production inhibition effect than altiratinib, which shows that altiratinib derivative compounds can inhibit melanin production induced by forskolin, that is, cAMP.

In addition, the results of confirming the melanin production inhibition effect of altiratinib derivatives in B16F10, another mouse melanocyte cell line, are shown in Table 5 and Figures 5 to 6. The melanin production inhibition effect of altiratinib derivatives from ALT-001 to ALT-014 is shown in FSK. The results expressed as a percentage relative to the untreated cell control group are shown in Table 6. As shown in Tables 5 to 6 and Figures 5 to 6, among altiratinib derivative compounds, ALT-002 (Compound 7a) and ALT-003 (Compound 6a) have the same or improved melanin production inhibitory effect as altiratinib. It was confirmed that it had an effect of suppressing melanin production.

Furthermore, the inhibitory effect of melanin production in human primary melanocytes (hMC) of compounds ALT-002 (Compound 7a) and ALT-003 (Compound 6a), which showed equivalent or improved effects to altiratinib in mouse melanocyte cell lines. As a result of comparing with altiratinib, it was confirmed that it showed a similar or improved effect as altiratinib, as shown in Figure 7.

In addition, as a result of comparing the melanin production inhibition effect of altiratinib derivatives ALT-015 to ALT-028 in human primary melanocytes with altiratinib, as shown in FIG. 8, ALT-024 and ALT-028 were superior to altiratinib. It was confirmed that it had a similar effect to the nib.

Example 4. Confirmation of cytotoxicity of altiratinib derivatives

As a result of confirming the cytotoxicity of altiratinib derivatives against Mel-Ab cells, a mouse melanocyte cell line, as shown in Table 7 and Figures 9 and 10, among altiratinib derivative compounds, ALT-002 (Compound 7a), ALT- It was confirmed that 003 (Compound 6a) and ALT-013 (Compound 8c) showed improved cytotoxicity (toxicity within 10% at 10uM) than altiratinib.

In addition, as a result of confirming the cytotoxicity of altiratinib derivatives on B16F10, another mouse melanocyte cell line, as shown in Table 8 and Figures 11 and 12, among altiratinib derivative compounds, ALT-002 (Compound 7a) and ALT- It was confirmed that 003 (Compound 6a) and ALT-013 (Compound 8c) showed improved cytotoxicity (toxicity within 10% at 10uM) than altiratinib.

In addition, as a result of confirming the cytotoxicity of altiratinib derivatives on human primary melanocytes (hMC), as shown in Table 9 and Figures 13 and 14, among altiratinib derivative compounds, ALT-002 ( It was confirmed that Compound 7a) and ALT-003 (Compound 6a) showed improved cytotoxicity (toxicity within 10% at 10 uM) than altiratinib.

The present inventors synthesized a novel altiratinib derivative compound, and the synthesized novel altiratinib derivative compound exhibits a similar or improved effect in inhibiting melanin production as altiratinib, but has significantly lower cytotoxicity and significantly improved melanin production inhibition effect. It was confirmed that it had skin permeability. Accordingly, the present inventors confirmed the potential of the novel altiratinib derivative compound according to the present invention as a treatment for skin pigmentation. In particular, among altiratinib derivatives, ALT-002 (Compound 7a) did not show cytotoxicity even at a concentration of 10uM in both mouse melanin cell lines and human melanocytes, but showed a similar or improved effect in inhibiting melanin production as altiratinib. , ALT-003 (Compound 6a) and ALT-013 (Compound 8c) showed similar or improved melanogenesis inhibitory effects as altiratinib in mouse melanocyte cell lines and human melanocytes, and were more cytotoxic than ALT-002 in human melanocytes. It was confirmed that this strong but much lower toxicity (30% toxicity at 10uM) than altiratinib (88% toxicity at 10uM), the novel altiratinib derivative compounds according to the present invention are effective in preventing or treating skin pigmentation. It is expected that it will be useful.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.

Claims (16)

Altiratinib derivative or salt thereof represented by the following formula (1):
[Formula 1]

In Formula 1,
R ₁ is a halogen element, or ego,
R ₂ is , , , , or ego,
n is 0, 1, or 2,
Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),
A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,
A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,
A ₇ to A ₁₀ is each independently C=O, or NH,
The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
According to paragraph 1,
The altiratinib derivative is an altiratinib derivative or a salt thereof, characterized in that it is represented by any one of the following formulas 2a to 2e:
[Formula 2a]

(In Formula 2a,
n is 0, 1, or 2,
R ₃ and R ₄ are each independently a halogen element, hydrogen (H), hydroxyl group (OH), methoxy (OCH ₃ ), methyl (CH ₃ ), ethyl (CH ₂ CH ₃ ), trifluoromethyl (CF ₃ ), or nitro group (NO ₂ ),
Wherein A ₁ is N, CH, CMe, or CPh,
The A ₂ is O, S, NH, NMe, NEt, or CH _2. )
[Formula 2b]

(In Formula 2b,
n is 1 or 2,
R ₅ and R ₆ are each independently a halogen element, hydrogen (H), methoxy (OCH ₃ ), or methyl (CH ₃ ),
A ₃ is N, CH, or CMe,
where A ₄ is O, S, NH, or NMe.)
[Formula 2c]

(In Formula 2c,
Wherein A ₅ is O, S, or NH,
A ₆ is N, or CH.)
[Formula 2d]

(In Formula 2d above,
R ₁ is a halogen element, or ego,
A ₇ and A ₈ are each independently C=O, or NH.)
[Formula 2e]


(In Formula 2e above,
A ₉ and A ₁₀ are each independently C=O, or NH.)
According to paragraph 1,
The altiratinib derivative is
In Formula 1,
The R ₁ is ego,
i) When n is 0,
The R ₂ is , or ego,
ii) When n is 1,
The R ₂ is , or An altiratinib derivative or salt thereof, characterized in that.
According to paragraph 1,
The altiratinib derivative is characterized in that it is any one selected from the group consisting of the following compounds:
(1) N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] ;
(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide];
(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] ;
(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] ;
(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide];
(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] ;
(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indene-3-carboxamide] ;
(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide] ;
(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] ;
(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide];
(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] ;
(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N -(4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] ; and
(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide].
In the presence of an organic solvent, an amide coupling reaction is performed between a compound selected from a compound of formula 3 or a compound of formula 4 below and a compound of formula 5 below with a coupling reagent. A method for producing the altiratinib derivative according to claim 1, characterized in that,
A manufacturing method characterized in that the coupling reagent is at least one selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC:
[Formula 3]

[Formula 4]

[Formula 5]

In Formula 5 above,
R is , , , , or ego,
n is 0, 1, or 2,
Wherein R ₃ to R ₆ are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C ₁ -C ₅ alkoxy group, substituted or unsubstituted C ₁ -C ₅ alkyl group, Or a nitro group (NO ₂ ),
A ₁ , A ₃ , and A ₆ are each independently N, CH, CMe, or CPh,
A ₂ , A ₄ , and A ₅ are each independently O, S, NH, NMe, NEt, or CH ₂ ,
A ₇ to A ₁₀ is each independently C=O, or NH,
The 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
According to clause 5,
The organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethyl sulfoxide. A manufacturing method, characterized in that at least one selected from the group consisting of (dimethyl sulfoxide, DMSO), and dichloroethylene (DCE).
A pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
In clause 7,
The pigmentation includes freckles, freckles, lentigines, age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, gravidic chlorasma, inflammation due to wounds or dermatitis. A pharmaceutical composition, characterized in that it is one or more selected from the group consisting of post-natal hyperpigmentation, senile pigmentation, and solar lentigines.
A cosmetic composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
According to clause 9,
The cosmetic composition includes serum, lotion, paste, patch, gel, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutritional lotion, cream, massage cream, nutritional cream, mist, moisture cream, hand Cream, hand lotion, foundation, essence, nutritional essence, pack, soap, oil, foundation, makeup base, wax, spray, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion or body cleanser formulation. Characterized by a cosmetic composition.
A skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to claim 9 to the skin of an individual in need thereof.
A topically applied preparation for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
According to clause 12,
The topical application preparation is characterized in that it is in the form of a cream, gel, lotion, powder, powder spray, oil, roll-on formulation, ointment, foam, spray, stick or tincture.
A food composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
A health functional food for preventing or improving pigmentation containing the altiratinib derivative of formula 1 of claim 1 or a salt thereof as an active ingredient.
A quasi-drug composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.