TW201305108A - Amino derivatives for the treatment of proliferative skin disorders - Google Patents

Abstract

Compositions comprising specific amino derivatives for their use in treating proliferative skin diseases or disorders and the use of specific amino derivatives in such a treatment is disclosed.

Description

Amino derivative for the treatment of proliferative skin diseases

The present invention relates to a method and composition for treating a proliferative skin disease or discomfort, and more particularly to a composition having a specific amino derivative for use in the treatment of a proliferative skin disease or discomfort, and a specific amino derivative. Reveal the use of therapies.

The skin is the largest organ in the human body, covering all the outside of the body, with layers such as epidermis, dermis and subcutaneous. A variety of skin diseases are known, which can only cause discomfort or psychological stress (such as rash), while those who are severe may threaten the life of the patient (such as skin cancer).

In some countries (such as Australia or the United States), skin cancer is the most common cancer. The classification of skin cancer can be distinguished according to the type of epidermal cells involved. Basal cell carcinoma is derived from the abnormal growth of the bottom cell of the epidermis and is the most common species in skin cancer; squamous cell carcinoma (SCC) is involved in the alteration of squamous epithelial cells, which are located in the epidermal layer. Middle position; melanoma cancer occurs in melanocytes. Compared with squamous epithelial cells or basal cell carcinoma (BCC), melanocytic carcinoma of the skin is less common, but the risk is higher, so it is often the main cause of death from skin cancer.

Synthetic (syn. solar) keratosis (AK) is a pre-cancerous skin condition, which is the initial characterization of keratinocyte disease-like hyperplasia, while AK lesions can be found in a variety of squamous cell carcinomas. Cytopathic. Although most AK lesions do not actually become cancer, some of these lesions can be converted to malignant.

Today's treatments for actinic keratosis include surgical and medical treatments as well as topical medicinal preparations, including (AK Guide, D. de Barker et al., British Journal of Dermatology, 2007, 156, pp. 222-230). ):

- Cryosurgery: Although nitrous oxide or carbon dioxide has been used in cryosurgery, cryosurgery using liquid nitrogen is the most common treatment for actinic keratosis; when used, liquid nitrogen is sprayed directly Or use a cotton swab to apply it to the lesion.

- Scrapping or resection: Use a sharp curette to mechanically scrape the diseased tissue.

- Photodynamic therapy: Applying a light-sensitive agent to the affected part of each actinic keratosis, and then exposing the affected part to light of a specific wavelength, thereby causing cell death.

- Topical smear therapy: Several topical smears have been used to treat actinic keratosis, including various salicylic acid ointments, 5-fluorouracil preparations, 5% imiquimod cream (Aldara), 3% of diclofenac gel (Solaraze), tretinoin cream or massoprocol cream.

On the other hand, the enzyme dihydroorotate dehydrogenase (DHODH) is an enzyme that can be used to catalyze the fourth step in the pyrimidine biosynthesis pathway, that is, the conversion of dihydroorotate to orotic acid, accompanied by a nucleus The flavin mononucleotide mediator transfers one electron to ubiquinone (cofactor Q) (Loffler et al., Mol Cell Biochem, 1997). Compared to the parasite (Plasmodium falciparum) (McRobert et al, Mol Biochem Parasitol 2002) and bacteria (E. coli), this re-synthesis pathway is the only source for obtaining pyrimidine, and mammalian cells have another Rescue path.

During a constant hyperplasia, this rescue pathway independent of DHODH provides sufficient pyrimidine bases to the cells. However, only cells with high culling rates and (especially) T and B lymphocytes need to be re-synthesized for proliferation. In these cells, inhibition of DHODH will stop the cell division cycle progression, inhibit DNA synthesis, and thereby impede cell proliferation (Breedveld FC et al, Ann Rheum Dis 2000).

According to recent reports, DHODH enzymes can be expressed in the following cells: pre-cancerous keratinocytes (HaCat cells) and cutaneous squamous cell carcinoma cell lines (COLO16 cell line derived from metastatic squamous cell carcinoma and derived from SCC-13, SRB1 and SRB2 cell lines in skin carcinoma in situ). In these keratinocytes, the extent of DHODH expression was similar to that observed before pre-cancerous (PWR-1E) and malignant prostate epithelial cells (DU-145, LNCaP, and PC-3). These results suggest that DHODH may play a critical role in the development of skin and prostate tumors. Triflurane (2-butene hydrazine, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-; CAS RN 108605-62-5), is a fluorine Active metabolite of mites (4-isoxazolemethylammonium, 5-methyl-N-[4-(trifluoromethyl)phenyl]-; CAS RN 75706-12-6), available under the trade name Arava, used in the treatment of rheumatoid arthritis, has been reported for pre-cancerous and malignant human skin keratinocytes, which will trigger a dose- and time-dependent cytostatic effect, which in turn leads to cell dying (Hial N et Al., Apoptosis 2010).

Because skin diseases or discomforts contain a wide range of clinical symptoms, and pathology and therapy need to be considered in terms of the symptoms, symptoms, and medical history of individual patients; therefore, there is a need to find alternative therapies for the treatment of these diseases.

Surprisingly, amino derivatives as DHODH inhibitors have been found to have a better effect in inhibiting abnormal proliferation of human skin keratinocytes than teriflurane, and thus can be used to treat proliferative skin diseases or discomfort.

The present invention provides an amino derivative of the formula (I) A-NH-B, or a pharmaceutically acceptable salt or N-oxide or solvate or deuterated derivative thereof, for use in the treatment of hyperplasia Skin disease or discomfort; wherein A represents a group having one of formula A1 or A2:

Wherein the asterisk mark (*) refers to a bond to the aforementioned -NH-B moiety; and wherein: - in the group of formula A1: ‧ R ¹ represents a group selected from one of the following: a hydrogen atom; a halogen atom C _1-4 alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from a hydrogen atom and a hydroxyl group; and a C _3-8 cycloalkyl group, as the case may be 1, 2 or 3 Substituted from a halogen atom and a substituent of a hydroxyl group; one of the ‧ G ³ and G ⁴ groups is a nitrogen atom, and the other is a CH group; ‧ M is a hydrogen atom or a medicine a pharmaceutically acceptable cation; in the group of formula A2: ‧ R ¹ ' is selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _3-4 ring The alkyl group, -CF ₃ and -OCF ₃ ; ‧ R ² ' are selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkyl group; ‧ R ³ ' is selected from the following The group consisting of: -COOR ⁵ ' , -CONHR ⁵ ' , tetrazolyl, -SO ₂ NHR ⁵ ', and -CONHSO ₂ R ⁵ ' groups, wherein R ⁵ ' is selected from the group consisting of Group: a hydrogen atom and a linear or branched chain C _1-4 alkyl; B represents a group having one of formula B1 or B2:

Wherein the asterisk mark (*) refers to a bond to the aforementioned A-NH- moiety; and wherein: - in the group of formula B1: one of the ‧ G ¹ groups represents a nitrogen atom or a CR ^c a group, the other represents a CR ^c group; ‧ G ² represents a nitrogen atom or a CR ^d group; ‧ R ² represents a group selected from the group consisting of: a hydrogen atom; a halogen atom; a hydroxy group; a C _1-4 alkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _1-4 alkoxy group, which may be 1, 2 or 3 as appropriate Substituted from a halogen atom and a substituent of a hydroxyl group; and a C _3-8 cycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ^a , R ^b and R ^c each independently represent a group selected from a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group. substituted; and C _1-4 alkoxy, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; ‧ R ^d represents a group selected from one of the following: a hydrogen atom ; A halogen atom; hydroxy; C _1-4 alkyl, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; C _1-4 alkoxy which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; The limitation is that when at least one of the aforementioned R ^a and R ^b groups represents a hydrogen atom and the G ² system is a CR ^d group, then R ^d represents a group selected from one of the following groups: a C _1-4 alkoxy group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, as the case may be 1, 2 or 3 Substituted by a substituent selected from a halogen atom and a hydroxyl group; - in the group of formula B2: ‧ R ⁴ ' is selected from the group consisting of: a hydrogen atom and a C _1-4 alkyl group ; ‧ R ⁹ ' is selected from the group consisting of: a hydrogen atom and a phenyl group; ‧ G ¹ ' represents a group selected from N and CR ⁶ ' , wherein R ⁶ ' is selected from Composed of the following Group: hydrogen atom, halogen atom, C _1-4 alkyl group, C _3-4 cycloalkyl group, C _1-4 alkoxy group, -CF ₃ , -OCF ₃ , monocyclic nitrogen-containing C _5-7 heteroaryl a monocyclic nitrogen-containing C _3-7 heterocyclic group and a C _6-10 aromatic group, wherein the aforementioned aromatic group is optionally selected from a halogen atom and a C _1-4 alkyl group by one or more Substituted by a substituent; ‧ G ² ' represents a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _1-4 alkoxy group, and -NR ^a ' R ^b ' , wherein R ^a ' represents a C _1-4 alkyl group, and R ^b ' is selected from the group consisting of C _1-4 alkyl and C _1-4 alkane Oxy-C _1-4 alkyl; or R ^a ' and R ^b ' and the nitrogen atom to which R ^a ' and R ^b ' are bonded together form a saturated 6 to 8 membered heterocyclic ring, the aforementioned heterocyclic ring optionally containing an oxygen An atom, as an additional hetero atom; ‧ a 5- to 10-membered heteroaryl ring of a monocyclic or bicyclic ring containing one or more nitrogen atoms, and optionally one or more selected from halogen atoms , C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, -CF ₃ , -OCF ₃ Substituted with a substituent of -CONR ⁷ ' R ⁸ ' , wherein R ⁷ ' and R ⁸ ' are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 ring Or an alkyl group; or R ⁷ ' and R ⁸ ' together with a nitrogen atom to which R ⁷ ' and R ⁸ ' are attached to form a group having the formula:

Wherein n is an integer from 0 to 3; and ‧ a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkane Oxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, cyano, -CF ₃ , -OCF ₃ , -CONR ₇ ' TR ₈ ' , oxadiazolyl, triazolyl, pyrazole And an imidazolyl group, wherein the aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ' and R ₈ ' are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 cycloalkyl group; or, R ₇ ' and R ₈ ' are associated with a nitrogen atom to which they are attached Forming a group having the formula:

Wherein n is an integer from 0 to 3; ‧ or, when G ¹ ' represents CR ⁶ ' , G ² ' and R ⁶ ' together form a non-aromatic C _5-10 ring carbon group or a C _6-10 alkane base.

Typically, the aforementioned disease or discomfort is selected from the group consisting of: a) epithelial and hair follicle tumors, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), actinic keratosis (AK), Bowen's disease ( Bowen's disease), erythroplasia of Queyrat, leukoplakia, oral florid papillomatosis, verrucous carcinoma or keratoacanthoma; b) sebaceous adenomas, such as sebaceous gland cancer; c) sweat adenomas, such as mammary Paget's disease, extraramamary Paget's disease, eccrine porocarcinoma, microcysts Microcystic adnexal carcinoma (MAC), or mucinous carcinoma of the skin; d) nervous system tumors, such as Merkel cell carcinoma (MCC); e) mesenchymal tumors, for example Dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), atypical fibrananthoma, a Epithelioid sarcoma, synovial sarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, cutaneous lymphoma or multiple myeloma; f) skin Metastatic cancer; g) melanoma of the skin; h) lamellar ichthyosis; i) acne; or j) hirsutism.

The invention also provides a pharmaceutical composition for topical administration, which comprises only an amino derivative having the formula (I) A-NH-B, or at the same time, further comprises one or more active ingredients, thereby being used for use. For the treatment of skin diseases or discomfort, especially for the treatment of diseases or discomforts mentioned above.

The invention also provides a method for treating an individual suffering from a proliferative skin disease, the method comprising the steps of: administering an effective amount of an amino derivative of formula (I) A-NH-B, or A pharmaceutical composition comprising an amino derivative having the formula (I) A-NH-B is applied to the skin affected part of the aforementioned individual, alone or in combination with one or more active ingredients.

The invention further provides the use of an amino derivative of formula (I) A-NH-B for the manufacture of a medicament for the treatment of proliferative skin diseases or disorders, in particular the diseases or disorders defined above.

Amino derivative having the formula (I) A-NH-B:

Generally, when A represents a group having the formula A1, B represents a group having the formula B1. Generally, when A represents a group having the formula A2, B represents a group having the formula B2.

In particular, the amino derivative of the present invention is a DHODH inhibitor and is selected from the group consisting of an amino(iso)nicotinic acid derivative having the formula (I-a),

Wherein: ‧ one of the G ¹ groups represents a nitrogen atom or a CR ^c group, the other represents a CR ^c group; ‧ G ² represents a nitrogen atom or a CR ^d group; R ¹ represents a group selected from the group consisting of a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; _{a 3-8} cycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ² represents a group selected from the group consisting of a hydrogen atom; a halogen atom; C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _1-4 alkoxy group, optionally selected 1, 2 or 3 Substituted from a halogen atom and a substituent of a hydroxyl group; and a C _3-8 cycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ^a , R ^b and R ^c each independently represent a system selected from the following groups: a hydrogen atom; a halogen atom; C _1-4 alkyl, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxy substituted Substituted; and C _1-4 alkoxy, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; ‧ R ^d represents a group selected from one of the following: a hydrogen atom Halogen atom; hydroxyl group; C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _1-4 alkoxy group, as the case may be 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ one of the G ³ and G ⁴ groups is a nitrogen atom and the other is a CH group; ‧ the M system is a hydrogen atom or a pharmaceutically acceptable cation; the limitation is that When at least one of the R ^a and R ^b groups represents a hydrogen atom and the G ² system is a CR ^d group, then R ^d represents a group selected from the group consisting of C _1-4 alkoxy groups, Optionally, substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _3-8 cycloalkoxy, optionally substituted by 1, 2 or 3, selected from a halogen atom and a hydroxyl group base Substituted; or a former pharmaceutically acceptable salt or solvate thereof or a N- oxide or a stereoisomer or deuterated derivatives thereof; or an aza-biphenyl-aminobenzoic acid derivative of formula (Ib) of:

Wherein: ‧ R ¹ ' is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkyl group, C _3-4 cycloalkyl group, —CF ₃ and —OCF ₃ ; ‧ R ² ' It is selected from the group consisting of a hydrogen atom, a halogen atom, and a C _1-4 alkyl group; ‧ R ³ ' is selected from the group consisting of -COOR ⁵ , -CONHR ⁵ , tetrazole a group such as -SO ₂ NHR ⁵ ' and -CONHSO ₂ R ⁵ ' , wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a linear or branched chain C _1-4 An alkyl group; ‧ R ⁴ ' is selected from the group consisting of a hydrogen atom and a C _1-4 alkyl group; ‧ R ⁹ ' is selected from the group consisting of: a hydrogen atom And a phenyl group; ‧ G ¹ ' represents a group selected from nitrogen or CR ⁶ ' , wherein R ⁶ ' is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkane a group, a C _3-4 cycloalkyl group, a C _1-4 alkoxy group, a —CF ₃ , an —OCF ₃ , a monocyclic nitrogen-containing C _5-7 heteroaryl group, a monocyclic nitrogen-containing C _3-7 heterocyclic group, and a C _6-10 aromatic group, the aforementioned C _6-10 aromatic group being optionally selected from a halogen atom and one or more Substituted by a substituent of a C _1-4 alkyl group; ‧ G ² ' represents a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _{1 -4} alkoxy is in the group -NR ^a ' R ^b ' , wherein R ^{a '} represents a C _1-4 alkyl group, and R ^{b '} is selected from the group consisting of C _1-4 alkyl And a C _1-4 alkoxy-C _1-4 alkyl group, or R ^{a '} and R ^{b '} and ^a nitrogen atom bonded to R ^{a '} and R ^{b '} together form a saturated 6 to 8 membered heterocyclic ring, The aforementioned heterocyclic ring optionally contains an oxygen atom as an additional hetero atom; ‧ a monocyclic or bicyclic 5 to 10 membered heterocyclic ring containing one or more nitrogen atoms and optionally one or more substituents Substituted, the aforementioned substituent is selected from a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _3-4 cycloalkyl group, a C _3-4 cycloalkoxy group, -CF ₃ , OCF ₃ and -CONR ^{7 '} R ^{8 '} , wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; Or R ^{7 '} and R ^{8 '} together with the nitrogen atom to which they are attached form a group having the formula:

Wherein n is an integer from 0 to 3; and ‧ a phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkane Oxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, cyano, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 '} , oxadiazolyl, triazolyl, pyrazolyl And an imidazolyl group, wherein the aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ' and R ₈ 'These are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 cycloalkyl group; or, R ₇ ' and R ₈ ' together with a nitrogen atom to which they are attached Has one of the following formulas:

Wherein n is an integer from 0 to 3; ‧ or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C _5-10 ring carbon group or a C _6-10 An alkyl group; or a pharmaceutically acceptable salt or solvate or N-oxide or a stereoisomer or a deuterated derivative.

In the foregoing, a DHODH inhibitor typically has a hDHODH IC _{50 of} about 10 or less, preferably 5 or less, preferably 1 or less, and 1 has a The chromogen reduction reagent of 2,6-dichlorophenol-nonylphenol (DCIP) was measured.

Usually, in the chromogen reducing reagent, the oxidizing matrix (dihydroorotate; L-DHO) and the reducing auxiliary matrix (coenzyme Q; CoQ) are bound to the reducing chromogen, and the enzyme activity makes the chromogen There is no light absorption at a wavelength of 600 nm.

More preferably, the aforementioned chromogen reducing reagent comprises: ‧ a culture enzyme extract (usually 8 μL, ~1.5 μg of human protein), preferably placed in a 96-well plate; ‧ a reagent mixture (usually 200 μL) ), comprising 200 μM CoQD, 100 μM L-DHO, 120 μM DCIP in reagent buffer (this reagent buffer typically contains 100 Mm and pH 8.0 HEPES, 150 mM NaCl, 10% Glicerol, 0.05% Triton X-100) and 2 μL of the test compound; wherein the compound is dissolved in a suitable solvent, typically DMSO, at a stock concentration of 1 mM; ‧ the enzyme and the reagent The mixture is in contact with each other; ‧ the enzyme is incubated with the reagent mixture for 10 minutes at room temperature; ‧ DCIP is measured by calculating the decrease in absorbance at a wavelength of 600 nm (usually using a full-wavelength microplate spectrometer) Reduction; ‧ Repeat the previous steps using different concentrations of test compound, usually at a concentration between 10 μM and 1 pM, thereby calculating an IC ₅₀ (the inhibitory concentration required for inhibition of 50%).

In general, all reactions were performed in duplicate, using software Abase chart, and determine IC ₅₀ values of the compounds.

Preferably, the amino derivative of the present invention which is a DHODH inhibitor has an hDHODH IC _{50 of} about 500 nM or less, preferably 300 nM or less, more preferably 200 nM or less than 200 nM. It was measured using a chromogen reduction reagent with 2,6-dichlorophenol-nonylphenol (DCIP).

Amino(iso)nicotinic acid derivative having the formula (I-a):

In one embodiment, the amino derivative having the formula (I) A-NH-B is an amino(iso)nicotinic acid derivative having the formula (I-a):

Wherein one of the ‧ G ¹ groups represents a nitrogen atom or a CR ^c group, the other represents a CR ^c group; ‧ G ² represents a nitrogen atom or a CR ^d group; ¹ represents a group selected from the group consisting of a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and C _{3 -8} cycloalkyl, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ² represents a group selected from the group consisting of a hydrogen atom; a halogen atom; a hydroxyl group; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _1-4 alkoxy group, which is optionally selected from 1, 2 or 3 Substituted with a halogen atom and a substituent of a hydroxyl group; and a C _3-8 cycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ^a , R ^b and R ^c each independently represent a system selected from the following groups: a hydrogen atom; a halogen atom; C _1-4 alkyl, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and hydroxy-substituted group of Substituted; and C _1-4 alkoxy, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; ‧ R ^d represents a group selected from one of the following: a hydrogen atom; a halogen atom; a hydroxy group; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _1-4 alkoxy group, as the case may be 1, 2 Or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; One of the G ³ and G ⁴ groups is a nitrogen atom and the other is a CH group; ‧ the M system is a hydrogen atom or a pharmaceutically acceptable cation; the limitation is that when When at least one of the R ^a and R ^b groups represents a hydrogen atom and the G ² system is a CR ^d group, then R ^d represents a group selected from the group consisting of C _1-4 alkoxy groups, The case is substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and C _3-8 cycloalkoxy, which optionally has 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group. Place Generation; the former and pharmaceutically acceptable salt or solvate thereof or a N- oxide or a stereoisomer or deuterated derivatives.

The above-mentioned amino (iso)nicotinic acid derivative having the formula (I-a) and its preparation method are described in the text of International Patent Application No. WO 2008/077639.

As used herein, the term alkyl refers to hydrocarbons having from 1 to 4 carbon atoms in a straight or branched chain. On the alkyl group, the substituent is preferably a halogen atom and a hydroxyl group, and more preferably a halogen atom. The foregoing examples include groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, sec -butyl, and tert -butyl.

The alkoxy group, as used herein, encompasses an oxygen-containing group of a straight or branched chain wherein each group has from 1 to 4 carbon atoms. On the alkoxy group, the substituent is preferably a halogen atom and a hydroxyl group, and more preferably a halogen atom. The foregoing examples include a group such as a methoxy group, an ethoxy group, an n -propoxy group, an i -propoxy group, an n -butoxy group, a sec -butoxy group, and a tert -butoxy group.

As used herein, the term cycloalkyl embraces saturated carbocyclic groups and (unless otherwise stated) a cycloalkyl group having from 3 to 8 carbon atoms. The foregoing examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. When a cycloalkyl group has 2 or more substituents, the substituents may be the same or different. In the cycloalkyl group, the above substituent is preferably a halogen atom and a hydroxyl group, and more preferably a halogen atom.

As used herein, the term cycloalkoxy embraces a saturated oxygen-containing carbocyclic group and (unless otherwise stated) a cycloalkoxy group having from 3 to 8 carbon atoms. The foregoing examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group. When the monocycloalkoxy group has 2 or more substituents, the substituents may be the same or different. On the cycloalkyloxy group, the above substituent is preferably a halogen atom and a hydroxyl group, and more preferably a halogen atom.

As used herein, some of the atoms, groups, motifs, chains or rings present in the chemical structures disclosed herein may be substituted as appropriate. In other words, these atoms, groups, motifs, chains or rings may be unsubstituted or substituted at any position via one or more substituents (eg 1, 2, 3 or 4 substituents) A hydrogen atom bonded to the aforementioned unsubstituted atom, group, motif, chain or ring may be substituted with a chemically acceptable atom, group, motif, chain or ring. When the number of substituents is two or more, the substituents may be the same or different.

As used herein, the term halogen atom embraces a chlorine, fluorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, and preferably includes a bromine or fluorine atom; the term halogen also has the same meaning.

M may be a hydrogen atom or a pharmaceutically acceptable cation; when M is a pharmaceutically acceptable cation, the compound represented by the formula (I-a) may be further represented by the following formula (I-a*):

As used herein, pharmaceutically acceptable cations include: inorganic cations such as alkali metal cations (Li ⁺ , Na ⁺ , K ⁺ ), alkaline earth metal cations (Ca ²⁺ , Mg ²⁺ ), and others in the art. Traditionally acceptable inorganic cations (Zn ²⁺ , Al ³⁺ ); and organic cations such as ammonium ions (ie NH ₄ ⁺ ) and substituted ammonium ions (eg NH ₃ R ¹⁺ , NH ₂ (R ^{1 )} ₂ ⁺ , NH(R ¹ ) ₃ ⁺ and N(R ¹ ) ₄ ⁺ , wherein each R ¹ is independently selected from the group consisting of monophenyl, monobenzyl, C _1-4 alkyl and C _3-8 ring alkyl). The foregoing examples include substituted ammonium ions including EtNH ₃ ⁺ , Et ₂ NH ₂ ⁺ , Et ₃ NH ⁺ , (C ₆ H ₁₁ ) ₂ NH ₂ ⁺ , CH ₃ CH ₂ CH ₂ CH ₂ NH ₃ ⁺ , PhCH ₂ NH ₃ ⁺ and (Ph)(PhCH ₂ )NH ₂ ⁺ ; another common example of tertiary ammonium ion is N(CH ₃ ) ₄ ⁺ .

Typically, the M system is a hydrogen atom or a pharmaceutically acceptable cation selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Ca ^{2+ ,} and Mg ²⁺ ; M is preferably a hydrogen atom or a selected A pharmaceutically acceptable cation from Li ⁺ , Na ⁺ and K ⁺ ; M is more preferably a hydrogen atom or Li ⁺ ; M is preferably a hydrogen atom.

If M in formula (I-a) is a pharmaceutically acceptable cation having a valence greater than +1, then other anions will be present simultaneously to maintain the electrical neutrality of the compound. The coexisting anion may be an anion X- as defined below or as found above in formula (I-a*).

As used herein, the term pharmaceutically acceptable salts encompasses salts having a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid and nitric acid; and organic acids such as citric acid, fumaric acid, maleic acid, Malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexanesulfonic acid (cyclohexylsulfonic acid) or p-toluenesulfonic acid. Pharmaceutically acceptable bases include: alkali metal (such as sodium or potassium) and alkaline earth metal (such as calcium or magnesium) hydroxide or organic base compounds, such as alkyl ammonia, aralkyl ammonia and heterocyclic A compound such as ammonia.

Further preferred salts according to the invention are tertiary ammonium compounds wherein the equivalent of one anion (X-) is related to the positive valence of the nitrogen atom. X- can be an anion of various mineral acids, such as chlorine, bromine, iodine, sulfate, nitrate, phosphate; or an anion of an organic acid, such as acetate, maleate, fumarate, lemon Acid salts, oxalates, succinates, tartrates, malates, mandelates, trifluoroacetates, methanesulfonates and p-toluenesulfonates. X- is preferably an anion selected from the group consisting of chlorine, bromine, iodine, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate; X-more preferably chlorine, Bromine, trifluoroacetate, methanesulfonate.

As used herein, an N-oxide is formed from a tertiary alkali ammonia or imine present in a molecule by the use of a suitable oxidizing agent.

As used herein, the term solvate refers to a compound which further includes a stoichiometric or non-stoichiometric solution, such as water, acetone, ethanol, methanol bonded by intermolecular forces of non-covalent bonds. , dichloromethane, 2-propanol or the like. When the solvent is water, it will be referred to as a hydrate rather than a solvate.

As used herein, the term deuterated derivative refers to a compound of the invention wherein at least one hydrogen atom is replaced with deuterium at a particular position. Rhodium (D or 2H) is a stable hydrogen isotope with a natural content of 0.015 mol%.

The hydroquinone interchange (incorporation of hydrazine) is a chemical reaction in which a hydrogen atom bonded by a covalent bond is replaced by a fluorene atom. The interchange (incorporation) reaction can be a full reaction or a partial reaction.

In general, a deuterated derivative of a compound of the present invention has an isotopic enrichment factor (the content of the isotope and the nature of the isotope) in respect of the position in each of the compounds designated to be deuterated. The ratio between the contents; that is, the specified number of incorporations of hydrazine-substituted hydrogen atoms at a specified position within one molecule) is at least 3,500 (52.5% hydrazine incorporation rate).

In a preferred embodiment, the isotope enhancement factor is at least 5,000 (i.e., 75% hydrazine); in a more preferred embodiment, the isotope enhancement factor is at least 6333.3 (i.e., 95% hydrazine incorporation rate); In a more preferred embodiment, the isotope enhancement factor is at least 6633.3 (i.e., 99.5% hydrazine incorporation rate). It will be understood that each oxime occurs in an isotope enhancing factor in a compound that is designated to be deuterated and is not affected by other deuterated positions.

For those of ordinary skill in the art, known analytical methods can be used to determine isotope enhancing factors, such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) methods.

Typically, R ¹ is selected from the group consisting of a hydrogen atom, a bromine and fluorine atom, a methyl group, an ethyl group, a cyclopropyl group, and a cyclobutyl group.

Typically, G ³ represents a nitrogen atom and G ⁴ represents a CH group.

Typically, G ³ represents a CH group and G ⁴ represents a nitrogen atom.

Typically, G ¹ represents a CR ^c group.

Typically, each R ^c is independently selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, and a C _1-3 alkyl group.

Typically, G ² represents a CR ^d group.

Typically, R ^d is selected from the group consisting of hydroxy, C _1-3 alkoxy, 2,2,2-trifluoroethoxy, and C _3-4 cycloalkoxy; preferably C _1-3 alkoxy, 2,2,2-trifluoroethoxy and C _3-4 cycloalkoxy.

Typically, R ^a is selected from the group consisting of a fluorine atom, a methyl group, and a trifluoromethoxy group.

Typically, R ^b is selected from the group consisting of a hydrogen atom, a fluorine atom, and a chlorine atom.

Usually, R ² is selected from the group consisting of a hydrogen atom and a halogen atom, preferably a hydrogen atom and a fluorine atom.

In general, the G ¹ group represents a C(R ^c ) group, G ² represents a C(R ^d ) group, and G ^{2 is} preferably selected from one of the following groups: C(OH), C(OMe And C(OEt), R ^a is selected from the group consisting of a fluorine atom and a 2,2,2-trifluoroethoxy group, and R ^b is selected from the group consisting of: a hydrogen atom and a fluorine atom, and R ¹ is selected from the group consisting of a hydrogen atom, a bromine atom, and a fluorine atom, a methyl group, an ethyl group, a cyclopropyl group or the like; preferably, a G ¹ group; The group represents a CH group, G ² is a group selected from C(OMe) and C(OEt), R ^a is a fluorine atom, and R ^b is selected from the group consisting of hydrogen atoms and A fluorine atom, and R ¹ is selected from the group consisting of hydrogen, bromine, a fluorine atom, a methyl group, an ethyl group, and a cyclopropyl group.

Preferably, R ^c is a hydrogen atom, R ^d is a hydroxyl group or a C _1-3 alkoxy group, and R ² is a hydrogen atom; preferably, R ^c is a hydrogen atom, R ^d is a C _1-3 alkoxy group, and R ² is a hydrogen atom.

Preferably, G ³ represents a nitrogen atom, G ⁴ represents a CH group, and R ^b is a fluorine atom; and in the compound, G ³ represents a CH group, and G ⁴ represents a nitrogen atom.

In a preferred compound of formula (Ia), the G ¹ group represents a C(R ^c ) group, G ² represents a C(R ^d ) group, and R ^a is selected from the group consisting of Group: a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethoxy group, and a 2,2,2-trifluoroethoxy group, and R ^b is selected from the group consisting of hydrogen atoms and fluorine. The atom, R ¹ is selected from the group consisting of hydrogen, bromine, chlorine, and a fluorine atom, a methyl group, an ethyl group, and a cyclopropyl group, and the R ² group is selected from the group consisting of hydrogen: An atom, a fluorine atom, a chlorine atom, and a methyl group, and G ³ represents a CH group, G ⁴ represents a nitrogen atom, or G ³ represents a nitrogen atom, and G ⁴ represents a CH group.

More preferably, G ¹ represents a C(R ^c ) group, G ² represents a C(R ^d ) group, R ^a is a fluorine atom, and R ^b is selected from the group consisting of A hydrogen atom and a fluorine atom, and R ¹ is selected from the group consisting of hydrogen, a bromine and a fluorine atom, a methyl group, an ethyl group, and a cyclopropyl group. Preferably, R ^c is a hydrogen atom, and R ^d is selected from the group consisting of C _1-3 alkoxy and C _3-4 cycloalkoxy, and R ² is a group. It is a hydrogen atom. In particular, in some preferred compounds, G ³ represents a nitrogen atom, G ⁴ represents a CH group, and R ^b is a fluorine atom; in other preferred compounds, G ³ represents a CH group, G ⁴ represents a nitrogen atom, and both R ^a and R ^b are fluorine atoms.

In particular, in preferred compounds, the G ¹ group represents a C(R ^c ) group, G ² represents a C(R ^d ) group; more preferably, the G ² group is selected from C (OH). a group of C(OMe) and C(OEt), Ra is selected from the group consisting of a fluorine atom and a group such as 2,2,2-trifluoroethoxy, and R ^b is selected From the group consisting of hydrogen atoms and fluorine atoms, R ¹ is selected from the group consisting of hydrogen, bromine and fluorine atoms, methyl, ethyl and cyclopropyl groups. G ³ represents a CH group, and G ⁴ represents a nitrogen atom.

Preferably, when the amino derivative having the formula (I) A-NH-B is an amino(iso)nicotinic acid derivative of the formula (Ia), it is selected from the group consisting of: 2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-ethoxy-3-fluorobiphenyl-4-ylamino)nicotinic acid; 2-(3-Fluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3'-ethoxy-3-(trifluoromethoxy)biphenyl -4-ylamino)nicotinic acid; 2-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(2,5-difluoro -3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-ethoxy-2,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-( 2',3-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(2-methyl-3'-(trifluoromethoxy)biphenyl-4-yl Amino)nicotinic acid; 2-(3-chloro-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3-chloro-3'-ethoxybiphenyl -4-ylamino)nicotinic acid; 2-(3-methyl-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3-chloro-3'- Methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-(difluoromethoxy)-3-fluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'- Cyclobutoxy-3-fluorine Benz-4-ylamino)nicotinic acid; 2-(3-fluoro-3'-(2,2,2-trifluoroethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3 '-Cyclobutoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-(trifluoromethoxy)biphenyl-4- Nicotinic acid; 2-(3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxy Benzyl-4-ylamino)nicotinic acid; lithium 3-(3'-ethoxy-3-fluorobiphenyl-4-ylamino)isonicotinate; 3-(3-fluoro-3' -Methoxybiphenyl-4-ylamino)isonicotinate lithium ester; 3-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)isonicotinic acid Lithium salt; lithium salt of 3-(3-fluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino)isonicotinic acid; 2-(3'-ethoxybiphenyl-4-yl Amino)nicotinic acid; 2-(5-fluoro-2-methyl-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(2',3-difluoro -5'-isopropoxybiphenyl-4-ylamino)nicotinic acid; 2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3,5-difluoro-3'-hydroxybiphenyl-4-ylamino)nicotinic acid; 5-bromo-2-(3-fluoro-3'-methoxybiphenyl-4-yl Amino)nicotinic acid; 5-bromo-2-(3,5-difluoro-3'-methoxybiphenyl-4-yl Nicotinic acid; 5-bromo-2-(3-fluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3-fluoro-3'-( Trifluoromethoxy)biphenyl-4-ylamino)-5-methylnicotinic acid; 5-cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino) Nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3'-ethoxy-5-fluoro -2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-( 3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)-5-methylnicotinic acid; 5-cyclopropyl-2-(3'-ethoxy-3,5- Difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)-5-ethylnicotinic acid; 5-bromine -2-(3'-ethoxy-2,5-difluorobiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3'-ethoxy-2,5-di Fluorobiphenyl-4-ylamino)nicotinic acid; 2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-5-methylnicotinic acid; 5- Cyclopropyl-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(2',3,5-trifluoro-3'- Methoxybiphenyl-4-ylamino)nicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'- Propyl-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; 5- Cyclopropyl-2-(2,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-difluoro Benz-4-ylamino)-5-cyclopropylnicotinic acid; 5-chloro-2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; -cyclopropyl-2-(3,5-difluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(2,3,5-trifluoro-3 '-Methoxybiphenyl-4-ylamino)nicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)-5-cyclopropylnicotinic acid; -(3,5-difluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methyl-3'- (trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(2'-chloro-3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; 5-chloro-2-(3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 5-chloro-2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino Nicotine; 2-(2,3,5,6-tetrafluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2'- Methylbiphenyl-4-ylamino)nicotinic acid; 3-(3'-cyclopropoxy-3-fluorobiphenyl-4-ylamino)isonicotinic acid; or a medicament thereof A salt or solvate or an N-oxide or a stereoisomer or a deuterated derivative.

More preferably, when the amino derivative having the formula (I) A-NH-B is an amino(iso)nicotinic acid derivative having the formula (Ia), it is selected from the group consisting of: 2-(3'-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3'-methoxy-3-(trifluoromethoxy) Biphenyl-4-ylamino)nicotinic acid; 2-(3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro- 3'-methoxybiphenyl-4-ylamino)nicotinic acid; lithium 3-(3'-ethoxy-3-fluorobiphenyl-4-ylamino)isonicotinate; 3-(3 -fluoro-3'-methoxybiphenyl-4-ylamino)isonicotinate lithium ester; 3-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino Lithium isonicotinate; 2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 5-bromo-2-(3,5-di Fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid ; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3,5-difluoro-3'-methoxy Biphenyl-4-ylamino)-5-ethylnicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'-ring Propyl-3,5-difluorobiphenyl- 4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(2,5-difluoro -3'-methoxybiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3,5-difluoro-3'-(trifluoromethoxy)biphenyl-4- Nicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)-5-cyclopropylnicotinic acid; 2-(2,3,5,6- Tetrafluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives.

Particularly preferably, when the amino derivative having the formula (I) A-NH-B is an amino(iso)nicotinic acid derivative of the formula (Ia), it is selected from the group consisting of :2-(3'-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl -4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2 -methylbiphenyl-4-ylamino)nicotinic acid; and 5-cyclopropyl-2-(3,5-difluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino) Nicotinic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives.

More preferably, when the amino derivative of the formula (I) is an amino(iso)nicotinic acid derivative of the formula (Ia), it is selected from the group consisting of 2-(3) '-Ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino Nicotinic acid; and 2-(3,5-difluoro-2-methoxybiphenyl-4-ylamino)nicotinic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxidation a substance, a stereoisomer or a deuterated derivative.

A pharmaceutically acceptable salt of an amino(iso)nicotinic acid derivative of the formula (Ia) is formed together with a pharmaceutically acceptable base selected from the group consisting of L-arginine and meglumine ( Meglumine) and tromethamine, among which meglumine and tromethamine are particularly preferred.

A salt of an amino(iso)nicotinic acid derivative of the formula (Ia) of particular interest is selected from the group consisting of 2-(3'-ethoxy-3-(trifluoromethoxy) Biphenyl-4-ylamino)nicotinic acid meglumine; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid meglumine; -(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid tromethamine salt; 2-(3,5-difluoro-3'-methoxybiphenyl -4-ylamino)nicotinic acid arginine salt; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid meglumine salt; and 2-(3, 5-Difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid tromethamine salt.

Azabiphenylaminobenzoic acid derivative having the formula (I-b)

In another embodiment, the amino derivative having the formula (I) A-NH-B is an azabiphenylaminobenzoic acid derivative having the formula (I-b):

Wherein R ^{1 '} is selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _3-4 cycloalkyl group, -CF ₃ and -OCF ₃ ; the R ^{2 '} is selected from A group consisting of a hydrogen atom, a halogen atom, and a C _1-4 alkyl group; R ^{3 '} is selected from the group consisting of -COOR ⁵ , -CONHR ⁵ , tetrazolyl, -SO _{a group of 2} NHR ⁵ ' and -CONHSO ₂ R ⁵ ' , wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a C _1-4 alkyl group of a straight or branched chain; ^{4 '} is selected from the group consisting of a hydrogen atom and a C _1-4 alkyl group; R ^{9 '} is selected from the group consisting of: a hydrogen atom and a phenyl group; ^{1 '} represents a group selected from N or CR ^{6 '} , wherein R ^{6 '} is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkyl group, C _3-4 ring Alkyl, C _1-4 alkoxy, -CF ₃ , -OCF ₃ , monocyclic nitrogen-containing C _5-7 heteroaryl, monocyclic nitrogen-containing C _3-7 heterocyclic group, and a C _6-10 aromatic group The above C _6-10 aromatic group is optionally substituted by one or more substituents selected from a halogen atom and a C _1-4 alkyl group. ; G ^{2 '} represents a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _1-4 alkoxy group, and -NR ^{a '} Rb ^' Wherein R ^{a '} represents a C _1-4 alkyl group, and R ^{b '} is selected from the group consisting of C _1-4 alkyl and C _1-4 alkoxy-C _1-4 alkane a group, or R ^{a '} and R ^{b '} and ^a nitrogen atom bonded to R ^{a '} and R ^{b '} together form a saturated 6 to 8 membered heterocyclic ring, the aforementioned heterocyclic ring optionally containing an oxygen atom as an additional impurity An atom; a monocyclic or bicyclic 5 to 10 membered heterocyclic ring containing one or more nitrogen atoms, optionally substituted with one or more substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, -CF ₃ , -OCF ₃ and -CONR ^{7 '} R ^{8 '} , wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a linear or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; or R ^{7 '} and R ^{8 '} and a nitrogen group attached thereto The atoms together form a group of the formula:

Wherein n is an integer from 0 to 3; and ‧ a phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkane Oxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, cyano, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 '} , oxadiazolyl, triazolyl, pyrazolyl And an imidazolyl group, wherein the aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ^' and R ₈ ^' Each is independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; or, R ₇ ^' and R ₈ ^' together with a nitrogen atom form a formula A group:

Wherein n is an integer from 0 to 3; or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C _{5-10 cyclocarbon} group or a C _6-10 alkane Or a pharmaceutically acceptable salt or solvate or N-oxide or stereoisomer or deuterated derivative.

The azabiphenylaminobenzoic acid derivative of the above formula (I-b) and the preparation method thereof are described in the text of the international patent application No. WO2009/021696.

The term aryl, as used herein, encompasses C ₆ -C ₁₀ monocyclic or polycyclic aromatic groups, such as phenyl, naphthyl, anthranyl, and phenanthryl, with phenyl being Good.

The above-mentioned aryl group which may be optionally substituted may be generally unsubstituted or substituted by 1, 2 or 3 substituents, and the above substituents may be the same or different. The substituent is preferably selected from a halogen atom (preferably a fluorine atom), a hydroxyl group, an alkoxycarbonyl group (wherein the alkyl group has 1 to 4 carbon atoms), a hydroxycarbonyl group, a methotrexate group, a nitrogen group, Cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ hydroxyalkyl. When an aromatic group has two or more substituents, the substituents may be the same or different. Unless otherwise stated, the substituents of the aryl group are generally unsubstituted by themselves.

As used herein, the terms heteroaryl and aromatic heterocyclic are used interchangeably and generally include a 5 to 14 membered ring system, preferably a 5 to 10 membered ring system, including at least one aromatic heterocyclic ring. And comprising at least one hetero atom selected from the group consisting of O, S, and N. The heteroaryl group can be a single ring (monocyclic), a di- or multi-fused ring (polycyclic) wherein at least one ring system comprises a hetero atom.

As used herein, the term heterocyclic embraces typically a non-aromatic, saturated or unsaturated C ₃ -C ₁₀ carbon of the ring system, for example a 5, 6 or 7 of the group, wherein one or more carbon The atom (e.g., 1, 2, 3 or 4 carbon atoms, preferably 1 or 2 carbon atoms) is substituted with a hetero atom selected from N, O and S; preferably a saturated heterocyclic group.

Typically, R ^{1 '} is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-4 alkyl group, a C _3-4 cycloalkyl group, and a group such as -CF ₃ .

Usually, R ^{2 '} is selected from the group consisting of a hydrogen atom, a halogen atom, and a methyl group.

Typically, G ^{1 '} is selected from the group consisting of nitrogen, CCl, CF, CH, C(CH ₃ ), C(cyclopropyl), C(phenyl), and C(CF ₃ ). And other groups.

In general, G ^{2 '} represents a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _1-2 alkoxy group, and -NR ^{a '} R ^{b '} , wherein R ^{a '} represents a C _1-2 alkyl group, and R ^{b '} is selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy-C _{1- a 2} alkyl group, or R ^{a '} and R ^{b '} and ^a nitrogen atom bonded to R ^{a '} and R ^{b '} together form a saturated 6 to 7 membered heterocyclic ring, the aforementioned heterocyclic ring optionally containing an oxygen atom as an addition a heterocyclic atom; a 5- to 10-membered heterocyclic ring of a monocyclic or bicyclic ring containing one or two nitrogen atoms and optionally substituted by one or more selected from the group consisting of a halogen atom and a C _1-4 alkyl group. Substituted; and ‧ a phenyl group, optionally substituted by one, two or three substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a group such as C _3-4 cycloalkoxy, cyano, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 ',} and oxadiazolyl, wherein the aforementioned oxadiazolyl group is optionally a C _1-4 alkane a C _3-7 cycloalkyl group or a substituted alkyl group, and wherein R ₇ 'and R _8' are each independently selected lines Hydrogen atom, a linear or branched chain C _1-4 alkyl or a C _3-7 cycloalkyl group; or, R ₇ 'and R _8' together with the nitrogen atom form one of the groups having the formula:

Wherein n is 1 or 2; or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C ₆ carbocyclic group or a phenyl group.

In particular, G ^{2 '} represents a group selected from the group consisting of: ‧ an oxygen atom, a fluorine atom, a cyclopropyl group, a monomethoxy group, -NMeEt, -NEt ₂ , -N(Me)-(CH ₂ ) _2- O-CH ₃ , 6-morpholinyl, azacyclo-1-yl and piperidin-1-yl; ‧ a pyridyl ring, pyrimidinyl ring, quinolyl ring or pyrazinyl ring, the foregoing The base ring is optionally substituted with one or two substituents selected from Me and F; and ‧ a phenyl group, optionally substituted by one, two or three substituents selected from the group consisting of fluorine atoms, Chlorine, methyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, cyano, -CF ₃ , OCF ₃ , oxadiazolyl and -CONR _{7 '} R _{8 'and} other groups, wherein the oxadiazolyl group optionally substituted by the Department of a methyl group, and wherein R _7' and R ₈ 'are each independently selected lines a hydrogen atom, methyl, isopropyl, cyclopropylmethyl Or a group such as: R ₇ ' and R ₈ ' together with the nitrogen atom to which it is attached form a group having the formula:

Wherein n is 1; or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C ₆ carbocyclic group or a phenyl group.

Most preferably, the G ^{2 '} group represents a group selected from the group consisting of methoxy and cyclopropyl, and optionally a group such as a phenyl group, a pyridyl group, a quinolyl group, a pyrimidinyl group, or a pyrazinyl group. Replaced.

In one embodiment of the invention, R ^{1 '} is selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _3-4 cycloalkyl group, -CF ₃ and - OCF ₃ ; R ^{2 '} is selected from the group consisting of a hydrogen atom, a halogen atom, and a C _1-4 alkyl group; and R ^{3 '} is selected from the group consisting of -COOR ^{5 '} a group such as -CONHR ^{5 '} , tetrazolyl, -SO ₂ NHR ⁵ ', and -CONHSO ₂ R ⁵ ' , wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a straight chain or a branched chain of C _1-4 alkyl; R ^{4 '} is selected from the group consisting of: a hydrogen atom and a C _1-4 alkyl group; R ^{9 '} represents a hydrogen atom; G ^{1 '} Is a group selected from N and CR ^{6 '} , wherein R ^{6 '} is selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _3-4 naphthenic ring. a group, a C _1-4 alkoxy group, a -CF ₃ , an -OCF ₃ , a monocyclic nitrogen-containing C _5-7 heteroaryl group, a monocyclic nitrogen-containing C _3-7 heterocyclic group, and a C _6-10 aromatic group. , the C _6-10 aromatic group-based group optionally substituted by one or more groups selected from halogen atoms and of a C _1-4 alkyl substituent; And, G ^{2 'represents} a group selected based on one of the following groups: ‧ a monocyclic or bicyclic heterocycle of from 5 to 10, which contains one nitrogen atom, and the system optionally substituted with one or more of the substituents The aforementioned substituent is selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _3-4 cycloalkyl group, a C _3-4 cycloalkoxy group, a —CF ₃ , and —OCF _{3 .} And -CONR ^{7 '} R ^{8 '} wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 cycloalkyl group; or R ^{7 '} and R ^{8 '} together with the nitrogen atom to which they are attached form a group having the formula:

Wherein n is an integer from 0 to 3; and ‧ a phenyl group optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group , C _3-4 cycloalkyl, C _3-4 cycloalkoxy, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 '} , oxadiazolyl, triazolyl, pyrazolyl, and imidazolyl, wherein The aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ' and R ₈ ' are each independently Selected from a hydrogen atom, a linear or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; or, R ₇ ' and R ₈ ' together with a nitrogen atom to which it is bonded, form one of the following formulas Group:

Wherein n is an integer from 0 to 3.

In another embodiment of the present invention, R ^{9 '} represents a hydrogen atom, and G ^{2 '} represents a group selected from the group consisting of: ‧ a monocyclic or bicyclic 5 to 10 membered heterocyclic ring, which comprises a nitrogen atom, and optionally substituted by one or more substituents selected from C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, C _{3 -4} cycloalkoxy, -CF ₃ , -OCF ₃ and -CONR ^{7 '} R ^{8 '} wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a straight chain or a branched chain C _{1- a 4} alkyl group, a C _3-7 cycloalkyl group; or, R ^{7 '} and R ^{8 '} together with a nitrogen atom to which they are attached form a group having the formula:

Wherein n is an integer from 0 to 3; and ‧ a phenyl group, optionally substituted by one or more substituents selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _{3 -4} cycloalkyl, C _3-4 cycloalkoxy, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 '} , oxadiazolyl, triazolyl, pyrazolyl and imidazolyl, wherein the aforementioned The oxazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl; and wherein R ₇ ^' and R ₈ ^' are each independently selected from a hydrogen atom, a linear or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; or, R ₇ ^' and R ₈ ^' together with a nitrogen atom to which it is bonded, form a group having the formula:

Wherein n is an integer from 0 to 3.

Typically, R ^{1 '} is selected from the group consisting of C _1-4 alkyl, C _3-4 cycloalkyl, and -CF ₃ , preferably methyl and cyclopropyl, most preferably cyclopropyl. base.

Typically, R ^{2 '} is selected from a hydrogen or halogen atom, preferably a hydrogen atom.

Typically, R ^{3 '} is selected from the group consisting of COOR ⁵ , -CONHR ⁵ and tetrazolyl, wherein R ^{3 ' is} preferably a COOH group.

Usually, R ^{4 '} represents a hydrogen atom or a monomethyl group, preferably a hydrogen atom.

Usually, R ^{9 '} represents a hydrogen atom.

In general, G ^{1 '} represents a group selected from the group consisting of N, CH, C(CH ₃ ), C(cyclopropyl), C(phenyl) or C(CF ₃ ).

Typically, G ^{2 '} is selected from the group consisting of monomethoxy, monocyclopropyl, and optionally substituted phenyl, pyridyl, quinolinyl, pyrimidinyl, and pyrazinyl; G ^{2 '} preferably selected from the group consisting of phenyl, pyridyl, quinolyl, pyrimidinyl and pyrazinyl optionally substituted; preferably selected from phenyl optionally substituted A group such as a 4-pyridyl group, a 5-quinolyl group, and a 2-pyrazinyl group.

In a preferred compound of formula (Ib), R ^{1 '} is selected from the group consisting of a hydrogen atom, a halogen atom, a methyl group, a CF 3 group, and a cyclopropyl group; and R ^{2 '} represents a hydrogen atom or a group. R ^{3 '} is a COOR ^{5 '} group, wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a methyl group, an ethyl group, and a t-butyl group; R ^{4 '} Represents a hydrogen atom, a fluorine atom or a monomethyl group; R ^{9 '} represents a hydrogen atom or a phenyl group; G ^{1 '} is selected from a nitrogen atom and CR ^{6 '} , wherein R ^{6 '} represents a hydrogen atom , a fluorine member, a chlorine atom, a monomethyl group, a trifluoromethyl group, a cyclopropyl group, and a phenyl group; and G ^{2 '} means a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group a monofluoro group, a cyclopropyl group, a monomethoxy group, and -NR ^{a '} R ^{b '} , wherein R ^{a '} represents a C _1-2 alkyl group, and R ^{b '} is selected from the group consisting of :C _1-2 alkyl and C _1-2 alkoxy-C _1-2 alkyl; or R ^{a '} and R ^{b '} together with the nitrogen atom to which they are attached form a saturated 6-7 heterocyclic ring, The aforementioned heterocyclic ring optionally contains an oxygen atom as Plus heteroatoms; ‧ per a monocyclic or bicyclic heteroaryl of 5 to 10 aromatic rings, the heteroaromatic ring containing one or two nitrogen atoms, and optionally substituted with one or two halogen atoms and -CONR ^{7 'R 8'} Substituted wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a C _1-2 alkyl group, and a cyclopropyl group; or, R ^{7 '} and R ^{8 '} and a nitrogen atom to which they are attached Together form a group with the following formula:

Wherein n is 1; and ‧ a phenyl group, which is optionally substituted with one, two or three substituents selected from the group consisting of fluorine atom, chlorine atom, hydroxyl group, C _1-3 alkoxy group, cyclopropyl group a group, a cyclopropoxy group, a cyano group, -CF ₃ , -OCF ₃ , -CONR _{7 '} R _{8 ',} and an oxadiazolyl group, wherein the aforementioned oxadiazolyl group is optionally substituted by a monomethyl group, and wherein R _{7 '} and R _{8 '} are as defined above; or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C ₆ ring carbon group or a phenyl group.

In another embodiment of the present invention, R ^{1 '} is selected from monomethyl or cyclopropyl; R ^{2 '} represents a hydrogen atom; R ^{3 '} is a COOH group; R ^{4 '} represents a a hydrogen atom or a monomethyl group; G ^{1 '} is selected from the group consisting of N, CH, C(CH ₃ ), C (cyclopropyl), C (phenyl), and C(CF ₃ ); and G ^{2 '} And is a group selected from the group consisting of a substituted phenyl group, a 4-pyridyl group, a 5-quinolyl group, and a 2-pyrazinyl group; and more preferably, R ^{9 '} represents a group. A hydrogen atom.

In still another embodiment of the present invention, R ^{1 '} is selected from monomethyl or monocyclopropyl; R ^{2 '} represents a hydrogen atom; R ^{3 '} is a COOH group; and R ^{4 '} represents a hydrogen. An atom; G ^{1 '} is selected from a nitrogen atom and a group such as CH, C(CH ₃ ), and C(CF ₃ ); and G ^{2 '} represents a phenyl group, which is optionally selected from the group consisting of Substituting one or two of the following substituents: chloro, fluoro, methoxy, ethoxy, isopropyl, trifluoromethoxy and -CONR ^{7 '} R ^{8 '} wherein R ^{7 '} is hydrogen The atom, R ^{8 '} is a cyclopropyl group; or, R ^{7 '} and R ^{8 '} together with the nitrogen atom to which it is attached form a group having the formula:

Where n is 1.

Preferably, when the amino derivative having the formula (I) A-NH-B is an azabiphenyl benzoic acid derivative having the formula (Ib), it is selected from the group consisting of Group: 5-cyclopropyl-2-(2-phenylpyrimidin-5-ylamino)benzoic acid; 2-(6-cyclopropyl-5-methylpyridin-3-ylamino)-5- Methyl benzoic acid; 5-(2-carboxy-4-cyclopropylphenylamino)-3-methyl-2-phenylpyrimidine 1-oxide; 5-methyl-2-(6-(3) -(Trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(6-hydroxy-5-phenylpyridin-3-ylamino)benzoic acid; -cyclopropyl-2-(2-(2,6-difluoro-4-hydroxyphenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-(6-methoxy- 5-phenylpyridin-3-ylamino)benzoic acid; 2-(5-fluoro-6-phenylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(ethyl (methyl)amino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(3'-fluoro-2,4'-dipyridine- 5-(amino)phenyl acid; 2-(6-(diethylamino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-((2) -methoxyethyl)(methyl)amino)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(5-chloro-6-phenylpyridine-3- Amino)-5-methylbenzoic acid; 5- Propyl-2-(2-(2-cyclopropylphenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-(5-phenylpyridin-3-ylamino)benzene Acid; 5-methyl-2-(quinolin-3-ylamino)benzoic acid; 5-methyl-2-(5,6,7,8-tetrahydroquinolin-3-ylamino)benzene Acid; 2-(5-chloro-2-phenylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(5,6-biphenylpyridin-3-ylamine Benzoic acid; 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-(5-methyl Pyridin-3-ylamino)benzoic acid; 2-(2-(3-cyclopropoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 5-methyl-2- (6-morpholinidin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-morpholinpyridin-3-ylamino)benzoic acid; 5-cyclopropane 2-(6-cyclopropyl-5-phenylpyridin-3-ylamino)benzoic acid; 2-(6-(2-cyclopropylphenyl)-5-methylpyridin-3-yl Amino)-5-methylbenzoic acid; 2-(6-(2-cyanophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(2- (3-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 5-methyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-yl Amino)benzoic acid; 5-methyl-2-(5-methyl-6-(piperidin-1-yl)pyridin-3-ylamino)benzoic acid; 2-(6-( N-cycloheptan-1-yl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-methoxyphenyl)-5-phenylpyridine 3-(amino)amino-5-methylbenzoic acid; 2-(2,3'-dipyridin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(3'-chloro-2 , 4'-dipyridin-5-ylamino)-5-methylbenzoic acid; 5-methyl-2-(3-methyl-2,2'-dipyridin-5-ylamino)benzoic acid ; 2-(5,6-difluoropyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-methoxyphenyl)pyridin-3-ylamino)benzoic acid ; 2-(6-(3-ethoxyphenyl)pyridin-3-ylamino)benzoic acid; 2-(6-(3-ethoxyphenyl)pyridin-3-ylamino)-5 -fluorobenzoic acid; 2-(6-(3-ethoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid; 2-(6-(3-ethoxyphenyl)pyridine -3-ylamino)-5-methylbenzoic acid; 2-(6-(3-ethoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-ethoxy-2-fluorophenyl)pyridin-3-ylamino)benzoic acid; 2-(6-(3-ethoxyphenyl)-4-methylpyridine- 3-ylamino)-5-methylbenzoic acid; 2-(6-(3-ethoxyphenyl)-4-methylpyridin-3-ylamino)benzoic acid; 5-bromo-2- (6-(3-ethoxyphenyl)pyridin-3-ylamino)benzoic acid; 5-chloro-2-(6-(3-ethoxyphenyl)pyridin-3-ylamino) Benzic acid; 2-(6-(5-ethoxy-2-fluorophenyl)pyridin-3-ylamino)benzoic acid; 2-(6-(3-ethoxyphenyl)-5- Pyridin-3-ylamino)-5-(trifluoromethyl)benzoic acid; 2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)-5 -(trifluoromethyl)benzoic acid; 2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6- (3-methoxyphenyl)-5-methylpyridin-3-ylamino)-6-methylbenzoic acid; 5-fluoro-2-(6-(3-methoxyphenyl)-5 -methylpyridin-3-ylamino)benzoic acid; 2-(6-(5-ethoxy-2-fluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2- (6-(2-Fluoro-5-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2-fluoro-5-methyl) Ethyl phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid ethyl ester; 2-(6-(2-fluorophenyl)pyridin-3-ylamino)-5 -methylbenzoic acid; 2-(6-(3-methoxyphenyl)-5-phenylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-A) Ethyl phenyl)-5-phenylpyridin-3-ylamino)-5-methylbenzoic acid ethyl ester; 5-methyl-2-(5-methyl-6-phenylpyridin-3-yl) Amino)benzoic acid; ethyl 5-methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoate; 5-methyl-2-(5-methyl-6 -( 3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl) Ethyl pyridin-3-ylamino)benzoate; 2-(5-cyclopropyl-6-(3-methoxyphenyl)pyridin-3-ylamino)-5-methylbenzoic acid; Ethyl 2-(5-cyclopropyl-6-(3-methoxyphenyl)pyridin-3-ylamino)-5-methylbenzoate; 2-(6-(2-fluoro-5-) Isopropoxyphenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino -5-methylbenzoic acid; 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid ethyl ester; 2-( 6-(3-cyclopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-cyclopropoxyphenyl)-5 -methylpyridin-3-ylamino)-5-methylbenzoic acid tert-butyl ester; 2-(6-(2-chlorophenyl)-5-methylpyridin-3-ylamino)-5 -methylbenzoic acid; tert-butyl 2-(6-(2-chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate; 2-(6-(3) -aminomethylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-aminomethylphenyl)-5-methylpyridine Ethyl 3-aminoamino)-5-methylbenzoate; 2-(6-(2-fluoro-5-methoxyphenyl)-4-methyl Pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2-fluoro-5-methoxyphenyl)-4-methylpyridin-3-ylamino)-5- Ethyl methyl benzoate; 2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6 -(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)-5-methylbenzoic acid ethyl ester; 2-(6-(3-(dimethylamine) Mercapto)phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-(dimethylaminocarbamoyl)phenyl)-5 -ethylpyridin-3-ylamino)-5-methylbenzoic acid ethyl ester; 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)- 3-methylbenzoic acid; tert-butyl 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)-3-methylbenzoate; 3-methyl 2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid; 3-methyl-2-(5-methyl-6-phenylpyridin-3-ylamino) Tert-butyl benzoate; 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2-chlorophenyl)pyridine-3 -butylamino)-5-methylbenzoic acid tert-butyl ester; 3-fluoro-2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid ; 3-fluoro-2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)benzoic acid third Ester; 5-cyclopropyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2- (5-Methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid ethyl ester; 5-cyclopropyl-2-(5-methyl-6- Phenylpyridin-3-ylamino)benzoic acid; ethyl 5-cyclopropyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoate; 5-methyl-2 -(5-methyl-6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-(2- (trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid tert-butyl ester; 2-(6-(3-chlorophenyl)-5-methylpyridin-3-ylamino)- 5-methylbenzoic acid; tert-butyl 2-(6-(3-chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate; 2-(6-( 2-fluorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2-fluorophenyl)-5-methylpyridin-3-ylamine Tert-butyl-5-methylbenzoate; 5-methyl-2-(5-methyl-6-(quinolin-5-yl)pyridin-3-ylamino)benzoic acid; 5- Methyl-2-(5-methyl-6-(quinolin-5-yl)pyridin-3-ylamino)benzoic acid tert-butyl ester; 2-(3'-fluoro-3-methyl-2 , 4'-dipyridin-5-ylamino)-5-methylbenzoic acid; 2-(3'-fluoro-3-methyl-2,4'-dipyridin-5-ylamine Tert-butyl-5-methylbenzoate; 5-methyl-2-(5-methyl-6-(pyrazin-2-yl)pyridin-3-ylamino)benzoic acid; 5- Methyl-2-(5-methyl-6-(pyrazin-2-yl)pyridin-3-ylamino)benzoic acid tert-butyl ester; 5-cyclopropyl-2-(6-phenyl- 5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzene Ethyl acetate; 5-cyclopropyl-2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl- Ethyl 2-(6-(3-methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)benzoate; 5-chloro-2-(6-(2-fluorobenzene) Pyridin-3-ylamino)benzoic acid; 5-chloro-2-(6-(2-chlorophenyl)pyridin-3-ylamino)benzoic acid; 5-chloro-2-(6-( Quinoline-5-yl)pyridin-3-ylamino)benzoic acid; 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoic acid; 2-( Ethyl 6-(2-chlorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoate; 5-chloro-2-(6-(2-(trifluoromethyl)phenyl)pyridine 3--3-aminoamino)benzoic acid; 5-fluoro-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid; 2-(3'-fluoro- 2,4'-dipyridin-5-ylamino)-5-methylbenzoic acid; 2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)-5-methylbenzene ; 2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid tert-butyl ester; 2-(6-(2,6-difluorophenyl)pyridine- 3-ylamino)-5-methylbenzoic acid; ethyl 2-(6-(2,6-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoate; 2-( 2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclo Methyl propyl benzoate; 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-methyl benzoic acid; 2-(2-(2-chlorophenyl)pyrimidine-5 -butylamino)-5-methylbenzoic acid tert-butyl ester; 5-methyl-2-(5-methyl-6-(3-(pyrrolidin-1-carbonyl)phenyl)pyridine-3- Benzyl)benzoic acid; 2-(6-(3-(cyclopropylaminecarbamido)phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5- Cyclopropyl-2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)benzoic acid; 2-(2-(2-trifluoromethylphenyl)pyrimidin-5-ylamino) -5-cyclopropyl benzoic acid; 2-(2-o-tolylpyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-cyclopropoxyphenyl)pyrimidine -5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2,5-difluorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; (2-(2,3-difluorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-fluoro-5-chloro) Pyrimido-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-trifluoromethylphenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid; 2-(2-(2-fluoro-5-trifluoromethoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(6-(2-trifluoromethylbenzene) Pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-phenylpyridin-3-ylamino)-5-cyclopropyl benzoic acid; 2-(6-(2- Fluorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoic acid; 2-(6-(3,5-difluoropyridin-4-yl)pyridin-3-ylamino)-5- Methyl benzoic acid; 2-(6-(3-cyclopropylaminoformamidophenyl)pyridin-3-ylamino)-5-methyl benzoic acid; 2-(6-(2,4-di) Fluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2,5-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid ; 2-(6-(2-fluorophenyl)pyridin-3-ylamino)-5-cyclopropyl-3-fluorobenzoic acid; 2-(6-(2,3,6-trifluorophenyl) Pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-(5-methyl-1,3,4-oxadiazolyl-2-yl)phenyl)pyridine 3--3-aminoamino)-5-methylbenzoic acid; 2-(5-methyl-6-(pyrimidin-5-yl)pyridin-3-ylamino)-5-methylbenzoic acid; 2- (6-(2,3-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(5-fluoro-2-methoxyphenyl)-5- Methylpyridine 3-(3-aminoamino)-5-methylbenzoic acid; 2-(6-(4-aminomethylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid ; 5-cyclopropyl-2-(2-(2-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoic acid methyl ester; 5-cyclopropyl-2-(2-o-toluene) Methyl pyrimidin-5-ylamino)benzoate; methyl 2-(2-(2-cyclopropoxyphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoate; - methyl cyclopropyl-2-(2-(2,5-difluorophenyl)pyrimidin-5-ylamino)benzoate; 5-cyclopropyl-2-(2-(2,3-di) Methyl fluorophenyl)pyrimidin-5-ylamino)benzoate; 2-(2-(5-chloro-2-fluorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid Ester; tert-butyl 5-methyl-2-(2-(2-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoate; 5-cyclopropyl-2-(2- (2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoic acid methyl ester; 2-(3',5'-difluoro-2,4'-dipyridine-5 -ethylamino)-5-methylbenzoic acid ethyl ester; 5-methyl-2-(6-(3-(5-methyl-1,3,4-oxadiazolyl-2-yl)benzene Tert-butyl pyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-(pyrimidin-5-yl)pyridin-3-ylamino)benzoic acid Tributyl ester; tert-butyl 2-(6-(2,3-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoate; And tert-butyl 2-(6-(5-fluoro-2-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate.

And a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer or deuterated derivative as described above.

More preferably, when the amine derivative having the formula (I) A-NH-B is an azabiphenyl benzoic acid derivative having the formula (Ib), it is selected from the group consisting of the following Group: 5-cyclopropyl-2-(2-phenylpyrimidin-5-ylamino)benzoic acid; 5-(2-carboxy-4-cyclopropylphenylamino)-3-methyl-2 -phenylpyridine 1-oxide; 5-methyl-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid; 2-(5-fluoro-6 -Phenylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(3'-fluoro-2,4'-dipyridin-5-ylamino)benzoic acid; 2-(5-chloro-6-phenylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(2-(2-cyclopropylphenyl)pyrimidine-5 -ylamino)benzoic acid; 5-cyclopropyl-2-(5-phenylpyridin-3-ylamino)benzoic acid; 2-(5-chloro-2-phenylpyridin-3-ylamino 5-methylbenzoic acid; 5-cyclopropyl-2-(5,6-biphenylpyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(2-(2,6) -difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino) Benzene; 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid; 2-(2-(3-cyclopropoxyphenyl) Pyrimidine-5-ylamino)-5-cyclopropyl benzoic acid; 5-methyl-2-(6-morpholinylpyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-morpholinylpyridin-3-ylamino) Benzene; 5-cyclopropyl-2-(6-cyclopropyl-5-phenylpyridin-3-ylamino)benzoic acid; 2-(6-(2-cyclopropylphenyl)-5- Methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(2-cyanophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid ; 2-(2-(3-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 5-methyl-2-(6-phenyl-5-(trifluoromethyl) Pyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-(piperidin-1-yl)pyridin-3-ylamino)benzoic acid; 2-(6 -(azacycloheptan-1-yl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(2,3'-dipyridin-5-ylamino) -5-cyclopropyl benzoic acid; 2-(3'-chloro-2,4'-dipyridin-5-ylamino)-5-methyl benzoic acid; 5-methyl-2-(3-methyl -2,2'-dipyridin-5-ylamino)benzoic acid; 2-(6-(3-ethoxyphenyl)-5-methylpyridin-3-ylamino)-5- Benzoic acid; 2-(6-(3-methoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-methyl-2-(5-A 2-(6-(3-isopropoxyphenyl)-5-methylpyridin-3-ylamino)-5-methyl Benzoic acid 5-cyclopropyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-( 5-methyl-6-phenylpyridin-3-ylamino)benzoic acid; 2-(6-(2-fluorophenyl)-5-methylpyridin-3-ylamino)-5-methyl Benzolic acid; 5-cyclopropyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(6-(3- Methoxyphenyl)-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-cyclo Propyl benzoic acid; 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-chlorophenyl)pyrimidine-5- Aminoamino)-5-methylbenzoic acid; 2-(6-(2,6-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 5-methyl-2- (5-methyl-6-(3-(pyrrolidin-1-carbonyl)phenyl)pyridin-3-ylamino)benzoic acid; 2-(6-(3-(cyclopropylaminemethanyl)) Phenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(2-(2-fluorophenyl)pyrimidin-5-ylamino) Benzoic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives.

Particularly preferably, when the amine derivative having the formula (I) A-NH-B is an azabiphenylanilide derivative having the formula (Ib), it is selected from the group consisting of Group: 5-methyl-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(2-(2, 6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino) Benzic acid; 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid; 2-(6-(2,6-difluorobenzene) Pyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-(cyclopropylaminecarbamimidino)phenyl)-5-methylpyridin-3-ylamino -5-methylbenzoic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives.

Most preferably, when the amino derivative having the formula (I) A-NH-B is an azabiphenyl benzoic acid derivative having the formula (Ib), it is selected from the group consisting of the following Group: 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-() Trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid; 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino) Benzoic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives.

Preferred pharmaceutically acceptable salts of the above aza-biphenylanilide derivatives of formula (Ib) are formed together with a pharmaceutically acceptable base selected from the group consisting of tromethamine. Sodium hydroxide or sodium methoxide, of which tromethamine and sodium hydroxide are preferred.

Among the above salts having an azabiphenylanilide derivative of the formula (Ib), those which are particularly concerned are selected from the group consisting of 5-cyclopropyl-2-(2-(2) ,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid tromethamine salt; 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-yl Amino) sodium benzoate; 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid tromethamine salt; 5-Methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid tromethamine salt.

In a preferred embodiment, the amine derivative having the formula (I) A-NH-B is selected from the group consisting of amine (iso) nicotinic acid derivatives of formula (Ia). And selected from the group consisting of 2-(3'-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-( 3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino) An alkali acid; and an azabenzidinebenzoic acid derivative having the formula (Ib) selected from the group consisting of 5-cyclopropyl-2-(2-(2,6-di) Fluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid; and the above pharmaceutically acceptable salts, the above solvates, the above The N-oxide, the above stereoisomer or the above-described deuterated derivative.

Preferably, the amine derivative having the formula (I) A-NH-B is selected from the group consisting of amine (iso) nicotinic acid derivatives of the formula (Ia), which are Selected from the group consisting of 2-(3'-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3,5- Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; An azabenzidinebenzoic acid derivative of the formula (Ib) selected from the group consisting of 5-cyclopropyl-2-(2-(2,6-difluorophenyl) Pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid; 5-A Base-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid; and the above pharmaceutically acceptable salt, the above solvate, the above N-oxidation Or a stereoisomer of the above or a deuterated derivative as described above.

In another preferred embodiment, the amine derivative having the formula (I) A-NH-B is selected from the group consisting of 2-(3,5-difluoro-3'-A Oxybiphenyl-4-ylamino)nicotinic acid; and 5-cyclopropyl-2-(2-(2,6-difluorobiphenyl)pyrimidin-5-ylamino)benzoic acid; A pharmaceutically acceptable salt, a solvate as described above, an N-oxide as described above, a stereoisomer as described above or a deuterated derivative as described above.

Skin disease and discomfort

The present invention provides an amino derivative having the formula (I) A-NH-B for use in the treatment of proliferative skin diseases or discomfort.

As used herein, the term proliferative skin disease or discomfort refers to a skin disease or discomfort characterized by a phenomenon in which the skin epithelium (the epidermal layer) and the supporting tissue of the skin (the dermis layer) or its appendages have accelerated cell division. And it involves incomplete differentiation of tissues (Vooorhees et al., The Journal of Investigate Dermatology , 1976, 67(3), pp 442-480).

Generally, the aforementioned skin diseases or discomforts do not include dryness, contact dermatitis, and atopic dermatitis.

Usually, the aforementioned skin disease or discomfort is not an inflammatory disease or discomfort.

Furthermore, the aforementioned skin diseases or discomforts are generally not an autoimmune disease or discomfort.

Preferably, the aforementioned skin disease or discomfort is generally not an autoimmune or inflammatory disease or discomfort.

Generally, the aforementioned skin diseases or discomforts are selected from a) epithelial and hair follicle tumors, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), actinic keratosis (AK), Bowen's disease ( Bowen's disease), erythroplasia of Queyrat, leukoplakia, oral florid papillomatosis, verrucous carcinoma or keratoacanthoma; b) sebaceous adenomas, such as sebaceous gland cancer; c) sweat adenomas, such as mammary Paget's disease, extraramamary Paget's disease, eccrine porocarcinoma, microcysts Microcystic adnexal carcinoma (MAC), or mucinous carcinoma of the skin; d) nervous system tumors, such as Merkel cell carcinoma (MCC); e) mesenchymal tumors, for example Dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), atypical fibrananthoma, Epithelioid sarcoma, synovial sarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, cutaneous lymphoma or multiple myeloma; f) skin Metastatic cancer; g) melanoma of the skin; h) lamellar ichthyosis; i) acne; or j) hirsutism.

Preferably, the aforementioned skin disease or discomfort is selected from the group consisting of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), actinic keratosis (AK), Bowen's Disease, Kui Swiss red skin hyperplasia, leukoplakia, oral cauliflower papilloma, squamous cell carcinoma or keratoacanthoma.

In a preferred embodiment, the aforementioned skin disease or discomfort is selected from the group consisting of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK). The aforementioned skin disease or discomfort is preferably actinic keratosis (AK).

Typically, an amine derivative having the formula (I) A-NH-B as defined hereinbefore is suitable for oral, inhalation, topical application, transdermal, nasal, rectal, subcutaneous or injection. Form to be administered.

Preferably, the amino derivative of formula (I) A-NH-B as defined hereinbefore is administered topically or transdermally.

As used herein, the term topical administration refers to a route of introducing a drug into the body, wherein the drug is applied to the skin (skin) to achieve a local effect, but the drug has only a low or even no systemicity. Absorption effect.

As used herein, transdermal administration refers to a route of introducing a drug into the body, wherein the drug is administered transdermally using a patch, a plaster, a patch or a pad to obtain a systemic effect. By administering the drug in this manner, the drug can be administered slowly and continuously (hours, days or longer). Thereby, the concentration of the drug in the blood can be relatively constant.

In a preferred embodiment, the amino derivative of formula (I) A-NH-B as defined hereinbefore is administered topically.

Pharmaceutical composition for local administration

The invention further relates to a pharmaceutical composition for topical administration comprising an amino derivative of formula (I) A-NH-B as defined above and a pharmaceutically acceptable excipient or carrier.

Examples of suitable shaped bodies or carriers in accordance with the present invention comprise water and oil. According to the present invention, the oil is a substance which is mucoid (oily) at room temperature or in a warm environment, and is both hydrophobic (not mixed with water) and lipophilic (mixable with other oils). According to the present invention, suitable oil phases are petroleum hydrocarbons (mineral oil, paraffin wax and wax), animal and vegetable fats and oils, fatty acids, fatty alcohols, natural waxes, polyfluorene oxides and hexylenes. a polyol other than an alcohol or a mixture of the foregoing.

According to the invention, suitable petroleum hydrocarbons (ie mineral oils, paraffin waxes and waxes derived from petroleum) are: solid paraffin, liquid paraffin (liquid paraffin or liquid paraffin), light liquid paraffin (light liquid paraffin) Or light liquid paraffin), white soft paraffin (white wax), yellow soft paraffin (yellow wax), bulk crystalline paraffin wax (mainly composed of the following: saturated C ₁₈ -C ₃₀ hydrocarbons and a small amount of isoalkanes and a cycloalkane, the molecular weight of the foregoing mixture is between 250 and 450 g/mol, and although the aforementioned mixture is solid at room temperature, its melting point is low, usually between 40 ° C and 60 ° C), small pieces a crystalline solid paraffin (which is composed of a C ₄₀ -C ₅₅ compound, which, in addition to the usual hydrocarbons, also includes a large amount of isoparaffins having an alkyl side chain and a cycloalkane, and the aforementioned isoalkane forms a large crystal. The small piece of crystalline solid paraffin has an average molecular weight of between 500 and 800 g/mol, is solid at room temperature, and has a melting point between 60 ° C and 90 ° C or a mixture of the foregoing. The petroleum hydrocarbon is preferably solid paraffin, liquid paraffin, light liquid paraffin, white soft paraffin or a mixture of the foregoing, and particularly preferably liquid paraffin, white soft paraffin or a mixture of the foregoing.

Suitable animal and vegetable fats and oils according to the invention are linear and/or branched chain esters, saturated and/or unsaturated alkyl carboxylic acids (chain lengths from 1 to 30 carbons) and straight Chains and/or branched chains, saturated and/or unsaturated alcohols (chain length from 1 to 30 carbons); or aromatic carboxylic acids and linear and/or branched chains, saturated and/or unsaturated alcohols Esters (chain lengths from 1 to 30 carbons).

The aforementioned oils are preferably selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, laurel N-hexyl acrylate, n-decyl oleate, isooctyl stearate, isodecyl stearate, isodecyl isononanoate, 2-ethylhexyl laurate, 2-ethylhexyl palmitate, coconut 2-ethylhexyl oleate, 2-hexyl decyl stearate, 2-ethylhexyl isostearate, 2-octylduccinate palmitate, hexadecyl palmitate, oleic acid oleic acid Esters, oleyl erucic acid esters, oleic acid oleate, succulent erucic acid esters, and synthetic, semi-synthetic and natural mixtures of the foregoing esters, such as jojoba oil (one having C ₁₈ -C single-chain _24-one of an unsaturated monocarboxylic acid and a C ₁₈ -C ₂₄ single-chain unsaturated monohydric alcohols of natural mixtures of esters formed).

Other suitable oils of the ester type formed from saturated alkyl carboxylic acids and alcohols are fatty acid methyl esters, preferably C ₆ -C ₂₄ fatty acid methyl esters derived from animal and vegetable fats and oils, for example all or Partially hydrogenated cotton oil, safflower oil, coconut oil, rapeseed oil, linseed oil, palm oil, palm kernel oil, sunflower oil, oleic acid, olive oil, olive residue, castor oil, animal fat, soybean oil, Oil slicks, etc.; and purified or synthesized fatty acids such as oleic acid, lanolinic acid, sunflower acid, lauric acid, myristic acid, palmitic acid (palmitic acid), palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, oleic acid, petrynic acid, linoleic acid, linolenic acid, arachidonic acid, decenoic acid, behenic acid, and erucic acid, or a mixture of the foregoing .

According to the invention, other suitable animal and vegetable fats and oils are fatty acid triglycerides, especially linear and/or branched chains, saturated and/or unsaturated alkyl carboxylic acids (having from 6 to 24 The chain length of carbon is preferably from 10 to 18 carbons of triglyceride. Different fatty acids can be used to esterify different positions of the glycerol, resulting in a large number of possible combinations, including combinations of positions. In natural triglycerides, the location of different fatty acids is not random, but is determined by the source of fat. The simplest form of triglyceride is composed of a single fatty acid.

The fatty acid triglyceride may preferably be selected, for example, from the group consisting of synthetic, semi-synthetic, and natural oils such as animal fats and oils such as butter, lard, bone oil, aquatic animal fat, and Oils (fish, such as salmon, mackerel or sardines; cetaceans; etc.); and vegetable fats and oils such as avocado, almond, hazelnut, baba, borage, peanut oil, Canola oil, hemp seed oil, chyle oil, safflower oil, eucalyptus oil, coconut oil, canola oil, black grass seed oil, wheat germ oil, sunflower oil, linseed oil, Queensland nut oil, corn oil, Pecan oil, olive oil and its by-products (such as olive residue), palm oil and its degradation products (such as soft palm oil and hard palm oil), evening primrose oil, rosehip oil, castor oil, rice bran oil, apricot kernel oil, cotton Seed oil, pumpkin seed oil, palm kernel oil and its degradation products (such as soft palm kernel oil and hard palm kernel oil), grape seed oil, bitter tea oil, soybean oil, cocoa butter, snow lipid and the like.

In particular, vegetable fats and oils as described above are preferred.

According to the present invention, suitable fatty acids may be C ₆ -C ₂₄ fatty acids derived from vegetable or animal fats and oils, such as those described above, such as wholly or partially hydrogenated cotton oil, safflower oil, coconut oil, rapeseed Seed oil, linseed oil, palm oil, palm kernel oil, sunflower oil, oleic acid, olive oil, olive residue, castor oil, animal fat, soybean oil, oil slick, etc., and purified or synthesized fatty acids such as oleic acid , lanolinic acid, sunflower acid, lauric acid, myristic acid, palmitic acid (palmitic acid), palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, Anti-oleic acid, petrynic acid, linoleic acid, linolenic acid, arachidonic acid, decenoic acid, behenic acid, and erucic acid, or a technical grade mixture of the foregoing; especially in plant sources, the fatty acid is preferably laurel Acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, behenic acid, and mixtures of the foregoing.

Suitable fatty alcohols according to the invention may be C ₆ -C ₂₄ fatty alcohols derived from vegetable or animal fats or oils, such as those described above, such as cotton, safflower, coconut, rapeseed, flaxseed, palm, Palm kernel, sunflower, oleic acid, olive, olive residue, castor oil, animal fat, soybean oil, oil slick, etc., which can be hydrogenated in whole or in part: and purified or synthesized fatty alcohols such as n-hexanol and n-octanol , sterol, lauryl alcohol, myristyl alcohol, palm (cetyl) alcohol, palmitol, stearyl alcohol, isostearyl alcohol, 2-octyldodecanol, 2-ethylhexanol, oleyl alcohol, Castor oil, oleyl alcohol, petrynyl alcohol, flax alcohol, linalol, arachidyl alcohol, terpene alcohol, behenyl alcohol, and erucic acid, or a technical grade mixture of the foregoing (e.g., cetearyl alcohol). Particularly in plant sources, the fatty alcohols are preferably lauryl alcohol, myristyl alcohol, palmitol, palmitol, stearyl alcohol, isostearyl alcohol, 2-octyldodecanol, oleyl alcohol, ricinoleic alcohol, and Behenyl alcohol, or a technical grade mixture of the foregoing (e.g., cetearyl alcohol).

Suitable natural waxes according to the present invention are candelilla wax, carnauba wax, Japanese wax, esparto wax, softwood wax, guaruma wax, Rice wax, sugar cane wax, small crown of ouricury wax, montan wax, beeswax, shellac wax, cetyl wax, lanolin (wax), tail wax, refined wax (ceresin waxes), peat waxes, ozokerites, and chemically modified waxes (hard waxes), the latter such as the montan wax ester, the funding Hill-Tropsch method (Fischer-Tropsch Process) The obtained wax, hydrogenated jojoba wax and synthetic wax.

In accordance with the present invention, suitable polyfluorene oxides are cyclic and/or linear polyfluorene oxides which may be in a monomeric form and generally have the following structural features, such as:

Wherein the indole may be substituted by the same or different alkyl or aryl group, and is generally referred to herein as an R ₁ -R ₄ group.

According to the present invention, a linear polyfluorene having a siloxane unit generally has the following structural features:

Wherein the ruthenium atoms may be substituted by the same or different alkyl or aryl groups, and are generally referred to herein as R ₁ -R ₄ groups (which means that the number of different groups is not necessarily limited to 4), and the m value is Between 2 and 200.000.

Suitable cyclic polyfluorenes in accordance with the present invention generally have the following structural features:

Wherein the ruthenium atoms may be substituted by the same or different alkyl or aryl groups, and are generally referred to herein as R ₁ -R ₄ groups (which means that the number of different groups is not necessarily limited to 4), and the n value is Between 3/2 and 20. When the value of n is a fraction, it means that an odd number of oxoalkyl groups are present in the ring.

Specific examples include a cyclomethoxane having the formula [(CH ₃ ) ₂ SiO] _x wherein x has a value of 3 to 6; or a short-chain linear type having the formula ((CH ₃ ) ₂ SiO [ (CH ₃ ) ₂ SiO] _y Si(CH ₃ ) ₃ methyl oxane wherein the y value is from 0 to 5.

Suitable cyclomethoxanes include: hexamethylcyclotrioxane (D3) which is a solid with the formula [(Me ₂ )SiO] ₃ and a boiling point of 134 ° C; octamethylcyclotetrazepine Oxyalkane (D4) having a boiling point of 176 ° C, a viscosity of 2.3 mm ² /s, and having the formula [(Me ₂ )SiO] ₄ ; decamethylcyclopentaoxane (D5) (cyclomethyloxirane) ), which has a boiling point of 210 ° C, a viscosity of 3.87 mm ² /s, a chemical formula of [(Me ₂ )SiO] ₅ , and a dodecamethylcyclohexaoxane (D6) having a boiling point of 245 ° C and a viscosity of 6.62. Mm ² /s, and the chemical formula is [(Me ₂ )SiO] ₆ .

Suitable short chain methyl oxanes include: hexamethyldioxane (MM) having a boiling point of 100 ° C, a viscosity of 0-65 mm ² /s, and a chemical formula of Me ₃ SiOMe ₃ ; Trioxane (MDM) has a boiling point of 152 ° C, a viscosity of 1.04 mm ² /s, a chemical formula of Me ₃ SiOMe ₂ SiOSiMe ₃ , a decamethyltetraoxane (MD2M), a boiling point of 194 ° C, and a viscosity of 1.53 mm ² /s, the chemical formula is Me ₃ SiO(MeSiO) ₂ SiMe ₃ ; dodecamethylpentaoxane (MD3M), its boiling point is 229 ° C, viscosity is 2.06 mm ² /s, and the chemical formula is Me ₃ SiO ( Me ₂ SiO) ₃ SiMe ₃ ; tetradecyl hexaoxane (MD4M) having a boiling point of 245 ° C, a viscosity of 2.63 mm ² /s, a chemical formula of Me ₃ SiO(Me ₂ SiO) ₄ SiMe ₃ ; Hexamethyl heptaoxane (MD5M) having a boiling point of 270 ° C, a viscosity of 3.24 mm ² /s, and a chemical formula of Me ₃ SiO(Me ₂ SiO) ₅ SiMe ₃ .

Further, a linear long chain type oxane includes, for example, phenyltrimethyloxane, bis(phenylpropyl)dimethyloxane, dimethyloxane, dimethyloxane. Alcohol, cyclomethoxane (octamethylcyclotetraoxane), hexamethylcyclotrioxane, polydimethyloxane, cetyldimethyloxane, and behenyloxy Dimethyl oxa oxide and the like.

Further, according to the present invention, a mixture of cyclomethoxane and isotridecyl isononanoate and a mixture of cyclomethoxane and 2-ethylhexyl isostearate are also suitable polycondensates. oxygen.

According to the invention, suitable polyols (other than hexene glycol) are preferably water-soluble polyols, such as polyhydric alcohols, the molecule of which contains two or more hydroxyl groups; specific examples include ethylene glycol, propylene glycol , 1,3-butanediol, 1,4-butanediol, dipropylene glycol, polyethylene glycol (having an average molecular weight of between 100 and 1000), glucose, fructose, galactose, mannose, ribose, Erythritol, maltose, maltitol, maltotriose, sucrose, xylitol, sorbitol, threitol, erythritol, glycerol, polyglycerol, and starch alcohol. Suitable polyols other than hexene glycol are preferably ethylene glycol, propylene glycol, 1,3-butanediol, 1,4-butanediol, dipropylene glycol, polyethylene glycol (the average molecular weight of which is between Between 100 and 1000), glycerol, polyglycerol, and mixtures of the foregoing.

The pH of the pharmaceutical composition for topical administration according to the present invention is in the range acceptable for topical administration, preferably between 3.0 and 6.0, more preferably between 3.5 and 5.0.

In a preferred embodiment, the pharmaceutical composition for topical administration of the present invention is prepared into the following forms: creams, gels, ointments, pastes, suspensions, lotions, foams, sprays. , spray or solution.

The viscosity of the pharmaceutical composition for topical administration of the present invention depends on the form of the composition. For example, when in the form of a cream, the viscosity is usually between 2,000 and 15,000 mPa.s, preferably between 2,500 and 10,000 mPa.s, and most preferably between 3,000 and 7,000 mPa.s; The viscosity values were measured using a DIN rotary rheometer (Paar Physica) at 20 ° C. The measurement system was Z 3 DIN; D = 57.1/s.

When it is a gel form, its viscosity is usually between 300 and 1,500 mPa.s, preferably between 500 and 1,200 mPa.s, preferably between 600 and 900 mPa.s; Values were measured using a DIN rotary rheometer (Paar Physica) at 20 ° C. The measurement system was Z 3 DIN; D = 57.2 / s.

The pharmaceutical composition for topical administration of the present invention may optionally include one or more active ingredients selected from the group consisting of: (a) an antibiotic; (b) an antifungal agent; (c) an antibiotic Organoamine; (d) antimetabolite; (e) corticosteroids; (f) immunosuppressants; (g) non-steroidal anti-inflammatory drugs (NSAIDs); (h) vitamin A analogs; and (i) vitamin D analog.

In the present invention, examples of suitable antibiotics include, but are not limited to, aclarubicin, actinomycin D, amrubicin, annamycin, ahamycin (adhamycin), bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin , idarubicin, mitomycin C, mupiricim, nemorubicin, neocarzinostatin, Pilocarpine Peplomycin, pirarubicin, rebeccamycin, retapamulin, stimalamer, streptozocin, pentorubicin Valrubicin, zostatin and combinations of the foregoing.

In the present invention, examples of suitable antifungal agents include, but are not limited to, amphotericin B, bifonazole, caspofungin, clotrimazole, and thorny white. Echinocandin B, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole , posaconazole, rabuconazole, terbinafine, tioconazole, voriconazole, and mixtures of the foregoing.

In the present invention, examples of suitable anti-histamine agents include, but are not limited to, clemastine, benadryl, doxylamine, loratadine. , desloratadine, fexofenadine, pheniramine, cetirizine, ebastine, promethazine, chlorine Chlorpheniramine, levocetirizine, olopatadine, quetiapine, meclizine, dimenhydrinate, Embramin (embramine), dimethindene, dexchlorpheniramine, cimetidine, famotidine, ranitidine, nizatidine Nizatidine), roxatidine, lafutidine, A-349,821, ABT-239, ciproxifan, clobenpropit, thioperamide, JNJ 7777120, VUF- 6002 and a combination of the foregoing.

In the present invention, examples of suitable antimetabolites include, but are not limited to, methotrexate, 6-mercaptopuhne riboside, mercaptopurine, alone or 5-fluorouracil (5-Fu), tegafur, UFT, dexifluhdine, carmofur, cytarabine, in combination with calcium leucovorin, Cytarabine ocfosfate, enocitabine, S-1, Alimta (pemetrexed disodium, LY231514, MTA), Gemcitabine (Gemcitabine, EIi Lilly), Fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, Eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, loja Nolatrexed, octadecyl phosphate, disodium premetrexed, pentastatin (pentostatin), pelitrerol, raltitrexed, thapine, trimetrexate, vidarabine, vincristine, vinorelbine, N-(5- [N-(3,4-Dihydro-2-methyl-4-hydroxyquinazolin-6-ylmethyl)-N-methylamino]-2-thiophene)-L-glutamic acid and the foregoing A mixture of substances; the antimetabolite is preferably methotrexate and 5-fluorouracil (5-Fu), wherein 5-fluorouracil (5-Fu) is the most preferred.

In the present invention, examples of suitable corticosteroids and glucocorticoids include, but are not limited to, prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, nafica. (naflocort), deflazacort, halopedone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, koji Triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palm Acid ester (dexamethasone palmitoate), tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, chlorodifluoroacetate Halometasone, methylprednisolone suleptanate, mometasone furoate, dipropionyl dragon Rimexolone), prednisolone farnesylate, ciclesonide, butixocort propionate, RS-85095, CGP-13774, GW-250495, Ponisson ( Deltacortisone), NO-Prednisolone, etiprednol dicloacetate, QAE-397, 7-fold-OH-EPIA, RPR-106541, deprodone propionate, fluticasone propionate (fluticasone propionate), fluticasone furoate, halobetasol propionate, ioteprednol etabonate, betamethasone butyrate propionate, flunisolide , prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, beta Betamethasone dipropionate, 21-chloro-11-hita-hydroxyl-17 alpha-[2-(methylsulfonyl)acetoxy]-4-alkenene-3,20-dione , isoisobutyrylciclesonide, hydrogen Hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium metasulfobenzoate, a combination of clobetasol propionate and the aforementioned substances; corticosteroids and saccharide steroids are preferably prednisone, prednisol, mometasone citrate and its derivatives, esters, steroids And mixtures, and combinations of the foregoing.

In the present invention, examples of suitable immunosuppressive agents include, but are not limited to, imiquimod, picremolimus, tacrolimus, cyclosporine A, anti-TUF agents. And a combination of the foregoing; the immunosuppressive agent is preferably imiquimod.

In the present invention, examples of suitable non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, oxicams, piroxicam, meloxicam, isosica ( Isoxicam), tenoxicam, sudoxicam, CP-14, 304, salicylate, aspirin (salicylic acid), disalicid, benoxyl ester (benorylate), trilisate, safapryn, soprnin, diflunisal, fendosal, acetic acid derivatives, aceclofenac (aceclofenac) ), diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furo Furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, Oxepinac, felbinac, etodolac, ketorolac, fenamates, mefenamic, meclofenamic acid (meclofenamic), flufenamic, niflumic, tolfenamic, propionic acid derivatives, ibuprofen, naproxen, benzoquinone Benzoprofen, flurbiprofen, ketoprofen, piketoprofen, fenoprofen, fenbufen, 吲哚布Indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, sulphur Tioxaprofe n, supprofe n, alminoprofen, tiaprofen, pyrazoles, phenylbutazone, phenoxybutene Azone, feprazone, azapropazone, trimethazone and derivatives, esters, salts and mixtures of the foregoing, and combinations of the foregoing; the aforementioned non-steroidal antibiotics The inflammatory drug is preferably aspirin (salicylic acid), aceclofenac, diclofenac, and derivatives, esters, salts thereof Mixtures of the foregoing, and combinations thereof; the non-steroidal anti-inflammatory drugs may be preferably diclofenac sodium.

In the present invention, examples of suitable vitamin A analogs include, but are not limited to, acitretin, isotretinoin, tretinoin, isotretinoin, Fenretinide and derivatives, esters, terpenoids and mixtures of the foregoing, and combinations of the foregoing; the vitamin A analogs described above are preferably retinoic acid.

In the present invention, examples of suitable vitamin D analogs include, but are not limited to, alfacalcidol, calcipotriol, calcitriol, dihydrostanol -2 (dihydrotachysterol-2), doxercalciferol, vitamin D3, 22-oxacalcitriol, paracalcitol, seocalcitol; EB 1089), tacalcitrol and combinations of the foregoing.

In one embodiment, the pharmaceutical composition for topical administration according to the present invention comprises: i) an amino derivative having the formula (I) A-NH-B selected from the group consisting of: 2 -(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; and 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidine -5-ylamino)benzoic acid, and pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof; and ii) 5-fluorouracil (5-FU).

In another embodiment, a pharmaceutical composition for topical administration according to the present invention comprises: i) an amino derivative having the formula (I) A-NH-B selected from the group consisting of: 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid and 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidine -5-ylamino)benzoic acid, and pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof; and ii) imiquimod.

In another embodiment, a pharmaceutical composition for topical administration according to the present invention comprises: i) an amino derivative having the formula (I) A-NH-B selected from the group consisting of: 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid and 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidine -5-ylamino)benzoic acid, and pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof; and ii) aspirin (salicylic acid).

In another embodiment, a pharmaceutical composition for topical administration according to the present invention comprises: i) an amino derivative having the formula (I) A-NH-B selected from the group consisting of: 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid and 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidine -5-ylamino)benzoic acid, and pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof; and ii) diclofenac sodium.

In another embodiment, a pharmaceutical composition for topical administration according to the present invention comprises: i) an amino derivative having the formula (I) A-NH-B selected from the group consisting of: 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid and 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidine -5-ylamino)benzoic acid, and pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof; and ii) vitamin A acid.

The pharmaceutical composition for topical administration according to the present invention may optionally include other known pharmaceutical and/or cosmetically acceptable additives, for example, anti-irritants, antioxidants, buffers (pH adjusters), chelating agents , emollients, penetration enhancers, preservatives, solubilizers, thickeners, wetting agents and the like, or mixtures of the foregoing.

Examples of suitable anti-irritant substances are aloe, chamomile, alpha-bisabolol, cola nitida extract, green tea extract, tea tree oil, licorice extract, shark liver Alcohol (α-octadecyl glyceryl ether), squalyl alcohol (α-9-octadecyl glyceryl ether), erythritol (α-cetyl glyceryl ether), panthenol, allantoin, coffee Or a mixture of other theophylline, glycyrrhizic acid, and derivatives of the foregoing, and the foregoing.

The antioxidant used may be any one suitable for or commonly used in makeup and/or treatment of skin diseases. Suitable antioxidants are preferably selected from the group consisting of amino acids (eg, glycine, histidine, tryptophan, tyrosine) and derivatives thereof, imidazoles (eg, urinary acid) and derivatives thereof Such as D, L-carnosine, D-carnosine, L-carnosine and other peptides and derivatives thereof (such as carnosine), carotenoids, carotene (such as α-carotene, β-carotene, lycopene) And its derivatives, fatty acids and their derivatives (such as dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (such as thioredoxin, glutathione, Cysteine, cystine and its glycosyl esters, N-ethyl decyl ester, methyl ester, ethyl ester, propyl ester, amyl ester, butyl and lauryl ester, palmitoyl ester, oleyl Base ester, γ-linoleate, cholesteryl ester and glyceride) and salts thereof; dilauryl thiodipropionate, distearyl thiodipropionate, thio Thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and And thiabine compounds (such as butyl sulfinine sulfite, homocysteine sulfite, butyl methionine, pentyl sulfoxide sulfite, hexyl thiosulfate sulfite, heptane sulphur Amino acid), the tolerated dose of the above substances is quite low (for example, pmol ~ μmol / kg); also includes (metal) chelating agents (such as α-hydroxy fatty acid, palmitic acid, phytic acid, lactoferrin), α- Hydroxy acids (eg citric acid, lactic acid, malic acid), humic acid, cholic acid, bile extract, bile pigment, biliverdin, EDTA, EGTA and its derivatives, unsaturated fatty acids and their derivatives (eg gamma-Asia) Sesic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and its derivatives, vitamin C and its derivatives (eg ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbic acid B) Acid esters, tocopherols and their derivatives (such as vitamin E acetate), as well as benzoic acid, benzoic acid, benzoic acid benzoic acid ester and its derivatives, ferulic acid and its derivatives, Hydroxytoluene, butylhydroxyanisole, nordihydroguaiare resin acid (nordihydr Oguaiac resin acid), nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (eg ZnO, ZnSO ₄ ), selenium And derivatives thereof (for example, methionine selenium), stilbene and derivatives thereof (for example, stilbene oxide, trans-stilbene oxide) and the aforementioned derivatives suitable for use in the active ingredient of the present invention (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids).

Any pharmaceutically acceptable buffer for adjusting the pH of the aqueous solution of the liquid pharmaceutical composition disclosed in the present invention is such that the pH can be adjusted to a range suitable for topical administration, preferably 3.0 to 6.0. Within the range, the best range is between 3.5 and 5. For example, a pharmaceutically acceptable acid composition can include the following inclusions: acetic acid, citric acid, fumaric acid, phosphoric acid, hydrochloric acid, lactic acid or nitric acid or the like, or a mixture of the foregoing. It will be appreciated that for certain compositions of the invention, the desired pH may be obtained even without the use of a pH adjusting agent. However, in compounds, an acid buffer system is typically used to achieve the desired pH. The monoacid buffer system includes an acid agent and a buffer. Among them, suitable acid agents well known to those skilled in the art include acetic acid, citric acid, fumaric acid, hydrochloric acid, phosphoric acid, lactic acid and nitric acid, and the like, and mixtures thereof; Suitable buffers well known to those skilled in the art include potassium metaphosphate, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate and the like, and mixtures of the foregoing.

Suitable softening agents which can be used in the compositions of the invention include, for example, dodecane, squalane, cholesterol, isohexadecane, isodecyl isononanoate, PPG ethyl ether, petrolatum, lanolin, safflower oil, castor oil , coconut oil, cottonseed oil, palm kernel oil, palm oil, peanut oil, soybean oil, carboxylic acid polyol esters, derivatives and analogs of the foregoing, and compositions.

The penetration enhancer may include, for example, dimethyl sulfoxide (DMSO), N-methylpyrrolidine, dimethylformamide (DMF), allantoin, urazole, N,N-dimethylacetamide (DMA), mercaptomethyl hydrazine, polyethylene glycol monolaurate, propylene glycol, propylene glycol monolaurate, glycerol laurate, lecithin, 1-substituted azacycloheptane 2-ketones, especially including 1-n-dodecylcycloazacycloheptan-2-one, ethanol, glycerol, hyaluronic acid, transcutol, and analogs and compositions of the foregoing. In addition, some oil compounds (such as some vegetable oils such as safflower oil, cottonseed oil, and corn oil) also have the property of enhancing penetration.

Suitable preservatives for preventing microbial contamination include, for example, alkylparabens, especially methyl methylparaben, methyl propylparaben and butylparahydroxybenzoate. Methyl formate; sodium benzoate; butylated hydroxytoluene; butylhydroxymethoxybenzene; ethylene diamine tetraacetic acid; chlorobutanol; benzyl alcohol; phenylethyl alcohol; dehydrated acetic acid; hexadienoic acid; potassium hexadienoate; Hydroxyl ammonium; benzyl ammonium chloride; and a mixture of the above. As for the amount of preservative used, it is usually determined by the type of preservative selected.

The co-solvent includes, for example, a nonionic surfactant from at least one of the following groups: a product obtained by adding 1 to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxide to the following materials: a linear C ₈ -C ₂₂ fatty alcohol having 8 to 15 carbon alkyl groups, a C ₁₂ -C ₂₂ fatty acid, and an alkyl phenol; an alkyl group and/or an alkenyl oligosaccharide (the alkyl group of which has 8 to 22 carbons) And its ethoxylated analog; 1 to 15 moles of addition product of ethylene oxide with castor oil and/or hydrogenated castor oil; 15 to 60 moles of ethylene oxide with castor oil and/or hydrogenated hydrazine Additive product of sesame oil; part of triglyceride and/or sorbitol having saturated or unsaturated, linear or branched chain fatty acids containing 12 to 22 carbons and/or hydroxycarboxylate containing 3 to 18 carbon atoms An acid, and an addition product of the foregoing with 1 to 30 moles of ethylene oxide; a mixture of alkoxylated glycerides and alkoxylated glycerol, partially polyglycerol (having an average degree of self-polycondensation of 2 to 8) , polyethylene glycol (having an average molecular weight of 400 to 5000), trimethylolpropane, pentaerythritol, sugar alcohol (such as Yamanashi Alcohols), alkyl glycosides (eg, methyl glycosides, butyl glycosides, lauryl glycosides) and polyglycosides (eg, cellulose) having saturated or unsaturated, linear or branched fatty acids containing 12 to 22 carbons and/or Or a hydroxycarboxylic acid having 3 to 18 carbon atoms, and an addition product of the foregoing with 1 to 30 moles of ethylene oxide; a mixed ester of isobaerythritol, a fatty acid, citric acid, and a fatty alcohol, and / or a mixed ester of 6 to 22 carbon fatty acids, methyl glucose and a polyol (preferably glycerol or polyglycerol); monoalkyl, dialkyl and trialkyl phosphate, And/or tri-PEG-alkyl phosphates and salts thereof; bulk copolymers such as polyethylene glycol-30 dipolyhydroxystearate; polymeric emulsifiers; polyolefin based diols and alkyl groups Glycerol ether. In particular, the co-solvent is preferably a product obtained by adding 1 to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxide to a linear C ₈ -C ₂₂ fatty alcohol such as lauryl alcohol. Myristyl alcohol, cetyl alcohol (palmitol), stearyl alcohol, oleyl alcohol and castor oil, and industrial mixtures thereof (such as whale alcohol or palmitol alcohol).

Thickeners or viscosity enhancers are generally used to increase the consistency of liquid pharmaceutical compositions. Any suitable thickening agent can be used in the compositions of the present invention. When used, a preferred thickening agent may include one or more of the following: gum arabic, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium or carboxymethyl. Cellulose sodium, cetearyl alcohol, methyl cellulose, ethyl cellulose, glycerin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, Polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, gum tragacanth and xanthan gum, and combinations thereof. The thickener is preferably glycerin, hydroxypropylmethylcellulose and xanthan gum and combinations thereof.

Wetting agents (chemicals that increase the dispersion and penetration of a liquid by reducing the surface tension) include, for example, one or more cationic surfactants such as chlorinated ammonium chloride; nonionic surfactants such as poly Oxyethylene and polyoxypropylene bulk copolymers, polyoxyethylene fatty acid glycerides or oils (such as polyoxyethylene (6) caprylic/capric acid mono or diglyceride, polyoxyethylene (40) hydrogenated castor oil) , polyoxyethylene sorbitan esters (such as polysorbate 20 and polysorbate 80), propylene glycol fatty acid esters (such as propylene glycol laurate), glycerol fatty acid esters (such as glyceryl monostearate), Yamanashi Alcohol esters (eg sorbitan monolaurate, sorbitan monooleate, sorbitol monopalmitate and sorbitan stearate), fatty acid glycerides (eg glyceryl monostearate), anionic interfacial activity Agents (such as sodium laurate sulfate, sodium laureth polyoxyethylene ether) or fatty acids and salts thereof (such as oleic acid, sodium oleate and triethanolamine oleate).

In the pharmaceutical composition for topical administration disclosed in the present invention, the weight percentage of the amino derivative having the formula (I) A-NH-B as defined above is usually in the range of 0.01 to 15 (compared to The overall weight of the composition is preferably in the range of from 0.02 to 10, more preferably in the range of from 0.05 to 7.5, most preferably in the range of from 0.1 to 6.

The present invention provides an amino derivative having the formula (I) A-NH-B for use in the treatment of a proliferative skin disease or discomfort, in particular for use in the treatment of a disease or discomfort selected from the group consisting of: a) epithelium and hair follicles Tumors, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), actinic keratosis (AK), Bowen's disease, Swiss red skin hyperplasia, leukoplakia, oral cauliflower-like papillomatosis , squamous cell carcinoma or keratoacanthoma; b) sebaceous adenoma, such as sebaceous gland cancer; c) sweat adenoma, such as breast bacillus, breast germination, small sweat gland cancer, microcyst adnexal cancer (MAC), or mucinous carcinoma of the skin; d) neurological tumors, such as Merkel cell carcinoma (MCC); e) mesenchymal tumors, such as dermatofibrosarcoma protuberans (DFSP), malignant fibrous tissue tumors ( MFH), atypical fibroids, epithelial sarcoma, synovial sarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, cutaneous lymphoma or multiple myeloma; f) metastatic cancer of the skin; g) melanin of the skin Tumor; h) lamellar ichthyosis; i) acne; or j) hirsutism.

The invention also provides a pharmaceutical composition for topical administration, comprising an amino derivative having the formula (I) A-NH-B, or simultaneously containing one or more active ingredients, for use in the treatment of proliferative skin diseases Or discomfort, especially for the treatment of diseases or discomforts as defined above.

The invention also provides a method of treating an individual suffering from a proliferative skin disease or discomfort comprising the steps of: administering an effective amount of an amino derivative of formula (I) A-NH-B or a pharmaceutical composition In the skin affected part of the aforementioned individual, wherein the pharmaceutical composition may separately comprise an amino derivative having the formula (I) A-NH-B or at the same time further comprising one or more active ingredients.

Typically, the area of skin in which the aforementioned disease or discomfort is afflicted is selected from the group consisting of the face, ears, scalp, neck, forearm, back, legs, arms or hands.

The pharmaceutical composition for topical administration of the present invention is used by completely covering the affected part in a smear manner to form a barrier layer. In addition, the amount of the pharmaceutical composition required depends on the size of the lesion area. At the time of treatment, the frequency of local administration is usually between one and four times a day, and during the administration period is between 10 and 120 days.

The invention further relates to the use of an amino derivative having the formula (I) A-NH-B for the preparation of a medicament for the treatment of a proliferative skin disease or discomfort, in particular a proliferative skin disease or discomfort as defined above .

The complete contents of the present invention are fully understood by those skilled in the art from the examples provided below, but should not be construed as limiting the scope of the foregoing.

Instance Example 1 Cell proliferation test

The human adult low calcium high temperature (HaCaT) cell line is a spontaneously transformed human keratinocyte characterized by basal epidermal keratinocytes (Boukamp et at. J Cell Biol 106:761-771, 1988). This cell line can be used as an in vitro culture model for highly proliferative epithelium (Ockenfels et at., Arch Dermatol Res 287:301-309, 1995).

The exponentially growing HaCaT cells were plated on a clear plate of 96-well plates at a density of 5000 cells and contained 100 μL of Dubbel modified Ingle culture containing 1% fetal bovine serum (FSB) (Dulbecco's Modified Eagle's medium; DMEM), and cultured at 37 ° C, 5% CO ₂ ; the next day, the culture solution in each well was replaced with 50 μL of growth medium containing 10% FBS. Two times as much as 50 μL of a compound containing 2% dimethyl sulfoxide (DMSO) at a desired concentration (in a normal growth medium) was added to the well. In the six wells, 100 μL of fresh medium containing 1% FBS and 1% DMSO was replaced as a control group for cell-free proliferation; in the other six wells, 100 μL of fresh 10% FBS and 1% DMSO was replaced. The culture medium was used as a control group for maximum proliferative capacity. The concentration of each compound was tested in triplicate and its concentration was serially diluted in a half logarithmic range from 100 μM to 0.4 μM. The plate was continuously cultured for 6 days under conditions of 37 ° C, 5% CO ₂ and the like. On the day of the test, the culture was removed and replaced with 100 μL of phosphate buffered saline (PBS). The intracellular adenosine-5'-triphosphate (ATP) content was assessed using a bioluminescence assay according to the manufacturer's instructions (ATP-lite, Perkin Elmer, Belgium). The results are expressed as follows: Percent inhibition of proliferation relative to wells with maximum and minimum proliferative capacity. Absolute IC ₅₀ values based causes inhibition of proliferation of 50% corresponding to a concentration of compound. Table 1 shows the average value of the three experiments of each compound and the values such as the standard deviation.

As is apparent from Table 1, the amino derivative of the present invention is more active in inhibiting the proliferation of HaCaT cells (keratinocytes of precancerous lesions) compared to terifluramine (a DHDOH inhibitor reported to inhibit HaCaT cells). . Therefore, in summary, the amino derivative of formula (I) A-NH-B, which is also a DHODH inhibitor, can be used for the treatment of proliferative skin diseases or discomforts, for the diseases mentioned above or Discomfort is more effective.

Any improvement to the main features of the aforementioned compounds, compositions or pharmaceutical compositions without affecting, altering, altering or modifying them is within the scope of the invention.

Claims (22)

An amino derivative of formula (I) for use in the treatment of a proliferative skin disease or discomfort, or a pharmaceutically acceptable salt or N-oxide or solvate or deuterated derivative thereof; A-NH -B formula (I) wherein A represents a group having one of formula A1 or A2, Wherein the asterisk mark (*) refers to a bond to the aforementioned -NH-B moiety; and wherein: - in the group of formula A1: ‧ R ¹ represents a group selected from one of the following: a hydrogen atom; a halogen atom C _1-4 alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from a hydrogen atom and a hydroxyl group; and a C _3-8 cycloalkyl group, as the case may be 1, 2 or 3 Substituted by a substituent selected from a halogen atom and a hydroxyl group; one of the ‧ G ³ and G ⁴ groups is a nitrogen atom, the other is a CH group; ‧ M is a hydrogen atom or a medicinal An acceptable cation; - in the group of formula A2: ‧ R ¹ ' is selected from the group consisting of: a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _3-4 cycloalkyl group , -CF ₃ and -OCF ₃ ; ‧ R ² ' is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkyl group; ‧ R ³ ' is selected from the following Group of: -COOR ⁵ ' , -CONHR ⁵ ' , tetrazolyl, -SO ₂ NHR ⁵ ', and -CONHSO ₂ R ⁵ ' groups, wherein R ⁵ ' is selected from the group consisting of: a hydrogen atom and the linear or branched chain C _1-4 Group; B represents one having the formula B1 or B2 groups: Wherein the asterisk mark (*) refers to a bond to the aforementioned A-NH- moiety; and wherein: - in the group of formula B1: one of the ‧ G ¹ groups represents a nitrogen atom or a CR ^c a group, the other represents a CR ^c group; ‧ G ² represents a nitrogen atom or a CR ^d group; ‧ R ² represents a group selected from the group consisting of: a hydrogen atom; a halogen atom; a hydroxy group; a C _1-4 alkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _1-4 alkoxy group, which may be 1, 2 or 3 as appropriate Substituted from a halogen atom and a substituent of a hydroxyl group; and a C _3-8 cycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ^a , R ^b and R ^c each independently represent a group selected from a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group. substituted; and C _1-4 alkoxy, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; ‧ R ^d represents a group selected from one of the following: a hydrogen atom ; A halogen atom; hydroxy; C _1-4 alkyl, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and the hydroxyl substituents; C _1-4 alkoxy which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; The limitation is that when at least one of the aforementioned R ^a and R ^b groups represents a hydrogen atom and the G ² system is a CR ^d group, then R ^d represents a group selected from one of the following groups: a C _1-4 alkoxy group, which is optionally substituted with 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group, as the case may be 1, 2 or 3 Substituted by a substituent selected from a halogen atom and a hydroxyl group; - in the group of formula B2: ‧ R ⁴ ' is selected from the group consisting of: a hydrogen atom and a C _1-4 alkyl group ; ‧ R ⁹ ' is selected from the group consisting of: a hydrogen atom and a phenyl group; ‧ G ¹ ' represents a group selected from N and CR ⁶ ' , wherein R ⁶ ' is selected from Composed of the following Group: hydrogen atom, halogen atom, C _1-4 alkyl group, C _3-4 cycloalkyl group, C _1-4 alkoxy group, -CF ₃ , -OCF ₃ , monocyclic nitrogen-containing C _5-7 heteroaryl a monocyclic nitrogen-containing C _3-7 heterocyclic group and a C _6-10 aromatic group, wherein the aforementioned aromatic group is optionally selected from a halogen atom and a C _1-4 alkyl group by one or more Substituted by a substituent; ‧ G ² ' represents a group selected from the group consisting of: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _1-4 alkoxy group, and -NR ^a ' R ^b ' , wherein R ^a ' represents a C _1-4 alkyl group, and R ^b ' is selected from the group consisting of C _1-4 alkyl and C _1-4 alkane Oxy-C _1-4 alkyl; or R ^a ' and R ^b ' and the nitrogen atom to which R ^a ' and R ^b ' are bonded together form a saturated 6 to 8 membered heterocyclic ring, the aforementioned heterocyclic ring optionally containing an oxygen An atom, as an additional hetero atom; ‧ a 5- to 10-membered heteroaryl ring of a monocyclic or bicyclic ring containing one or more nitrogen atoms, and optionally one or more selected from halogen atoms , C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, -CF ₃ , -OCF ₃ Substituted with a substituent of -CONR ⁷ ' R ⁸ ' , wherein R ⁷ ' and R ⁸ ' are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 ring Or an alkyl group; or R ⁷ ' and R ⁸ ' together with a nitrogen atom to which R ⁷ ' and R ⁸ ' are attached to form a group having the formula: Wherein n is an integer from 0 to 3; and ‧ a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkane Oxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, cyano, -CF ₃ , -OCF ₃ , -CONR ₇ ' R ₈ ' , oxadiazolyl, triazolyl, pyrazole And an imidazolyl group, wherein the aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ' and R ₈ ' are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl, a C _3-7 cycloalkyl group; or, R ₇ ' and R ₈ ' are associated with a nitrogen atom to which they are attached Forming a group having the formula: Wherein n is an integer from 0 to 3; ‧ or, when G ¹ ' represents CR ⁶ ' , G ² ' and R ⁶ ' together form a non-aromatic C _5-10 ring carbon group or a C _6-10 alkane base. An amino derivative according to claim 1, which is selected from the group consisting of amino (iso) nicotinic acid derivatives of formula (Ia), or pharmaceutically acceptable Accepted salts or solvates or N-oxides or stereoisomers or deuterated derivatives: Wherein one of the ‧ G ¹ groups represents a nitrogen atom or a CR ^c group, the other represents a CR ^c group; ‧ G ² represents a nitrogen atom or a CR ^d group ‧ R ¹ represents a group selected from the group consisting of a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group. And a C _3-8 cycloalkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ² represents a group selected from the group consisting of hydrogen atoms; halogen Atom; hydroxy; C _1-4 alkyl, optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxy group; C _1-4 alkoxy, optionally as 1, 2 or 3 substituents selected from halogen atoms and hydroxy groups of the substituted group; and C _3-8 cycloalkyl, which is optionally substituted with 1, 2 or 3 substituents selected from halogen atoms and hydroxy groups of the substituted; ‧ R ^a And R ^b and R ^c each independently represent a group selected from the group consisting of a hydrogen atom; a halogen atom; a C _1-4 alkyl group, which is optionally selected from a halogen atom and a hydroxyl group by 1, 2 or 3 take Substituted by a substituent; and a C _1-4 alkoxy group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; ‧ R ^d represents a group selected from the group consisting of: a hydrogen atom; a halogen atom; a hydroxyl group; a C _1-4 alkyl group, which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; and a C _1-4 alkoxy group, as the case may be 1, 2 or 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group; and a C _3-8 cycloalkoxy group optionally having 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group Substituted; ‧ one of the G ³ and G ⁴ groups is a nitrogen atom, the other is a CH group; ‧ M is a hydrogen atom or a pharmaceutically acceptable cation; That is, when at least one of the R ^a and R ^b groups represents a hydrogen atom and the G ² system is a CR ^d group, then R ^d represents a group selected from the group consisting of C _1-4 alkoxy groups. , which is optionally substituted by 1, 2 or 3 substituents selected from a halogen atom and a hydroxyl group; C _3-8 cycloalkoxy, which is optionally selected from a halogen atom and a hydroxyl group by 1, 2 or 3 Replace Substituted; or a pharmaceutically acceptable salt or solvate or N-oxide or a stereoisomer or a deuterated derivative; or an azabiphenyl benzoic acid derivative of formula (Ib) Wherein: ‧ R ^{1 '} is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkyl group, C _3-4 cycloalkyl group, —CF ₃ and —OCF ₃ ; ‧ R ^{2 '} It is selected from the group consisting of a hydrogen atom, a halogen atom, and a C _1-4 alkyl group; ‧ R ^{3 '} is selected from the group consisting of -COOR ⁵ , -CONHR ⁵ , tetrazole a group such as -SO ₂ NHR ⁵ ' and -CONHSO ₂ R ⁵ ' , wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a linear or branched chain C _1-4 An alkyl group; ‧ R ^{4 '} is selected from the group consisting of a hydrogen atom and a C _1-4 alkyl group; ‧ R ^{9 '} is selected from the group consisting of: a hydrogen atom And a phenyl group; ‧ G ^{1 '} represents a group selected from N and CR ^{6 '} , wherein R ^{6 '} is selected from the group consisting of hydrogen atom, halogen atom, C _1-4 alkane a group, a C _3-4 cycloalkyl group, a C _1-4 alkoxy group, a —CF ₃ , an —OCF ₃ , a monocyclic nitrogen-containing C _5-7 heteroaryl group, a monocyclic nitrogen-containing C _3-7 heterocyclic group, and a C _6-10 aromatic group, the C _6-10 aromatic-based group optionally substituted with one or more substituents selected from halogen atoms and The C _1-4 alkyl substituents; ‧ G ^{2 'represents} a group selected from one of the following: ‧ a hydrogen atom, a hydroxyl group, a halogen atom, a C _3-4 cycloalkyl group, a C _{1 a 4} -alkoxy group and -NR ^{a '} R ^{b '} , wherein R ^{a '} represents a C _1-4 alkyl group, and R ^{b '} is selected from the group consisting of C _1-4 alkyl groups and C _1-4 alkoxy-C _1-4 alkyl, or R ^{a '} and R ^{b '} and ^a nitrogen atom bonded to R ^{a '} and R ^{b '} together form a saturated 6 to 8 membered heterocyclic ring, as described above The heterocycle optionally contains an oxygen atom as an additional heteroatom; ‧ a monocyclic or bicyclic 5 to 10 membered heterocyclic ring containing one or more nitrogen atoms and optionally one or more substituents Substituted, the aforementioned substituent is selected from a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _3-4 cycloalkyl group, a C _3-4 cycloalkoxy group, -CF ₃ , OCF ₃ and -CONR ^{7 '} R ^{8 '} , wherein R ^{7 '} and R ^{8 '} are each independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; Or R ^{7 '} and R ^{8 '} together with the nitrogen atom to which they are attached form a group having the formula: Wherein n is an integer from 0 to 3; and ‧ a phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkane Oxy, C _3-4 cycloalkyl, C _3-4 cycloalkoxy, cyano, -CF ₃ , OCF ₃ , -CONR _{7 '} R _{8 '} , oxadiazolyl, triazolyl, pyrazolyl And an imidazolyl group, wherein the aforementioned oxadiazolyl, triazolyl, pyrazolyl and imidazolyl are optionally substituted by C _1-4 alkyl or C _3-7 cycloalkyl, and wherein R ₇ ' and R ₈ ' Each is independently selected from a hydrogen atom, a straight or branched chain C _1-4 alkyl group, a C _3-7 cycloalkyl group; or, R ₇ ' and R ₈ ' together with a nitrogen atom form a formula A group: Wherein n is an integer from 0 to 3; ‧ or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C _5-10 ring carbon group or a C _6-10 An alkyl group; or a pharmaceutically acceptable salt or solvate or N-oxide or a stereoisomer or a deuterated derivative. An amino derivative according to claim 2, wherein in the amino(iso)nicotinic acid derivative having the formula (Ia), all of the G ¹ groups represent a C(R ^c ) group; G ² represents a C(R ^d ) group; R ^a is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethoxy group, and 2,2,2- a trifluoroethoxy group; R ^b is selected from the group consisting of a hydrogen atom and a fluorine atom; and R ¹ is selected from the group consisting of a hydrogen atom, a bromine atom, a chlorine atom, and fluorine. An atom, a methyl group, an ethyl group, and a cyclopropyl group; R ² is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, and a methyl group; and G ³ represents a CH group, G ⁴ It means a nitrogen atom, or G ³ means a nitrogen atom, and G ⁴ means a CH group. The amino derivative according to claim 3, wherein in the amino(iso)nicotinic acid derivative having the formula (Ia), all of the G ¹ groups represent a C(R ^c ) group; G ² represents a C(R ^d ) group; R ^a is selected from the group consisting of a fluorine atom and 2,2,2-trifluoroethoxy; and R ^b is selected from the following a group consisting of a hydrogen atom and a fluorine atom; R ¹ is selected from the group consisting of a hydrogen atom, a bromine atom, and a fluorine atom, a methyl group, an ethyl group, and a cyclopropyl group; and the G ³ system represents a CH group. The group, G ⁴ system, represents a nitrogen atom. The amino derivative according to claim 2, wherein the amino(iso)nicotinic acid derivative having the formula (Ia) is selected from the group consisting of 2-(3'-B Oxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino Nicotine; 2-(3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxy linkage Phenyl-4-ylamino)nicotinic acid lithium; lithium 3-(3'-ethoxy-3-fluorobiphenyl-4-ylamino)isonicotinate; 3-(3-fluoro-3'-A Lithium oxybiphenyl-4-ylamino)isonicotinic acid; 3-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)isonicotinic acid ester; -(3-fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 5-bromo-2-(3,5-difluoro-3'-methoxy linkage Benz-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-di Fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)- 5-ethylnicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-di Fluorine biphenyl-4- Amino)nicotinic acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(2,5-difluoro-3' -Methoxybiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3,5-difluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino) Nicotinic acid; 2-(2'-chloro-3,5-difluorobiphenyl-4-ylamino)-5-cyclopropylnicotinic acid; or 2-(2,3,5,6-tetrafluoro -3'-methoxybiphenyl-4-ylamino)nicotinic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives. The amino derivative according to claim 5, wherein the amino(iso)nicotinic acid derivative having the formula (Ia) is selected from the group consisting of 2-(3'-B Oxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotine Acid; 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers Or deuterated derivatives. The amino derivative according to claim 2, wherein in the azabiphenylaminobenzoic acid derivative having the formula (Ib), R ^{1 '} is selected from the group consisting of a hydrogen atom, a halogen atom, and a methyl group. a CF3 group and a cyclopropyl group; R ^{2 '} represents a hydrogen atom or a methyl group; R ^{3 '} is a COOR ^{5 '} group, wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom, a monomethyl group, a monoethyl group and a tert-butyl group; R ^{4 '} represents a hydrogen atom, a fluorine atom or a monomethyl group; R ^{9 '} represents a hydrogen atom or a phenyl group; G ^{1 '} is selected From a nitrogen atom and CR ^{6 '} , wherein R ^{6 '} represents a hydrogen atom, a fluorine atom-a chlorine atom, a monomethyl group, a trifluoromethyl group, a cyclopropyl group and a phenyl group; and G ^{2 '} represents an election From the following groups: ‧ a hydrogen atom, a monohydroxy group, a monofluoro atom, a cyclopropyl group, a monomethoxy group, and -NR ^{a '} R ^{b '} , wherein R ^{a '} represents a C _1-2 alkyl group, and R ^{b '} is selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy-C _1-2 alkyl; or R ^{a '} and R ^{b '} and the nitrogen to which it is attached The atoms together form a saturated 6~7 member heterocycle, before The heterocyclic ring optionally includes an oxygen atom as an additional hetero atom; ‧ a 5- to 10-membered heteroaryl ring of a monocyclic or bicyclic ring containing one or two nitrogen atoms, and optionally Substituted by two halogen atoms and -CONR ⁷ ' R ⁸ ' , wherein R ⁷ ' and R ⁸ ' are each independently selected from a hydrogen atom, a C _1-2 alkyl group, and a cyclopropyl group; or, R ⁷ ' and R ⁸ ' and the nitrogen atom to which it is attached form a group having the formula: Wherein n is 1; and ‧ a phenyl group, which is optionally substituted with one, two or three substituents selected from the group consisting of fluorine atom, chlorine atom, hydroxyl group, C _1-3 alkoxy group, cyclopropyl group , cyclopropoxy, cyano, -CF ₃ , -OCF ₃ , -CONR _{7 '} R _{8 ',} and oxadiazolyl, wherein the aforementioned oxadiazolyl is optionally substituted with a monomethyl group, and wherein R _{7 '} and R _{8 '} are as defined above; ‧ or, when G ^{1 '} represents CR ^{6 '} , G ^{2 '} and R ^{6 '} together form a non-aromatic C ₆ ring carbon group or a phenyl group. The amino derivative according to claim 7, wherein in the azabiphenylaminobenzoic acid derivative of the formula (Ib), R ^{1 '} is selected from monomethyl or cyclopropyl; R ^{2 '} represents a hydrogen atom; R ^{3 '} is a COOR ^{5 '} group, wherein R ^{5 '} is selected from the group consisting of: a hydrogen atom and a C _1-4 alkane of a straight or branched chain R ^{4 '} represents a hydrogen atom; G ^{1 '} is selected from a nitrogen atom and a CH, C(CH ₃ ) and C(CF ₃ ) group; G ^{2 '} represents a cyclopropyl group or a phenyl group, the aforementioned phenyl group Substituted by one or two substituents selected from the group consisting of chloro, fluoro, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy and -CONR ^{7 '} R ^{8 '} wherein R ^{7 '} is a hydrogen atom, R ^{8 '} is a cyclopropyl group, or R ^{7 '} and R ^{8 '} together with a nitrogen atom to which it is bonded form a group having the formula: Where n is 1. The amino derivative according to claim 2, wherein the azabiphenylaminobenzoic acid derivative having the formula (Ib) is selected from the group consisting of 5-cyclopropyl-2 -(2-phenylpyrimidin-5-ylamino)benzoic acid; 5-(2-carboxy-4-cyclopropylphenylamino)-3-methyl-2-phenylpyrimidine 1-oxide; 5- Methyl-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzene acid; 2-(5-fluoro-6-phenylpyridin-3-ylamino)-5 -methylbenzoic acid; 5-cyclopropyl-2-(3'-fluoro-2,4'-dipyridin-5-ylamino)benzoic acid; 2-(5-chloro-6-phenylpyridine-3 -ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-(2-(2-cyclopropylphenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2- (5-phenylpyridin-3-ylamino)benzoic acid; 2-(5-chloro-2-phenylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropyl-2-( 5,6-biphenylpyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-ring Propyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid; 5-methyl-2-((6-(2,3-difluoro) Phenyl)pyridin-3-yl)amino)benzoic acid; 2-(2-(3-cyclopropylphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid; 5-A 5-(6-morpholinopyridin-3-ylamino)benzoic acid; 5-methyl-2-(5-methyl-6-morpholinpyridin-3-ylamino)benzoic acid; 5- Cyclopropyl-2-(6-cyclopropyl-5-phenylpyridin-3-ylamino)benzoic acid; 2-(6-(2-cyclopropylphenyl)-5-methylpyridine-3- Benzyl)-5-methylbenzoic acid; 2-(6-(2-cyanophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(2-(3) -Chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 5-methyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzene Acid; 5-methyl-2-(5-methyl-6-(piperidin-1-yl)pyridin-3-ylamino)benzene acid; 2-(6-(azacycloheptan-1-yl) -5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(2,3'-dipyridin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(3 '-Chloro-2,4'-dipyridin-5-ylamino)-5-methylbenzoic acid; 5-methyl-2-(3-methyl-2,2'-dipyridin-5-ylamino Benzic acid; 2-(6-(3-ethoxyphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 2-(6-(3-methoxybenzene) 5-(methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-methyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid; -(6-(3-isopropylphenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-ring Propyl-2-(5-methyl-6-(3-(trifluoromethoxy)phenyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(5-methyl- 6-phenylpyridin-3-ylamino)benzoic acid; 2-(6-(2-fluorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoic acid; 5-cyclopropane 2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 5-cyclopropyl-2-(6-(3-methoxyphenyl)-5 -(trifluoromethyl)pyridin-3-ylamino)benzoic acid; 2-(6-(2-chlorophenyl)pyridin-3-ylamino)-5-cyclopropylbenzoic acid; 2-(2- (2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropyl benzoic acid; 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-methylbenzoic acid; 2-(6-(2,6-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoic acid; 5-methyl-2-(5-methyl-6-(3-(pyrrole) Pyridin-1-carbonyl)phenyl)pyridin-3-ylamino)benzoic acid; 2-(6-(3-(cyclopropylcarbamoyl)phenyl)-5-methylpyridin-3-ylamino 5-methylbenzoic acid; 5-cyclopropyl-2-(2-(2-fluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-(2-(2) Methyl (-trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoate; methyl 5-cyclopropyl-2-(2-o-tolypyrimidin-5-ylamino)benzoate; (2-(2-cyclopropylphenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzene Methyl ester; methyl 5-cyclopropyl-2-(2-(2,5-difluorophenyl)pyrimidin-5-ylamino)benzoate; 5-cyclopropyl-2-(2-(2, Methyl 3-difluorophenyl)pyrimidin-5-ylamino)benzoate; 2-(2-(5-chloro-2-fluorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid Methyl ester; tert-butyl 5-methyl-2-(2-(2-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoate; 5-cyclopropyl-2-(2- Methyl (2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)benzoate; 2-(3',5'-difluoro-2,4'-dipyridine-5- Ethylamino)-5-methylbenzoic acid ethyl ester; 5-methyl-2-(6-(3-(5-methyl-1,3,4-oxadiazolyl-2-yl)phenyl) Tert-butyl pyridin-3-ylamino)benzoate; tert-butyl 5-methyl-2-(5-methyl-6-(pyrimidin-5-yl)pyridin-3-ylamino)benzoate; T-butyl 2-(6-(2,3-difluorophenyl)pyridin-3-ylamino)-5-methylbenzoate; 2-(6-(5-fluoro-2-methoxybenzene) Tert-butyl-5-methylpyridin-3-ylamino)-5-methylbenzoate; and the aforementioned pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or oximes Derivatives. The amino derivative according to claim 9, wherein the azabiphenylaminobenzoic acid derivative having the formula (Ib) is selected from the group consisting of 5-cyclopropyl-2 -(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid; 5-cyclopropyl-2-((2-(2-trifluoromethyl)phenyl)pyrimidine-5 -amino)aminobenzoic acid; 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid; and the aforementioned pharmaceutically acceptable salts, Solvates, N-oxides, stereoisomers or deuterated derivatives. The amino derivative according to any one of claims 1 to 10, wherein the amino derivative is a DHODH inhibitor, and the DHODH inhibitor has a hDHODH IC _{50 of} about 500 or less, which is The measurement was carried out using a chromogen reduction reagent having 2,6-dichlorophenol-nonanol (DCIP). The amino derivative according to any one of claims 1 to 11, wherein the skin disease or discomfort is not an autoimmune or inflammatory disease or discomfort. The amino derivative according to claim 12, wherein the skin disease or discomfort is selected from the group consisting of: a) epithelial and hair follicle tumors, such as basal cell carcinoma (BCC), squamous Epithelial cell carcinoma (SCC), actinic keratosis (AK), Bowen's disease, Swiss red hyperplasia, leukoplakia, oral caulifloweroma, squamous cell carcinoma or keratoacanthoma; b) Sebaceous adenomas, such as sebaceous gland cancer; c) sweat adenomas, such as breast bacillus, breast germination, small sweat gland cancer, microcyst adnexal cancer (MAC), or mucinous carcinoma of the skin; d Nervous system tumors, such as Merkel cell carcinoma (MCC); e) mesenchymal tumors, such as dermatofibrosarcoma protuberans (DFSP), malignant fibrous tissue tumors (MFH), atypical fibroids, epithelial sarcoma , synovial sarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, cutaneous lymphoma or multiple myeloma; f) metastatic cancer of the skin; g) melanoma of the skin; h) lamellar ichthyosis; i) Acne; and j) hirsutism. The amino derivative according to claim 13, wherein the skin disease or discomfort is selected from the group consisting of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), light. Keratosis (AK), Bowen's disease, Swiss red skin hyperplasia, leukoplakia, oral cauliflower papilloma, sickle cell carcinoma, and keratoacanthoma. The amino derivative according to any one of claims 1 to 11, wherein the amino derivative is administered topically or transdermally. A pharmaceutical composition for topical administration comprising an amino derivative as described in any one of claims 1 to 11 and a pharmaceutically acceptable excipient or carrier. The pharmaceutical composition for topical administration as described in claim 16 wherein the composition is prepared in the form of a cream, a gel, an ointment, a paste, a suspension, a lotion, a foaming agent. , spray, spray or solution. The pharmaceutical composition for topical administration as described in claim 16 or 17, wherein the composition further comprises one or more active ingredients selected from the group consisting of: (a) an antibiotic; b) antifungal agents; (c) anti-histamines; (d) antimetabolites; (e) corticosteroids; (f) immunosuppressants; (g) non-steroidal anti-inflammatory drugs (NSAIDs); (h) vitamins A analog; and (i) a vitamin D analog. The pharmaceutical composition for topical administration according to any one of claims 16 to 18, wherein the composition further comprises an anti-irritant, an antioxidant, a buffer, a chelating agent, a softening agent, and a penetration enhancer. , preservatives, solubilizers, thickeners, wetting agents or mixtures of the foregoing. A pharmaceutical composition for topical administration according to any one of claims 16 to 19, which is for use in the treatment of a skin disease according to any one of claims 1 to 12 to 14 Or not. A method of treating an individual suffering from a skin disease or discomfort according to any one of claims 1 to 12, comprising the step of: having an effective dose as in claims 1 to 11 The amino derivative according to any one of claims 16 to 20, which is applied to the skin affected part of the aforementioned individual. The use of an amino derivative according to any one of claims 1 to 11 for the treatment of a skin disease as described in any one of claims 1 to 12 to 14 Or uncomfortable drugs.