KR20060129413A - 2- (3-substituted-aryl) amino-4-aryl-thiazole as a tyrosine kinase inhibitor - Google Patents

Abstract

The present invention selectively modulates, modulates and / or inhibits signal transduction mediated by certain natural and / or mutant tyrosine kinases causing various human and animal diseases such as cell proliferative, metabolic, allergic and degenerative disorders. , New compounds selected from 2- (3-substituted -aryl) amino-4-aryl-thiazole. More specifically, the compound is a potent and selective c-kit inhibitor.

Description

2- (3-substituted-aryl) amino-4-aryl-thiazole as a tyrosine kinase inhibitor {2- (3-SUBSTITUTED-ARYL) AMINO-4-ARYL-THIAZOLES AS TYROSINE KINASE INHIBITORS}

The present invention selectively modulates, modulates and / or inhibits signal transduction mediated by certain natural and / or mutant tyrosine kinases causing various human and animal diseases such as cell proliferative, metabolic, allergic and degenerative disorders. , New compounds selected from 2- (3-substituted -aryl) amino-4-aryl-thiazole. More specifically, the compound is a potent and selective c-kit inhibitor.

Tyrosine kinases are receptor-type or non-receptor-type proteins, which deliver terminal phosphates of ATP to tyrosine residues in the protein, thereby activating or inactivating signal transduction pathways. These proteins are known to be involved in many cellular mechanisms and, when destroyed, cause disorders such as abnormal cell proliferation and migration, as well as inflammation.

Currently, about 58 tyrosine kinases are known. Other tyrosine kinases are well known VEGF receptors (Kim et al., Nature 362, pp. 841-844, 1993), PDGF receptors, c-kits and the FLK family. These receptors can signal other tyrosine kinases such as Src, Raf, Frk, Btk, Csk, Abl, Fes / Fps, Fak, Jak, Ack and the like.

Of the tyrosine kinase receptors, the c-kit is of particular interest. Indeed, c-kits are key receptors for activating mast cells that have been demonstrated to be directly or indirectly involved in a number of pathologies, in which Applicants disclose WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, US 60 / 359,652 and Filed US 60/359651.

Mast cells present in the tissues of a patient are involved in or contribute to the development of diseases such as autoimmune diseases (rheumatic arthritis, inflammatory bowel disease (IBD)), allergic diseases, tumor angiogenesis, inflammatory diseases, and interstitial cystitis. Was found. In these diseases, mast cells are characterized by different proteases and mediators such as histamine, neutral proteases, lipid-induced mediators (prostaglandins, thromboxanes and leukotrienes) and various cytokines (IL-1, lL-2, IL-3). Participate in tissue disruption by releasing cocktails of IL-4, IL-5, IL 6, IL-8, TNF-α, GM-CSF, MIP-la, MIP-lb, MIP-2 and IFN-γ Proved to be.

c-kit receptors are also constantly activated by mutations leading to abnormal cell proliferation and to the development of diseases such as mastocytosis and various cancers.

For this reason, it has been proposed to target c-kits to inhibit mast cells causing the disorder.

Thus, the primary object of the present invention is to find potent and selective compounds capable of inhibiting wild type and / or mutant c-kits.

Many different compounds have been described as tyrosine kinase inhibitors, examples of which are bis monocyclic, bicyclic or heterocyclic aryl compounds (WO 92/20642), vinylene-azaindole derivatives (WO 94/14808) and 1-cyclopropyl- 4-pyridyl-quinolone (US 5,330,992), styryl compound (US 5,217,999), styryl substituted pyridyl compound (US 5,302,606), selenoindole and selenide (WO 94/03427), tricyclic polyhydroxyl compound (WO 92/21660) and benzylphosphonic acid compounds (WO 91/15495), pyrimidine derivatives (US 5,521,184 and WO 99/03854), indolin derivatives and pyrrole-substituted indolinones (US 5,792,783, EP 934 931, US) 5,834,504, US 5,883,116, US 5,883,113, US 5,886,020, WO 96/40116 and WO 00/38519), as well as bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295 and US 4,343,940) and aryl and heteroaryl quinazolines (US 5,72 1,237, US 5,714,493, US 5,710,158 and WO 95/15758.

However, none of these compounds have been described as potent and selective inhibitors of the c-kit or c-kit pathway.

 In the context of the invention described in WO2004014903, the inventors have found that the compound corresponding to 2- (3-aminoaryl) amino-4-aryl-thiazole is a potent and selective inhibitor of the c-kit or c-kit pathway. Found. The compounds are excellent candidates for treating diseases such as autoimmune diseases, inflammatory diseases, cancer and mastocytosis.

We have found that other 2- (3-substituted-aryl) amino-4-aryl-thiazole derivatives show very potent inhibitory activity on several forms of c-kit.

Accordingly, the present invention relates to compounds belonging to 2- (3-ketoarylamino-4-aryl-thiazole, which selectively inhibits signal transduction, including tyrosine phosphokinase c-kit and mutated forms thereof. In a first embodiment, the present invention relates to compounds of formula (I), which may represent substances in free base form or pharmaceutically acceptable salts thereof:

In the above formula,

R6 and R7 are each independently of the following (i) to (v):

(i) hydrogen, halogen (selected from F, Cl, Br or I);

(ii) one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as linear, branched or cyclic alkyl groups having 1 to 10 carbon atoms, or 2 or 3 to 10 carbon atoms optionally substituted with trifluoromethyl, carboxyl, cyano, nitro, and formyl (e.g., methyl, ethyl, Alkyl ¹ groups defined as propyl, butyl, pentyl, hexyl ...);

(iii) phenyl, or

Halogen (selected from I, F, Cl or Br);

Alkyl ¹ groups;

Cycloalkyl, aryl or heteroaryl groups optionally substituted with pendant basic nitrogen functionality;

Trifluoromethyl, O-alkyl ¹ , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl ¹ , N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally basic nitrogen In the form of functional groups)

An aryl ¹ group defined as a substituted variant of phenyl having any combination of one or more substituents at any position of the ring, including;

(iv)

Halogen (selected from F, Cl, Br or I);

Alkyl ¹ groups;

Cycloalkyl, aryl or heteroaryl groups optionally substituted with pendant basic nitrogen functionality;

Trifluoromethyl, O-alkyl ¹ , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl ¹ , N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally basic In the form of bovine functional groups)

Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, which may further possess any combination of one or more substituents, including at any one position in the ring Heteroaryl ¹ groups defined as pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group;

(v) trifluoromethyl, carboxyl, cyano, nitro, formyl, hydroxy, N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally in the form of a basic nitrogen functional group)

Is selected from one of;

R8 is the following (i) to (iii):

(i) hydrogen, or

(ii) a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups), or

(iii) CO-R8 or COOR8 or CONHR8 or SO ₂ R8 wherein R8 is

Linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups), or

Phenyl or halogen (selected from F, Cl, Br or I); An alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, C _1-6 alkylamino, di (C _1-6 alkyl) amino, and amino (last nitrogen Substituents are optionally in the form of pendant basic nitrogen functional groups); As well as CO-R, COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R, wherein R is at least one heteroatom, in particular halogen (selected from F, Cl, Br or I), oxygen, And a phenyl having any combination of one or more substituents at any one position in the ring, including a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with nitrogen (optionally in the form of pendant basic nitrogen functional groups). Aryl groups, including modified variants, or

Halogen (selected from F, Cl, Br or I); An alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, C _1-6 alkylamino, di (C _1-6 alkyl) amino, and amino (last nitrogen Substituents are optionally in the form of basic nitrogen functional groups); As well as CO-R, COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R, wherein R is at least one heteroatom, in particular halogen (selected from F, Cl, Br or I), oxygen, And any linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with nitrogen (optionally in the form of pendant basic nitrogen functional groups). Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl , A heteroaryl group including benzimidazole, quinolinyl group]

One of;

R2, R3, R4 and R5 are each independently hydrogen; Halogen (selected from F, Cl, Br or I); Linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, carboxyl, cyano, nitro, formyl, hydroxy and CO-R , COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R wherein R is one or more heteroatoms, in particular halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally pendant) A linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with a basic nitrogen functional group);

A is CH ₂ , O, S, S0 ₂ , CO, or COO;

B is a bond or NH, NCH ₃ , NR *, (CH ₂ ) _n (where n is 0, 1 or 2), O, S, S0 ₂ , CO, or COO;

B 'is a bond or NH, NCH ₃ , NR *, (CH ₂ ) _n (where n is 0, 1 or 2), O, S, S0 ₂ , CO or COO;

R * is alkyl ¹ , aryl ¹ or heteroaryl ¹ ;

W is a bond, or NH, NHCO, NHCOO, NHCONH, NHS0 ₂ , NHS0 ₂ NH, CO, CONH, COO, COCH ₂ , (CH ₂ ) _n (n is 0, 1 or 2), CH ₂ -CO, A linker selected from CH ₂ COO, CH ₂ —NH, O, OCH ₂ , S, SO ₂ , and SO ₂ NH;

R1 is the following a) to c):

a) a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality;

b) aryl or heteroaryl groups optionally substituted with heteroatoms, especially halogens selected from I, Cl, Br and F or optionally substituted with alkyl or aryl groups having pendant basic nitrogen functionality;

c) alkyl ¹ , aryl ¹ or heteroaryl ¹

to be.

C ₁ -C ₁₀ alkyl will be understood to include methyl, ethyl, propyl, and C ₂ -C ₄ alkyl or C ₂ -C ₁₀ alkyl.

For example, some of the compounds

In the above formula, R1, R4 and R6 have the meaning as defined above.

A-B-B '

CH ₂ , CH ₂ -CO, CH ₂ -CO-CH ₂ , CH ₂ COO, CH ₂ -CH ₂ -CO, CH ₂ -CH ₂ -COO, CH ₂ -NH, CH ₂ -CH ₂ -NH, CH ₂ -NH-CH ₂ , CH ₂ -NH-CO or CH ₂ -CO-NH

It is to be understood that the invention includes, but is not limited to:

A-B-B 'degree

CO-CH ₂ , COO-CH ₂ , CO-CH ₂ -CH ₂ , CO-NH, or CO-NH-CH ₂ as well as O-CH ₂

It is to be understood that the invention includes, but is not limited to:

It will be understood that NH in B or B 'may be NCH ₃ .

In Formula (I) above, it will be understood that when W is not a single bond, A may be NH or NCH ₃ .

In the above formula, the following combinations can be considered:

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CO-NH and R 1 is as defined above.

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CH ₂ —CO-NH and R 1 is as defined above.

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CH ₂ —CO and R 1 is as defined above.

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CH ₂ —NH—CO and R 1 is as defined above.

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CH ₂ —NH and R 1 is as defined above.

R 6 is (iv), R 4 is H or CH ₃ , AB-B ′ is CH ₂ and R 1 is as defined above.

- R6 is W- (iv), R4 is an C ₁ -C ₂ alkyl, AB-B 'is CO-NH Rl is as defined above.

R 6 is (iv), R 4 is C ₁ -C ₂ alkyl, AB-B ′ is CH ₂ -CO-NH and R 1 is as defined above.

R 6 is (iv), R 4 is C ₁ -C ₂ alkyl, AB-B ′ is CH ₂ -CO and R 1 is as defined above.

R 6 is pyridyl according to (iv), R 4 is C ₁ -C ₂ alkyl, AB-B ′ is CO—NH, CH ₂ —CO—NH, CH ₂ —CO, CH ₂ —NH, CH ₂ -NH-CO and Rl is as defined above.

In the above combination, R ¹ may be alkyl ¹ .

In the above combination, R 1 may be aryl ¹ .

In the above combination, R may be heteroaryl ¹ .

In one preferred embodiment, ABB ′ is CONH and the present invention relates to compounds of formula I-1

In the above formula,

R is H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms or having a pendant basic nitrogen functional group; Selected from heteroatoms, especially cycloalkyl, aryl or heteroaryl groups optionally substituted with halogens selected from I, Cl, Br and F and / or optionally substituted with alkyl, cycloalkyl, aryl or heteroaryl groups having pendant basic nitrogen functionality It can be an organic group.

In one other preferred embodiment, the invention relates to an amide-aniline compound of formula I-2:

In the above formula,

R is H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms or having a pendant basic nitrogen functional group; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F and / or bear pendant basic nitrogen functionality; Or an organic group which may be selected from cycloalkyl, aryl or heteroaryl groups optionally substituted with cycloalkyl, aryl or heteroaryl groups optionally substituted with the following groups:

Heteroatoms, in particular halogen selected from I, Cl, Br and F;

-A SO ₂ -R group, wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality );

Group CO-R or CO-NRR 'wherein R and R' are independently substituted with H, one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or pendant basic nitrogen functionality Independently selected from the group having alkyl, cycloalkyl, aryl or heteroaryl).

Among certain compounds in which R 1 has the meanings defined above, the present invention relates to amide-benzylamine compounds of formula I-3:

In the above formula,

R is a linear or branched alkyl group of 1 to 10 carbon atoms which is optionally substituted with H or a halogen selected from one or more heteroatoms, in particular I, Cl, Br and F and / or bears pendant basic nitrogen functional groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having pendant basic nitrogen functionality; Or alkyl, cycloalkyl, aryl or heteroaryl groups optionally substituted with heteroatoms, in particular halogens selected from I, Cl, Br and F or substituted with alkyl, cycloalkyl, aryl or heteroaryl groups bearing pendant basic nitrogen functional groups; A SO ₂ -R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality; Or CO-R or CO-NRR 'groups, wherein R and R' are independently selected from aryl, heteroaryl, alkyl and cycloalkyl groups optionally substituted with H or one or more heteroatoms and / or bear pendant basic nitrogen functional groups ) Is an organic group which can be selected.

Among certain compounds in which R 1 has the meanings defined above, the present invention relates to amide-phenol compounds of formula (I-4)

In the above formula,

R is a linear or branched alkyl group of 1 to 10 carbon atoms which is optionally substituted with H or a halogen selected from one or more heteroatoms, in particular I, Cl, Br and F and / or bears pendant basic nitrogen functional groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F and / or bear pendant basic nitrogen functionality; Or an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality ; A SO ₂ -R group wherein R is a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality; Or a CO-R or CO-NRR 'group wherein R and R' are independently aryl, heteroaryl, alkyl and cycloalkyl groups optionally substituted with H or one or more heteroatoms and / or bear pendant basic nitrogen functionality. It is an organic group that can be selected from.

Among the compounds of formula (I), the invention relates in particular to the 3- (thiazol-2-ylamino) -benzamide compounds of formula (I-5)

In the above formula,

Y is a single bond, a linear or branched alkyl group having 1 to 10 carbon atoms, in particular CH ₂ or CH ₂ -CH ₂ ; Or NH;

Wherein Z is the following group:

Halogen, such as F, Cl, Br, I;

Linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functionality; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F and / or bear pendant basic nitrogen functionality; Or cycloalkyl, aryl or heteroaryl groups optionally substituted with heteroatoms, especially halogens selected from I, Cl, Br and F and / or substituted with alkyl, cycloalkyl, aryl or heteroaryl groups bearing pendant basic nitrogen functional groups;

OR (wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or bears pendant basic nitrogen functional groups; heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Or cycloalkyl, aryl or heteroaryl groups substituted with alkyl, cycloalkyl, aryl or heteroaryl groups bearing pendant basic nitrogen functional groups;

NRaRb wherein Ra and Rb are hydrogen or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functionality; A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from among the above heteroatoms, in particular I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or among heteroatoms, in particular I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a selected halogen and / or substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality)

Any combination of represents an aryl or heteroaryl group optionally substituted at one or more positions of the ring;

R ₂ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy;

R ₃ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy;

R ₄ is hydrogen, halogen or a linear or branched alkyl group of 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy;

R ₅ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl groups, including phenyl or substituted variants of phenyl having any combination of one or more substituents, including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; ;

(ii) 2, 3, or 4-pyridyl, which may further retain any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl and alkoxy, at any one position of the ring Heteroaryl groups including groups;

(iii) 2-thienyl, 3-thier, which may further retain any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; 5-membered ring aromatic heterocyclic groups including nil, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl;

(iv) H; Halogen selected from I, F Cl or Br; NH ₂ , NO ₂ or SO ₂ -R, wherein R is from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

One of;

R ₇ is the following (i) to (iv):

(i) aryl groups, including phenyl or substituted variants of phenyl having any combination of one or more substituents, including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; ;

(ii) 2, 3, or 4-pyrides which may further retain any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; Heteroaryl groups including diyl groups;

(iii) 2-thienyl, 3-thier, which may further retain any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; 5-membered ring aromatic heterocyclic groups, such as nil, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, such as;

(iv) H; Halogen selected from I, F, Cl or Br; NH ₂ , NO ₂ or SO ₂ -R wherein R contains at least one group such as 1 to 10 carbon atoms and is optionally substituted with at least one heteroatom, in particular halogen selected from I, Cl, Br and F / Or a linear or branched alkyl group having a pendant basic nitrogen functional group)

Is one of.

Examples of preferred compounds of the above formula include the following compounds:

001: 4- [4-Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzoylamino] -benzoic acid 2-diethylamino-ethyl ester

Among the compounds of formula (I), the present invention is particularly embodied by the compounds of formula (II):

In the above formula,

X is R or NRR 'wherein R and R' are independently H; aryl, heteroaryl optionally substituted with one or more hetero atoms, such as a halogen selected from F, I, Cl and Br and optionally having pendant basic nitrogen functionality , Alkyl, or cycloalkyl group; or aryl optionally substituted with one or more heteroatoms such as halogens selected from F, I, Cl and Br and optionally substituted with aryl, heteroaryl, alkyl or cycloalkyl groups having pendant basic nitrogen functionality , Heteroaryl, alkyl or cycloalkyl group);

R ₂ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₃ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₄ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₅ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl groups, including phenyl or substituted variants of phenyl having any combination of one or more substituents, including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; ;

(ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) 2-thienyl, 3-thienyl, 2-thiazolyl, which may further bear any combination of halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl and one or more substituents including alkoxy, 5-membered ring aromatic heterocyclic groups including 4-thiazolyl and 5-thiazolyl;

(iv) H; Halogen selected from I, F, Cl or Br; NH ₂ , NO ₂ or SO ₂ -R, wherein R is from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

Is one of.

Among the preferred compounds corresponding to formulas (I) and (II), the present invention is represented, for example, by the structural formulas of the following a to m, wherein the wavy and arrow lines correspond to the point of binding to the nuclear structure of formula , Substituted alkyl, aryl or heteroaryl group having a pendant basic nitrogen functional group:

Of the groups a to f and g to m, R 1 in formula (I) and X in formula (II) are preferably d groups. In addition, in the case of g to m, the arrow includes the point where it is bonded to the nuclear structure through the phenyl group.

Furthermore, of the preferred compounds of formula (I) or (II), the invention relates to compounds wherein R 2 and R 3 are hydrogen. Preferably, R 4 is a methyl group and R 5 is hydrogen. In addition, R 6 is preferably a 3-pyridyl group (see formula g below) or a 4-pyridyl group (see formula h below). The wavy lines of the structures g and h correspond to the point at which they are bonded to the nuclear structure of formula (I) or (II).

Accordingly, the present invention relates to the following compounds:

1- A compound of formula (II) as described above wherein X is group d and R6 is 3-pyridyl group.

2- A compound of formula (II) as described above wherein X is group d and R4 is methyl group.

3- A compound of formula (I) or (II) as described above wherein R 1 is group d and R 2 is H.

4- A compound of formula (I) or (II) described above wherein R 1 is group d and R 3 is H.

5- A compound of formula (I) or (II) as described above, wherein R 1 is group d and R 2 and / or R 3 and / or R 5 are H.

6- A compound of formula (I) or (II) described above, wherein R6 is a 3-pyridyl group and R3 is a methyl group.

7- A compound of formula (I) or (II) as described above, wherein R6 is a 3-pyridyl group and R2 is H.

8- A compound of formula (I) or (II) as described above wherein R 2 and / or R 3 and / or R 5 are H and R 4 is a methyl group.

9- A compound of formula (I) or (II) as described above wherein R 2 and / or R 3 and / or R 5 are H, R 4 is a methyl group, and R 6 is a 3-pyridyl group.

Among the compounds of formula (II), the invention is embodied by compounds wherein R ₂ , R ₃ , R ₅ are hydrogen, in particular corresponding to compounds of formula (II-1):

In the above formula,

X is R or NRR 'wherein R and R' are independently H or a linear or branched alkyl group optionally substituted with one or more hetero atoms, or having a pendant basic nitrogen functional group; hetero atoms, in particular I, Cl , Cycloalkyl, aryl or heteroaryl groups optionally substituted with halogen selected from Br and F or having a pendant basic nitrogen functionality; or pendant basic nitrogen functionality optionally substituted with a hetero atom, in particular halogen selected from I, Cl, Br and F Selected from cycloalkyl, aryl or heteroaryl groups optionally substituted with cycloalkyl, aryl or heteroaryl groups;

R ₄ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl having any combination of one or more substituents, including phenyl or halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position in the ring or including substituted variants of phenyl group;

(ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) 2-thienyl, 3-thienyl, 2-thiazolyl, which may further bear any combination of one or more substituents including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, 5-membered ring aromatic heterocyclic groups including 4-thiazolyl and 5-thiazolyl;

(iv) H; Halogen selected from I, F Cl or Br; NH ₂ , NO ₂ or SO ₂ -R wherein R is of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

Is one of.

In another alternative, the substituent R 6 bonded at the 4 position of the thiazole ring in Formula II may be bonded at the 5 position of the thiazole ring.

Yes:

002: N- (3,5-bis-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridyl-4-yl-thiazol-2-ylamino) -benzamide

¹ H NMR (DMSOd ⁶ ) δ = 2.36 (s, 3H, ArCH ₃ ); 7.43 (d, 1 H, J = 7.5 Hz, Ar-H); 7.68 (dd, IH, J = 7.5, 1.5 Hz, Ar-H); 7.73 (s, IH, thiazole-H); 7.82 (m, 3 H, pyridyl-H + Ar-H); 8.54 (m, 4H, pyridyl-H + 2xAr-H); 8.85 (br s, 1 H, Ar-H); 9.67 (s, 1 H, NH), 10.84 (s, 1 H, NH).

003: N- (3,5-bis-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

092: N-cyclohexyl-4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

¹ H NMR (DMSO-d ⁶ ) δ = 1.00-1.40 (m, 5H, cyclo-H); 1.50-1.85 (m, 5H, cyclo-H); 2.34 (s, 3H, ArCH ₃ ); 7.28 (d, 1 H, J = 7.9 Hz, Ar-H); 7.48 (dd, 1H, J = 7.9, 1.5 Hz, Ar-H); 7.67 (s, 1 H, thiazole-H); 7.82 (d, 2H, J = 6.0 Hz, pyridyl-H); 8.57 (d, 2H, J = 6.0 Hz, pyridyl H); 8.63 (d, 1 H, J = 1.5 Hz, Ar-H); 9.55 (s, 1 H, NH).

093: 4-methyl-N- (1-methyl-1H-indol-6-yl) -3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

094: N- (2-methoxy-ethyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

096: N- (2-cyano-ethyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benz amide

Among the compounds of the formula (II), the invention is embodied in particular by compounds in which X is a substituted aryl group, corresponding to the N- [3- (thiazol-2-ylamino) -phenyl] -amide family of formula (II-3) do:

In the above formula,

Ra, Rb, Rc, Rd, Re are independently H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having a pendant basic nitrogen functional group; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having pendant basic nitrogen functionality; Or a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality. Organic group;

-A SO ₂ -R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality; Or a -CO-R or -CO-NRR 'group wherein R and R' are independently substituted with H or one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or pendant basic nitrogen Selected from alkyl, cycloalkyl, aryl or heteroaryl groups bearing functional groups;

Ra, Rb, Rc, Rd, Re are also

Halogen, such as I, Cl, Br and F;

-NRR 'groups wherein R and R' are H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Br and F or having a pendant basic nitrogen functionality; or a pendant basic nitrogen functionality optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group that it possesses;

OR groups, wherein R is a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with H or one or more heteroatoms and / or having pendant basic nitrogen functional groups; among heteroatoms, in particular I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a selected halogen or having a pendant basic nitrogen functionality; or a cyclo optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with an alkyl, aryl or heteroaryl group, a -SO ₂ -R 'group wherein R' is optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Or alkyl, cycloalkyl, aryl or heteroaryl bearing pendant basic nitrogen functionality;

NRaCORb groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group;

NRaCONRbRc groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group;

COOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functionality; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having pendant nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functional group;

CONRaRb wherein Ra and Rb are hydrogen or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms , In particular cycloalkyl, aryl or heteroaryl groups optionally substituted with halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functional groups; or with a heteroatom, in particular halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality;

NHCOOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F / Or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality;

OSO ₂ R, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functional groups; one or more heteroatoms, in particular A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a halogen selected from heteroatoms, in particular I, Cl, Br and F And / or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having pendant basic nitrogen functionality;

NRaOSO ₂ Rb, wherein Ra and Rb are linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bear pendant basic nitrogen functional groups; Hydrogen; a cycloalkyl, aryl or heteroaryl group optionally substituted with one or more heteroatoms, in particular a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or a heteroatom, in particular I, Cl, Br And a cycloalkyl, aryl or heteroaryl group optionally substituted with halogen selected from F and / or substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant nitrogen functional group;

A CN group;

-Trifluoromethyl group

Can be;

R ₄ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl having any combination of one or more substituents, including phenyl or halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position in the ring or including substituted variants of phenyl group;

(ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) 2-thienyl, 3-thienyl, 2-thiazolyl, which may further bear any combination of one or more substituents including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, 5-membered ring aromatic heterocyclic groups including 4-thiazolyl and 5-thiazolyl;

(iv) H; Halogen selected from I, F Cl or Br; NH ₂ , NO ₂ or SO ₂ -R, wherein R is from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

Is one of.

Yes

028: N- (2-fluoro-3-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

029: N- (3-fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

030: 4-Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -N- (3-trifluoromethyl-phenyl) -benzamide

031: 4-methyl-N- (4-methyl-3-trifluoromethyl-phenyl) -3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

032: N- (2-Fluoro-5-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

¹ H NMR (DMSOd ⁶ ) δ = 2.39 (s, 3H, ArCH ₃ ); 7.41 (d, 1 H, J = 7.9 Hz, Ar-H); 7.54-7.70 (m, 3H, Ar-H); 7.72 (s, 1 H, thiazole-H); 7.82 (d, 2H, J = 6.0 Hz, pyridyl-H); 8.10 (dd, 1H, J = 6.8, 2.2 Hz, Ar-H); 8.55 (d, 2H, J = 6.0 Hz, pyridyl-H); 8.84 (d, 1 H, J = 1.8 Hz, Ar-H) 9.65 (s, 1H, NH); 10.31 (s, 1 H, NH).

033: N- (4-cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

034: N- (4-Fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

035: N- (3-fluoro-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

036: N- (4-tert-butyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

038: N- (3-cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

039: N- (3-cyano-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

¹ H NMR (DMSO-d ⁶ ) δ = 2.37 (s, 3H, ArCH ₃ ); 2.46 (s, 3H, ArCH ₃ ); 7.43 (m, 2 H, Ar H); 7.63 (dd, 1H, J = 7.9, 1.8 Hz, Ar-H); 7.72 (s, 1 H, thiazole-H); 7.83 (d, 2H, J = 6.0 Hz, pyridyl-H); 7.96 (dd, 1H, J = 8.3, 1.8 Hz, Ar-H); 8.19 (d, 1 H, J = 2.3 Hz, Ar-H); 8.55 (d, 2H, J = 6.0 Hz, pyridyl-H); 8.81 (d, 1 H, J = 1.5 Hz, Ar-H); 9.65 (s, 1 H, NH); 10.46 (s, 1 H, NH).

040: N- (3-Bromo-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

041: N- (3-bromo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

042: N- (3,5-dibromo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

043: N- (3-chloro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

044: N- (3-chloro-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

045: N- (3-methoxy-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

046: 4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -N-m-tolyl-benzamide

047: N- (4-fluoro-3-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

048: N- (3-iodo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

049: 4-Methyl-N- (3-nitro-phenyl) -3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

050: 4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -N-p-tolyl-benzamide

051: 4-methyl-N-phenyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

052: N- (3,4-dimethyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

053: 4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -N- (3-trifluoromethoxy-phenyl) -benzamide

054: N- (3,4-dicyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

055: N- (2-Fluoro-5-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

056: N- (2,4-difluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

057. N- (4-cyano-2-fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

058: N- (2-Fluoro-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

059: N- (2,4-difluoro-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

060: N- (4-cyano-2-fluoro-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

061: N- (2-fluoro-4-methyl-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

062: N- (4-cyano-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

065: N- (4-Fluoro-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

099: 4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -N-m-tolyl-benzamide

100: 4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -N- (3-trifluoromethyl-phenyl) -benzamide

101: 4-Methyl-N- (4-methyl-3-trifluoromethyl-phenyl) -3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

102: N- (2-fluoro-3-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

105: N- (4-cyano-3-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

106: N- (4-cyano-3-methyl-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

Among the compounds of the formula (II), the present invention is particularly represented by the following formula (II-4) and 4- (4-substituted-1-ylmethyl) -N- [3- (thiazol-2-ylamino) -phenyl]- It is implemented by compounds wherein X is a -substituted-aryl group, corresponding to the benzamide family:

In the above formula,

X is a heteroatom such as O or N;

Wherein Ra, Rb, Rd, Re, Rf, Rg, Rh are independently H or linear or branched, having from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functionality Alkyl groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having pendant basic nitrogen functionality; Or a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality. Organic group; or

-NRR 'groups wherein R and R' are H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Br and F or having a pendant basic nitrogen functional group or a heteroatom, in particular a pendant basic nitrogen functional group optionally substituted with a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group that it possesses; or

OR groups, wherein R is a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with H or one or more heteroatoms and / or having pendant basic nitrogen functional groups; among heteroatoms, in particular I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a selected halogen or having a pendant basic nitrogen functionality; or a cycloalkyl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with an aryl or heteroaryl group, a -SO ₂ -R 'group wherein R' is optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Alkyl, cycloalkyl, aryl or heteroaryl bearing pendant basic nitrogen functionality; or

NRaCORb groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; or

NRaCONRbRc groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; or

COOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functionality; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having pendant nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functional group; or

CONRaRb wherein Ra and Rb are hydrogen or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms , In particular cycloalkyl, aryl or heteroaryl groups optionally substituted with halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functional groups; or with a heteroatom, in particular halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; or

NHCOOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; or

OSO ₂ R, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functional groups; one or more heteroatoms, in particular A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a halogen selected from heteroatoms, in particular I, Cl, Br and F And / or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having pendant basic nitrogen functionality; or

NRaOSO ₂ Rb, wherein Ra and Rb are linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bear pendant basic nitrogen functional groups; Hydrogen; a cycloalkyl, aryl or heteroaryl group optionally substituted with one or more heteroatoms, in particular a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or a heteroatom, in particular I, Cl, Br And a cycloalkyl, aryl or heteroaryl group optionally substituted with halogen selected from F and / or substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant nitrogen functional group; or

-SO ₂ -R group, wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality; or

-CO-R or -CO-NRR 'group wherein R and R' are independently substituted with H, one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or pendant basic nitrogen functionality Selected from alkyl, cycloalkyl, aryl or heteroaryl groups having

Is selected from;

Ra, Rb, Rd, Re may also be halogen such as Cl, F, Br, I or trifluoromethyl;

R ₄ is hydrogen, halogen, or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl having any combination of one or more substituents, including phenyl or halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position in the ring or including substituted variants of phenyl group;

(ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) 2-thienyl, 3-thienyl, 2-thiazolyl, which may further bear any combination of one or more substituents including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, 5-membered ring aromatic heterocyclic groups including 4-thiazolyl and 5-thiazolyl;

(iv) H; Halogen selected from I, F Cl or Br; NH ₂ , NO ₂ or SO ₂ -R wherein R is of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

Is one of.

Yes

004: 4-methyl-N- {4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -3- (4-pyridin-4-yl-thiazole-2 -Ylamino) -benzamide

¹ H NMR (MeOH-d ₄ ) δ = 2.41 (s, 6H, NCH ₃ + ArCH ₃ ); 2.50-2.70 (m, 4H, piperazine-H); 2.90 (m, 4H, piperazine-H); 3.68 (br s, 2H, CH ₂ -piperazine); 7.38 (d, 1 H, J = 7.9 Hz, Ar-H); 7.50 (m, 1 H, thiazole-H); 7.60 (m, 1 H, Ar-H); 7.76 (d, 1 H, J = 8.3 Hz, Ar-H); 7.90 (m, 2 H, pyridyl-H); 8.00 (m, 1 H, Ar-H); 8.12 (m, 1 H, Ar-H); 8.46 (m, 2 H, pyridyl-H); 8.90 (m, 1 H, Ar-H).

005: 4-Methyl-N- {4- [1- (4-methyl-piperazin-1-yl) -ethyl] -phenyl} -3- (4-pyridin-3-yl-thiazol-2-yl Amino) -benzamide

Among the compounds of the formula (II), the present invention in particular corresponds to the 3-disubstituted-amino-N- [3- (thiazol-2-ylamino) -phenyl] -benzamide family represented by the following formula (II-5), X is implemented by a compound that is an aryl-substituted group:

In the above formula,

Ra, Rb, Rc, Rd, Re, Rf, Rg are independently H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having pendant basic nitrogen functionality; Or a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality. Organic group; or

-NRR 'groups wherein R and R' are H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Br and F or having a pendant basic nitrogen functionality; or a pendant basic nitrogen functionality optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group that it possesses; or

OR groups, wherein R is a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with H or one or more heteroatoms and / or having pendant basic nitrogen functional groups; among heteroatoms, in particular I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a selected halogen or having a pendant basic nitrogen functionality; or a cycloalkyl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with an aryl or heteroaryl group, a -SO ₂ -R 'group wherein R' is optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Alkyl, cycloalkyl, aryl or heteroaryl bearing pendant basic nitrogen functionality; or

NRaCORb groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; or

NRaCONRbRc groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; or

COOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functionality; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having pendant nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functional group; or

CONRaRb wherein Ra and Rb are hydrogen or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms , In particular cycloalkyl, aryl or heteroaryl groups optionally substituted with halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functional groups; or with a heteroatom, in particular halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; or

NHCOOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; or

OSO ₂ R, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functional groups; one or more heteroatoms, in particular A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a halogen selected from heteroatoms, in particular I, Cl, Br and F And / or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having pendant basic nitrogen functionality; or

NRaOSO ₂ Rb, wherein Ra and Rb are linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bear pendant basic nitrogen functional groups; Hydrogen; a cycloalkyl, aryl or heteroaryl group optionally substituted with one or more heteroatoms, in particular a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or a heteroatom, in particular I, Cl, Br And a cycloalkyl, aryl or heteroaryl group optionally substituted with halogen selected from F and / or substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant nitrogen functional group; or

-SO ₂ -R group, wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality; or

-CO-R or -CO-NRR 'group wherein R and R' are independently substituted with H, one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or pendant basic nitrogen functionality Selected from alkyl, cycloalkyl, aryl or heteroaryl groups having

Is selected from;

Ra, Rb, Rc, Re may also be halogen or trifluoromethyl, such as Cl, F, Br, I;

R 4 is hydrogen, halogen, or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R ₆ is the following (i) to (iv):

(i) aryl groups, including phenyl or substituted variants of phenyl having any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, in any position of the ring; ;

(ii) 2, 3, or 4-pyridyl, which may further retain any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl and alkoxy, at any one position of the ring Heteroaryl groups including groups;

(iii) 2-thienyl, 3-thienyl, 2-thia with any combination of one or more substituents, including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl and alkoxy, in any position of the ring; 5-membered ring aromatic heterocyclic groups including zolyl, 4-thiazolyl, 5-thiazolyl;

(iv) H; Halogen selected from I, F, Cl or Br; NH ₂ , NO ₂ or SO ₂ -R, wherein R is from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups)

Is one of.

Yes

089: N- (3-dimethylamino-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

¹ H NMR (DMSOd ⁶ ) δ = 2.36 (s, 3H, ArCH ₃ ); 2.88 (s, 6H, 2xCH ₃ ); 6.50 (d, 1H, J = 7.9 Hz, Ar-H); 7.10-7.30 (m, 3H. Ar-H); 7.38 (d, 1 H, J = 7.9 Hz, Ar-H); 7.62 (dd, 1H, J = 7.9, 1.5 Hz, Ar-H); 7.70 (s, 1 H, thiazole-H); 7.85 (d, 2H, J = 6.4 Hz, pyridyl-H); 8.54 (d, 1 H, J = 6.4 Hz, pyridyl-H); 8.78 (br s, 1 H, Ar-H); 9.63 (s, 1 H, NH), 10.04 (s, 1 H, NH).

090: N- (3-dimethylamino-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide

In a second embodiment, the invention relates to a process for the preparation of the compound of formula (I) as described above. This includes the condensation reaction of a substrate of formula 10 with a thiourea of type 11.

Substituent “L” in Formula 10 is a nuclear rejection group in a nucleophilic substitution reaction (eg, L is chloro, bromo, iodo, toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy And L is preferably a bromo group).

The R 1 group in formula 11a corresponds to an alkoxy group.

The reaction of 10 with 1 a to d produces a thiazole type product of formula 12 a to d.

Formula 12a is identical to Formula I. Thus, R 1 of 12a corresponds to R 1 of formula (I).

Synthesis Example of Compound

General: All compounds used were commercially available reagent grade products. Dimethylformamide (DMF) and methanol (MeOH) were anhydrous commercial grade products which were used without further purification. Dichloromethane and tetrahydrofuran (THF) were freshly distilled under argon stream before use. The reaction process was monitored by thin layer chromatography using precoated silica gel 60F 254, Fluka TLC plate, which was visualized under UV light. The multiplicity of the ¹ H-NMR spectrum is represented by single line (s), wide single line (br, s), double line (d), triplet (t), quartet (q) and multiline (m). Spectra were shown on a 300 MHz Brucker spectrometer.

4-bromoacetyl-pyridine, HBR salt

Dibrom (17.2 g, 108 mmol) was added dropwise to a cold (0 ° C.) solution of 4-acetyl-pyridine (12 g, 99 mmol) in acetic acid containing 33% HBr (165 mL) under vigorous stirring. The vigorously stirred mixture was warmed to 40 ° C. for 2 hours and then to 75 ° C. After 2 h at 75 ° C., the mixture was cooled and diluted with ether (400 mL) to precipitate the product which was recovered by filtration and washed with ether and acetone to give white crystals (100%). The material can be recrystallized from methanol and water.

¹ H NMR (DMSOd ⁶ ) δ = 5.09 (s, 2H, CH ₂ Br); 8.62 (m, 2H, pyridyl-H); 9. 07 (m, 2H, pyridyl-H).

4-Methyl-3-thioureido-benzoic acid methyl ester

Benzoyl chloride (5.64 g, 80 mmol) was added dropwise to a well stirred solution of ammonium thiocyanate (3.54 g, 88 mmol) in acetone (50 mL). After refluxing the mixture for 15 minutes, 3-amino-4-methyl-benzoic acid methyl ester (13.2 g, 80 mmol) was added in portions. After 1 hour, the reaction mixture was poured into water (350 mL) and a light yellow precipitate was isolated by filtration. The crude solid was stirred for 2 h at room temperature using excess potassium carbonate in 200 ml of methanol. Thereafter, the solvent was removed under reduced pressure, and the crude product wax was extracted with ethyl acetate and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give a white solid. The solid was stirred for 15 min in ether and filtered to give the final product as a white solid.

¹ H NMR (DMSO-d ⁶ ) δ = 2.22 (s, 3H, ArCH ₃ ); 3.81 (s, 3 H, CO ₂ CH ₃ ); 7.38 (d, 1 H, J = 7.9 Hz, Ar-H); 7.70 (dd, 1H, J = 7.9, 1.5 Hz, Ar-H); 7.82 (d, 1 H, J = 1.8 Hz, Ar-H).

4-Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzoic acid methyl ester

4-bromoacetyl-pyridine, HBr salt (0.40 g, 1.43 mmol), 4-methyl-3-thiourea-benzoic acid methyl ester (0.32 g, 1.43 mmol) and KHCO ₃ (-0.4 g) in ethanol (10 mL) ) Was heated at 75 ° C. for 20 hours. The mixture was cooled down, filtered (removing KHCO ₃ ) and evaporated under reduced pressure. The residue was dissolved in CHCl ₃ (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was triturated in a small amount of ethyl acetate to give the final product as an orange solid.

¹ H NMR (DMSOd ⁶ ) δ = 2.38 (s, 3H, ArCH ₃ ); 3.88 (s, 3 H, CO ₂ CH ₃ ); 7.58 (dd, 1H, J = 7.9, 1.8 Hz, Ar-H); 7.75 (s, 1 H, thiazole-H); 7.85 (d, 2H, = 6.0 Hz, pyridyl-H); 8.62 (d, 1 H, = 6.0 Hz, pyridyl-H); 9.12 (d, 1 H, = 1.8 Hz, Ar-H); 9.63 (s, 1 H, NH).

N- (4-Cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide

4-Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzoic acid methyl ester

Trimethyl ammonium 2M solution in hexanes (1.9 mL) was added dropwise to a low temperature (0 ° C.) solution of 4-amino-benzonitrile (0.29 g, 2.46 mmol) in anhydrous dichloromethane (30 mL) under an argon atmosphere. The mixture was warmed to room temperature and stirred at room temperature for 30 minutes. 4-Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzoic acid methyl ester (0.80 g, 2.46 mmol) in anhydrous dichloromethane (30 mL) was added slowly, resulting mixture Heated at reflux for 5 h. The mixture was cooled to 0 ° C. and quenched by the dropwise addition of 4N aqueous sodium hydroxide solution (3 mL). The mixture was extracted with dichloromethane (3x20 mL). The combined organic layer was washed with brine (3x20 mL) and dried over anhydrous MgSO ₄ . The crude product in methanol was triturated to give 98% N- (4-cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2ylamino) -benzoamide It was.

¹ H NMR (CDCl ₃ ) δ = 2.40 (s, 3H, ArCH ₃ ); 7.40 (d, 1 H, J = 7.9 Hz, Ar-H); 7. 63 (dd, 1H, J = 7.9, 1.5 Hz, Ar-H); 7.72 (s, 1 H, thiazole-H); 7.80-7.88 (m, 4H, Ar-H); 8.10 (d, 2H, J = 8.6 Hz, Ar-H); 8.56 (m, 2H, Ar-H); 8.86 (d, 1 H, J = 1.8 Hz, Ar-H); 9.66 (br s, 1 H, NH).

Yes:

In a third embodiment, the present invention relates to a pharmaceutical composition comprising the compound described above.

The medicament may be in the form of a pharmaceutical composition for oral administration, which may be formulated in a suitable dosage using pharmaceutically acceptable carriers well known in the art. Such carriers make it possible to formulate pharmaceutical compositions as tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like that can be digested by a patient. In addition to the active ingredient, the pharmaceutical composition may contain a suitable pharmaceutically acceptable carrier, including excipients and auxiliaries which facilitate processing of the active compounds into pharmaceutically acceptable formulations. Further details on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

The composition of the present invention may also be in the form of a pharmaceutical composition or cosmetic composition for topical administration.

The composition may be in the form of a gel, paste, ointment, cream, lotion, aqueous liquid suspension, aqueous-alcohol solution, or oily solution, or in the form of a dispersion of lotion type or serum type, in the form of anhydrous gel or lipophilic gel, or In the form of a liquid emulsion, or in the form of a milk of semisolid concentration obtained by dispersing the fatty acid in the aqueous phase or vice versa, in the form of a cream or gel of semisolid concentration, or alternatively in the form of a microemulsion, in the form of microcapsules, microparticles It may be provided in the form of or in the form of vesicular dispersion in ionic form and / or nonionic form. The composition is prepared according to standard methods.

The composition according to the present invention comprises any ingredient conventionally used in skin diseases and cosmetics. It is a hydrophilic or lipophilic gelling agent, hydrophilic or lipophilic active agent, preservative, emollient, viscosity enhancing polymer, humectant, surfactant, preservative, antioxidant, solvent, and filler, antioxidant, solvent, perfume, filler, masking agent It may include one or more components selected from among fungicides, odor absorbers and coloring agents.

Examples of the oil that can be used in the present invention include mineral oil (liquid paraffin), vegetable oils (liquid separation of shea butter and sunflower oil), animal oils, synthetic oils, silicone oils (cyclomethicone) and fluorinated oils. Fatty alcohols, fatty acids (stearic acid) and waxes (paraffins, carnauba, beeswax) can also be used as fatty substances.

Examples of the emulsifier that can be used in the present invention include glycerol stearate, polysorbate 60 and PEG-6 / PEG-32 / glycolic acid stearate.

Hydrophobic gelling agents include carboxyvinyl polymers (carbomers), acrylic acid copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and natural gums. Lipid gelling agents include modified clays such as benton, metal salts of fatty acids such as aluminum stearate and hydrophobic silica, or alternatively ethylcellulose and polyethylene.

As hydrophilic active agents, protein or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, vitamins, starch and plant extracts, in particular extracts of aloe vera can be used.

As lipophilic active agents, retinol (vitamin A) and derivatives thereof, tocopherol (vitamin E) and derivatives thereof, essential fatty acids, ceramides and essential oils can be used. These formulations provide additional moisturizing or softening properties when used.

In addition, surfactants can be included in the composition to submerge compounds, such as tyrosine kinase inhibitors, preferably c-kit inhibitors, which can reduce giant cells.

Among the possible components, the present invention provides a permeation enhancer selected from the group consisting of mineral oil, water, ethanol, triacetin, glycerin and propylene glycol; Flocculants and thickeners selected from polyisobutylene, polyvinyl acetate and polyvinyl alcohol.

Chemical methods of enhancing local absorption of drugs are well known in the art. For example, sodium lauryl sulfate (Dugard, PH and Sheuplein, RJ, "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60 as a compound having permeability enhancing properties). , pp. 263-69, 1973), laurylamine (Johnson et. al., US 4,411,893), Ajad (Rajadhyaksha, US 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, DL. and Scala, J., "The Percutaneous Absorption of Alkylmethyl Sulfides," Pharmacology of the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V. 12, pp. 257-69, 1972). Increasing the polarity of the head groups of the amphoteric molecules has been observed to enhance their permeability enhancing properties while increasing skin irritation (Cooper, ER and Berner, B., "Interaction of Surfactants with Epidermal Tissues: Physiochemical Aspects, '' Surfactant Science Series, V. 16, Reiger, MM ed. (Marcel Dekker, Inc.) pp. 195-210, 1987).

The second class of chemical enhancers is generally referred to as co-solvents. These materials are relatively easily absorbed topically and the permeability to some drugs is enhanced by various mechanisms. Ethanol (Gale et. Al., US Pat. Nos. 4,615,699 and Campbell et. Al., US Pat. Nos. 4,460,372, and 4,379,454), dimethyl sulfoxide (US 3,740,420 and 3,743,727, and US 4,575,515), and glycerin derivatives (US 4,322,433) ) Has been shown to have the ability to enhance the absorption of various compounds.

The pharmaceutical composition of the present invention may also be for administration as an aerosolized agent to a target area of the patient's airways.

Delivery devices and methods of delivery of aerosolized bursts of drug formulations are disclosed in US Pat. No. 5,906,202. The formulations are preferably solutions, for example aqueous solutions, ethanol based solutions, aqueous / ethanol based solutions, saline, colloidal suspensions and microcrystalline suspensions. For example, the aerosolized particles comprise the active ingredients and carriers described above (eg, pharmaceutically active respiratory drugs and carriers), which are formed when the formulation is pushed through a nozzle, the nozzle being flexible It is preferably in the form of a porous membrane. The particles must be small enough to remain suspended in air for a sufficient time when they are formed so that the patient can inhale them into the lungs.

The present invention includes the following systems described in US 5,556,611:

Liquid gas systems in pressurized vessels (liquefied gases are used as propellant gases (for example low boiling point FCHC or propane, butane)),

Suspended aerosols (the particles of active substance are suspended in solid form in the liquid propulsion phase),

A pressurized gas system (using a compressed gas such as nitrogen, carbon dioxide, dinitrogen monoxide, air).

Thus, according to the invention, the pharmaceutical preparations are prepared such that the active substance is dissolved or dispersed in a suitable non-toxic medium and the solution or dispersion is sprayed with an aerosol, ie extremely finely distributed in the carrier gas. This is technically possible in the form of, for example, aerosol propellant gas packs, pump aerosols, or other devices known per se, for liquid sprays and solid sprays, which enable particularly accurate individual administration.

Accordingly, the present invention also relates to an aerosol device comprising said formulation and the compound as defined above, preferably having a metering spray valve.

The pharmaceutical compositions of the invention may also be for intranasal administration.

In this regard, pharmaceutically acceptable carriers for administering the compound to the nasal mucosal surface can be readily identified by those skilled in the art. Such carriers are described in Remington's Pharmaceutical Sciences "16th edition, 1980, Ed. By Arthur Osol, the contents of which are incorporated herein by reference.

Appropriate carriers are selected depending on the particular dosage form employed. For administration via the upper gastrointestinal tract, the composition is formulated as a solution for intranasal administration as a droplet or as a spray, for example as water or as a buffered or unbuffered isotonic saline or as a suspension. Preferably, the solution or suspension is isotonic with the nasal secretions and has a nearly identical pH, for example in the range of about pH 4.0 to about pH 7.4, or pH 6.0 to pH 7.0. The buffer should be physiologically affinity, for example phosphate buffer. For example, a representative nasal decongestant is described as buffered to about pH 6.2 (Remington's Id. 1445 page). Of course, those skilled in the art can readily determine the saline content and pH suitable for a harmless aqueous carrier for nasal and / or upper respiratory administration.

Common nasal carriers include nasal gels, creams, pastes or ointments having a viscosity of about 10 to about 300 cps, or about 2500 to about 6500 cps or more, which may also allow for more continuous contact with the nasal mucosal surface. The mucolytic carrier formulation can be based, for example, on alkylcellulose and / or high viscosity biocompatible carriers well known to those skilled in the art (see, for example, Remington's references mentioned above). Preferred alkylcelluloses are, for example, methylcelluloses whose concentrations range from about 5 to about 1000 mg or more per 100 ml of carrier.

Other ingredients such as preservatives, colorants, lubricants, or mineral oils or vegetable oils, perfumes, natural or synthetic plant extracts such as fragrance oils, and moisturizers, and viscosity enhancers such as glycerol, as known in the art, such as additional viscosity, It can provide moisture retention, pleasant texture and aroma. In nasal administration of solutions or suspensions according to the invention, various devices for producing droplets, droplets and sprays are available in the prior art.

A premeasured unit dosage dispenser comprising a dropper or spray device containing a solution or suspension for delivery as a droplet or spray is prepared to contain at least one batch of drug to be administered and this is another object of the present invention. . In addition, the present invention includes kits containing one or more dehydrated dosage units of a compound together with any necessary salts and / or buffers, preservatives, colorants, etc., ready to make a solution or suspension by adding a suitable amount of water. .

Another object of the invention relates to the use of said compound for the manufacture of a medicament. In other words, the present invention includes a method of treating a disease associated with uncontrolled transduction of a c-kit, comprising administering an effective amount of a compound as defined above to a mammal in need thereof.

More specifically, the present invention comprises administering an effective amount of a compound described above to a mammal in need thereof, autoimmune disease, allergic disease, bone loss, cancer such as leukemia and GIST, tumor angiogenesis, inflammatory The present invention relates to a method for treating diseases selected from diseases, inflammatory bowel disease (IBD), interstitial cystitis, mastocytosis, infectious diseases, metabolic disorders, fibrosis, diabetes and CNS disorders.

The compounds described above are useful for the manufacture of a medicament for the treatment of diseases associated with uncontrolled c-kit transduction, including but not limited to the following.

Neoplastic diseases such as mastocytosis, canine mastocytoma, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colon Rectal carcinoma, gastric carcinoma, gastrointestinal stromal tumor, testicular cancer, glioblastoma, solid tumor and astrocytoma.

Tumor angiogenesis.

Metabolic diseases such as diabetes mellitus and chronic complications thereof; obesity; Type 2 diabetes; Hyperlipidemia and dyslipidemia; Atherosclerosis; High blood pressure; And cardiovascular disease.

Allergic diseases such as asthma, allergic rhinitis, allergic yeast infection, anaphylaxis syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, nodular erythema, polymorphic erythema, cutaneous necrotic phlebitis and insect ulcer skin inflammation and vampire parasites infection.

-Interstitial cystitis.

-Bone loss (osteoporosis).

Inflammatory diseases such as rheumatoid arthritis, conjunctivitis, ankylosing spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms.

Autoimmune diseases such as multiple sclerosis, psoriasis, intestinal inflammatory disease, ulcerative colitis, chromium disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatitis, polymyositis , Sjogren's syndrome, nodular pneumonitis, autoimmune bowel disease, as well as proliferative glomerulonephritis.

Graft versus host disease or transplant rejection in any organ, such as kidney, pancreas, liver, heart, lung, and bone marrow transplants.

Other autoimmune diseases included in the present invention, such as active chronic hepatitis and chronic fatigue syndrome.

Subepithelial bullous disorders, such as a sacrum.

Vasculitis.

-Melanoma hyperplasia resulting from melanin cell dysfunction, such as melanocyte dysfunction, such as surplus, sun surplus and elderly surplus, preblastoblastic melanoma, as well as malignant melanoma, in this regard, the human skin Use of a compound as defined above to prepare a pharmaceutical composition or cosmetic composition for whitening.

CNS disorders such as mental illness, migraine, pain, memory loss and neuronal degeneration. More specifically, the method according to the invention is useful for the treatment of the following disorders: depression, such as mood disorders, circulatory disorders, bipolar depression, severe depression or "anxiety" depression, atypical depression, refractory depression, seasonal depression, Anorexia, bulimia, premenstrual syndrome, postmenopausal syndrome, other syndromes such as mental retardation and loss of concentration, pessimistic anxiety, nervousness, self-inferiority, libido, pain, such as acute pain, postoperative pain, chronic pain, pain pain, cancer Pain, neuropathic pain, mental pain syndrome, anxiety disorders such as anxiety associated with hyperventilation and cardiac arrhythmias, fear disorders, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, mental emergencies such as panic attacks, Psychosis, paranoid disorders, transition disorders, phobias, mania, delirium, dissociative disorders such as dissociative amnesia, dissociative glutes, dissociation Subjective disorders, diversion, tension, seizures, severe mental emergencies such as suicide behavior, self- neglect, violent or aggressive behavior, trauma, borderline personality and acute psychosis, schizophrenia, such as paranoid schizophrenia, deconstructive schizophrenia, tension Schizophrenia, and undifferentiated schizophrenia.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease (MND), and amyotrophic axon sclerosis (ALS).

Drug use disorders, including but not limited to drug addiction, drug abuse, drug habituation, drug dependence, withdrawal symptoms and overdose.

-Cerebral infarction.

-Fibrosis.

-Duchenne muscular dystrophy.

In the context of mastocytosis, the present invention relates to the use of a compound as defined above for the treatment of different categories of diseases which can be classified in the following categories.

Category I consists of two subcategories (IA and IB). Category IA is a disease in which giant cell infiltration is strictly confined to the skin. This category is the most frequent form of the disease, i) to iv): i) the most common form of cutaneous mastocytosis, in particular pigmented urticaria in children, ii) diffuse skin mastocytosis, iii) isolated mastocytoma and iv) some rare subtypes such as erythematous mastocytosis and vasodilated mastocytosis. This type of disease can be accurately prognostic and is characterized by spontaneous relief in children and almost painless in adults. The long-term survival of this disease type is comparable to that of the normal population, and conversion to other types of mastocytosis is rare. Category IB refers to painless systemic diseases (SM) that are or are not related to skin. This form is much more common in adults than in children. The progression of the disease is often painless, but often aggressive or malignant mastocytosis results in progressive organ function impairment.

Category II includes related blood abnormalities such as myeloproliferative or myelodysplastic syndromes, or mastocytosis with acute leukemia. These malignant mastocytosis usually does not include skin. These diseases depend on the type of blood abnormality involved and thus the prognosis.

Category III is characterized by massive invasion of multiple organs by abnormal macrophages as a general aggressive systemic mastocytosis. Patients in this type of aggressive clinical course are more common in peripheral blood characteristics that indicate rabies proliferation disorder. The progression of the disease is very rapid, similar to acute leukemia, or some patients have longer survival times.

Finally, category V of mastocytosis includes giant cell leukemia, where more than 10% of leukocytes are present as circulating giant cells and giant cell precursors. This type of disease is the rarest type of leukemia in humans and is very difficult to prognostic, similar to the rapid progressive variant of malignant mastocytosis. Giant cell leukemia may develop newly or as a late stage of pigmentary urticaria or systemic mastocytosis.

The invention also relates to a method for the treatment of recurrent bacterial infections, such as bacterial cystitis, which recurs after an asymptomatic period. More specifically, the present invention relates to Gram negative enterobacteria such as E. coli, Klebsiella pneumoniae , Serratia marcescens , Citrobactor freudii and Salmonella typhimu It can be used to treat FimH expressing bacterial infections such as Salmonella typhimurium . A method of treating bacterial infection, the method comprising: at least one antibiotic selected from bacitracin, cephalosporin, penicillin, aminoglycoside, tetracycline, streptomycin, and erythromycin, fluoroquinolone, actinomycin, sulfonamide and Microlide antibiotics, such as trimetaprim, are administered separately, sequentially or simultaneously.

In one preferred embodiment, the present invention comprises administering a compound as defined herein to a human or mammal, in particular dogs and cats, in need of treatment, tumorous diseases such as mastocytosis, canine mastocytoma Human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, colorectal carcinoma, gastric carcinoma, gastrointestinal stromal tumor, testicular cancer, A method of treating glioblastoma, solid tumor and astrocytoma.

In one other preferred embodiment, the present invention comprises administering a compound as defined herein to a human or mammal, in particular dogs and cats, in need thereof, such as allergic diseases such as asthma, allergic rhinitis , Allergic sinusitis, anaphylaxis syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, nodular erythema, polymorphic erythema, cutaneous necrotic phlebitis, and insect autologous skin inflammation and vampire parasite infection.

In another preferred embodiment, the present invention comprises administering a compound as defined herein to a human or mammal in particular, a dog and a cat in need thereof, such as multiple sclerosis, psoriasis, intestines Inflammatory diseases, ulcerative colitis, chromium disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid erythematosus, cutaneous lupus, dermatitis, polymyositis, Sjogren's syndrome, nodular pneumonitis, autoimmune intestinal disease , As well as methods of treating proliferative glomerulonephritis.

In another preferred embodiment, the present invention comprises administering a compound as defined herein to a human or mammal in particular, a dog and a cat in need thereof, such as any organ, such as kidney, pancreas, liver, A method of treating graft-versus-host disease or transplant rejection in heart, lung, and bone marrow transplantation.

Example 1 In Vitro TK Inhibition Assay

step

Experiments were performed using purified intracellular domains of c-kit expressed in baculovirus. Kinase activity measurements were assessed by phosphorylation of tyrosine containing target peptides measured by established ELISA assays.

Experimental Results for Test Compounds

The results in Table 1 show the inhibitory action of the catalytic activity of strong c-kits with IC 50 <10 μM. Further experiments (not described) indicate that at least one compound acts as a complete competitive inhibitor of ATP.

Example 2: In Vitro TK Inhibition Assay

step

C-kit of WT and c-kit (JM) analysis of mutations

Proliferation assay

Cells were washed twice in PBS, then plated at 5 × 10 ⁴ cells per well of 96 well plates and were or were not stimulated with hematopoietic growth factor (HGF). After incubation for 2 days, 37 Bq (1.78 Tbq / mmol) of [3H] thymidine (Amersham Life Science, UK) was added for 6 hours. Cells were harvested and purified through glass fiber filters and [3H] thymidine incorporation was measured in a scintillation counter. For proliferation analysis, all drugs were prepared as stock solutions of 20 mM in DMSO and stored at -80 ° C. Each experiment was performed after preparing fresh dilutions in PBS. Drugs dissolved in DMSO were added at the beginning of the culture. Controls were incubated with the corresponding DMSO dilutions. The proliferation rate in the absence of inhibitor was 100% and the result is expressed as a percentage.

cell

Ba / F3 mouse kit and human kit, Ba / F3 mkitD27 (mesenchymal deletion), are derived from mouse IL-3 deficient Ba / F3 ProB lymphoid cells. The FMA3 and P815 cell lines are mastocytoma expressing the endogenous mutant form of the kit, ie frame deleted in the proximity coding region of the receptor-codons 573-579 of mice. Human leukemia MC strain HMC-1 expresses mutant JM-V560G.

Immunoprecipitation and Western Blot Analysis

For each assay, 5.106 Ba / F3 cells and Ba / F3-derived cells of various c-kit mutations were lysed and immunoprecipitated as described in (Beslu et al., 1996), except that 250 ng of cells were Stimulation with rmKL of / ml. Cell lysates were immunoprecipitated with rabbit immunoserum anti mouse KIT against the KIT cytoplasmic domain (Rottapel et al., 1991). Western blots were hybridized with 4G10 anti-phosphotyrosine antibody (UBI) or rabbit immunoserum anti-mouse KIT, or with different antibodies (as described in the antibody paragraph). The membrane was then incubated with HRP-bound goat anti mouse IgG antibody or HRP-linked goat anti rabbit IgG antibody (Immunotech). The protein of interest was then visualized by incubation with ECL reagent (Amersham).

Experiment result

The experimental results of the various compounds according to the invention using the protocol described above are shown in Table 2:

Claims (14)

A compound of formula (I) [Formula I]

In the above formula, R6 and R7 are each independently of the following (i) to (v): (i) hydrogen, halogen (selected from F, Cl, Br or I); (ii) one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as linear, branched or cyclic alkyl groups having 1 to 10 carbon atoms, or 2 or 3 to 10 carbon atoms optionally substituted with trifluoromethyl, carboxyl, cyano, nitro, and formyl (e.g., methyl, ethyl, Alkyl ¹ groups defined as propyl, butyl, pentyl, hexyl ...); (iii) phenyl, or Halogen (selected from I, F, Cl or Br); Alkyl ¹ groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with pendant basic nitrogen functionality; Trifluoromethyl, O-alkyl ¹ , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl ¹ , N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally basic nitrogen In the form of functional groups) An aryl ¹ group defined as a substituted variant of phenyl having any combination of one or more substituents at any position of the ring, including; (iv) Halogen (selected from F, Cl, Br or I); Alkyl ¹ groups; Cycloalkyl, aryl or heteroaryl groups optionally substituted with pendant basic nitrogen functionality; Trifluoromethyl, O-alkyl ¹ , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl ¹ , N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally basic nitrogen In the form of functional groups) Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, which may further possess any combination of one or more substituents, including at any one position in the ring Heteroaryl ¹ groups defined as pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl groups; (v) trifluoromethyl, carboxyl, cyano, nitro, formyl, hydroxy, N (alkyl ¹ ) (alkyl ¹ ), and amino (the last nitrogen substituent is optionally in the form of a basic nitrogen functional group) Is selected from one of; R8 is the following (i) to (iii): (i) hydrogen, or (ii) a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups), or (iii) CO-R8 or COOR8 or CONHR8 or SO ₂ R8 wherein R8 is Linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups), or Phenyl or halogen (selected from F, Cl, Br or I); An alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, C _1-6 alkylamino, di (C _1-6 alkyl) amino, and amino (last The nitrogen substituents are optionally in the form of pendant basic nitrogen functional groups); As well as CO-R, COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R, wherein R is at least one heteroatom, in particular halogen (selected from F, Cl, Br or I), oxygen, And a phenyl having any combination of one or more substituents at any one position in the ring, including a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with nitrogen (optionally in the form of pendant basic nitrogen functional groups). Aryl groups, including modified variants, or Halogen (selected from F, Cl, Br or I); An alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, C _1-6 alkylamino, di (C _1-6 alkyl) amino, and amino (last nitrogen Substituents are optionally in the form of basic nitrogen functional groups); As well as CO-R, COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R, wherein R is at least one heteroatom, in particular halogen (selected from F, Cl, Br or I), oxygen, And any combination of one or more substituents, including nitrogen (optionally in the form of pendant basic nitrogen functional groups), linear or branched alkyl groups of 1 to 10 carbon atoms, optionally in any position of the ring. Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, May be a heteroaryl group including benzimidazole, quinolinyl group] One of; R2, R3, R4 and R5 are each independently hydrogen; Halogen (selected from F, Cl, Br or I); Linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally in the form of pendant basic nitrogen functional groups); As well as trifluoromethyl, C _1-6 alkyloxy, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, carboxyl, cyano, nitro, formyl, hydroxy and CO-R , COO-R, CONH-R, SO ₂ -R and SO ₂ NH-R wherein R is one or more heteroatoms, in particular halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (optionally pendant) A linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with a basic nitrogen functional group); A is CH ₂ , O, S, S0 ₂ , CO, or COO; B is a bond or NH, NCH ₃ , NR *, (CH ₂ ) _n (where n is 0, 1 or 2), O, S, S0 ₂ , CO, or COO; B 'is a bond or NH, NCH ₃ , NR *, (CH ₂ ) _n (where n is 0, 1 or 2), O, S, S0 ₂ , CO or COO; R * is alkyl ¹ , aryl ¹ or heteroaryl ¹ ; W is a bond, or NH, NHCO, NHCOO, NHCONH, NHS0 ₂ , NHS0 ₂ NH, CO, CONH, COO, COCH ₂ , (CH ₂ ) _n (n is 0, 1 or 2), CH ₂ -CO, A linker selected from CH ₂ COO, CH ₂ —NH, O, OCH ₂ , S, SO ₂ , and SO ₂ NH; R1 is the following a) to c): a) a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality; b) aryl or heteroaryl groups optionally substituted with heteroatoms, especially halogens selected from I, Cl, Br and F or optionally substituted with alkyl or aryl groups having pendant basic nitrogen functionality; c) alkyl ¹ , aryl ¹ or heteroaryl ¹ to be. The compound of claim 1, wherein R 6 is (iv), R 4 is H or CH ₃ , and AB-B ′ is CO-NH. The compound of claim 1, wherein the compound is represented by Formula II: [Formula II]

In the above formula, X is R or NRR 'wherein R and R' are independently H; aryl, heteroaryl optionally substituted with one or more hetero atoms, such as a halogen selected from F, I, Cl and Br and optionally having pendant basic nitrogen functionality Aryl optionally substituted with one or more heteroatoms, such as halogens selected from F, I, Cl and Br, optionally substituted with aryl, heteroaryl, alkyl or cycloalkyl groups, Heteroaryl, alkyl or cycloalkyl group); R ₂ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R ₃ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R ₄ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R ₅ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R ₆ is the following (i) to (iv): (i) aryl groups, including phenyl or substituted variants of phenyl having any combination of one or more substituents, including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position of the ring; ; (ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy; (iii) 2-thienyl, 3-thienyl, 2-thiazolyl, 4, which may further bear any combination of one or more substituents including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl and alkoxy 5-membered ring aromatic heterocyclic groups including thiazolyl and 5-thiazolyl; (iv) H; Halogen selected from I, F, Cl or Br; NH ₂ , NO ₂ or SO ₂ -R, wherein R is from 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups) Is one of. A compound according to claim 1 or 3, wherein R 1 and X are each a substituted alkyl, aryl or heteroaryl group having pendant basic nitrogen functional groups, for example represented by the structural formulas a to m:

Wherein the wavy and arrowed lines correspond to the point of attachment to the nuclear structure of formula (I) or (II). The compound of claim 4, wherein the arrow is the point of attachment to the nuclear structure through a phenyl group. The compound of claim 1 or 3, wherein R6 is a 3-pyridyl group represented by the following structural formula g, or a 4-pyridyl group represented by the following structural formula h, and the wavy lines of the structural formulas g and h are nuclei of the formula (I) or (II). The compound corresponding to the point of attachment to the structure:

The compound of claim 3, wherein the compound is represented by Formula II-3: [Formula II-3]

In the above formula, Ra, Rb, Rc, Rd, Re are independently H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having a pendant basic nitrogen functional group; Cycloalkyl, aryl or heteroaryl groups optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having pendant basic nitrogen functionality; Or a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, in particular a cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality. Organic group; A SO ₂ -R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality; Or a -CO-R or -CO-NRR 'group wherein R and R' are independently substituted with H or one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or pendant basic nitrogen Selected from alkyl, cycloalkyl, aryl or heteroaryl groups bearing functional groups; Ra, Rb, Rc, Rd, Re are also Halogen, such as I, Cl, Br and F; -NRR 'groups wherein R and R' are H or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Br and F or having a pendant basic nitrogen functionality; or a pendant basic nitrogen functionality optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group that it possesses; OR groups, wherein R is a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with H or one or more heteroatoms and / or having pendant basic nitrogen functional groups; among heteroatoms, in particular I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with a selected halogen or having a pendant basic nitrogen functionality; or a cycloalkyl optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with an aryl or heteroaryl group, a -SO ₂ -R 'group wherein R' is optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Alkyl, cycloalkyl, aryl or heteroaryl bearing pendant basic nitrogen functionality; NRaCORb groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; NRaCONRbRc groups, wherein Ra and Rb are H or a linear or branched alkyl group having 1 to 10 carbon atoms optionally substituted with one or more heteroatoms and / or having pendant basic nitrogen functional groups; heteroatoms, in particular I, Cl, Br and A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from F or having a pendant basic nitrogen functionality; or a heteroatom, in particular optionally substituted with a halogen selected from I, Cl, Br and F or having a pendant basic nitrogen functionality A cycloalkyl, aryl or heteroaryl group optionally substituted with a cycloalkyl, aryl or heteroaryl group; COOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functionality; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having pendant nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functional group; CONRaRb wherein Ra and Rb are hydrogen or a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (eg halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms , In particular cycloalkyl, aryl or heteroaryl groups optionally substituted with halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functional groups; or with a heteroatom, in particular halogen selected from I, Cl, Br and F A cycloalkyl, aryl or heteroaryl group optionally substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; NHCOOR, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or having pendant basic nitrogen functional groups; one or more heteroatoms, in particular I, A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a heteroatom, in particular a halogen selected from I, Cl, Br and F Or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant basic nitrogen functionality; OSO ₂ R, wherein R is a linear or branched alkyl group of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bearing pendant basic nitrogen functional groups; one or more heteroatoms, in particular A cycloalkyl, aryl or heteroaryl group optionally substituted with a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or optionally substituted with a halogen selected from heteroatoms, in particular I, Cl, Br and F And / or a cycloalkyl, aryl or heteroaryl group substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having pendant basic nitrogen functionality; NRaOSO ₂ Rb, wherein Ra and Rb are linear or branched alkyl groups of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms (for example halogen) and / or bear pendant basic nitrogen functional groups; Hydrogen; a cycloalkyl, aryl or heteroaryl group optionally substituted with one or more heteroatoms, in particular a halogen selected from I, Cl, Br and F and / or having a pendant basic nitrogen functionality; or a heteroatom, in particular I, Cl, Br And a cycloalkyl, aryl or heteroaryl group optionally substituted with halogen selected from F and / or substituted with an alkyl, cycloalkyl, aryl or heteroaryl group having a pendant nitrogen functional group; A CN group; -Trifluoromethyl group Can be; R ₄ is hydrogen, halogen or a linear or branched alkyl group having 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R ₆ is the following (i) to (iv): (i) aryl having any combination of one or more substituents, including phenyl or halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, at any one position in the ring or including substituted variants of phenyl group; (ii) heteroaryl groups, including 2, 3, or 4-pyridyl groups, which may further bear any combination of one or more substituents including halogen, alkyl groups having 1 to 10 carbon atoms, trifluoromethyl and alkoxy; (iii) 2-thienyl, 3-thienyl, 2-thiazolyl, which may further bear any combination of one or more substituents including halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, and alkoxy, 5-membered ring aromatic heterocyclic groups including 4-thiazolyl and 5-thiazolyl; (iv) H; Halogen selected from I, F Cl or Br; NH ₂ , NO ₂ or SO ₂ -R wherein R is of 1 to 10 carbon atoms optionally substituted with one or more heteroatoms, in particular halogen selected from I, Cl, Br and F and / or having pendant basic nitrogen functionality Linear or branched alkyl groups) Is one of. 8. N- (2-fluoro-3-trifluoromethyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide , N- (3-fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-3- (4-pyridine- 4-yl-thiazol-2-ylamino) -N- (3-trifluoromethyl-phenyl) -benzamide, 4-methyl-N- (4-methyl-3-trifluoromethyl-phenyl)- 3- (4-Pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (2-fluoro-5-trifluoromethyl-phenyl) -4-methyl-3- (4- Pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (4-cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-yl Amino) -benzamide, N- (4-fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-fluoro R-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (4-tert-butyl-phenyl) -4- Methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzia De, N- (3-cyano-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-cyano-4- Methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-bromo-phenyl) -4-methyl-3- ( 4-Pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-bromo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl- Thiazol-2-ylamino) -benzamide, N- (3,5-dibromo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2- Monoamino) -benzamide, N- (3-chloro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-chloro -4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3-methoxy-phenyl) -4-methyl- 3- (4-Pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -Nm-tolyl -Benzamide, N- (4-fluoro-3-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benza De, N- (3-iodo-4-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-N- (3-nitro-phenyl) -3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-3- (4-pyridin-4-yl-thiazole- 2-ylamino) -Np-tolyl-benzamide, 4-methyl-N-phenyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (3,4 -Dimethyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-3- (4-pyridin-4-yl-thiazole 2-ylamino) -N- (3-trifluoromethoxy-phenyl) -benzamide, N- (3,4-dicyano-phenyl) -4-methyl-3- (4-pyridin-4-yl -Thiazol-2-ylamino) -benzamide, N- (2-fluoro-5-methyl-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino ) -Benzamide, N- (2,4-difluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (4 -Cyano-2-fluoro-phenyl) -4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benz Amide, N- (2-fluoro-4-methyl-phenyl-4-methyl-3- (4-pyridin-4-yl-thiazol-2-ylamino) -benzamide, N- (2,4- Difluoro-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (4-cyano-2-fluoro-phenyl)- 4-Methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (2-fluoro-4-methyl-phenyl) -4-methyl-3- (4 -Pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (4-cyano-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2- Monoamino) -benzamide, N- (4-fluoro-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, 4-methyl-3 -(4-pyridin-3-yl-thiazol-2-ylamino) -Nm-tolyl-benzamide, 4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino)- N- (3-Trifluoromethyl-phenyl) -benzamide, 4-methyl-N- (4-methyl-3-trifluoromethyl-phenyl) -3- (4-pyridin-3-yl-thiazole 2-ylamino) -benzamide, N- (2-fluoro-3-trifluoromethyl-phen ) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (4-cyano-3-trifluoromethyl-phenyl) -4-methyl -3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (4-cyano-3-methyl-phenyl) -4-methyl-3- (4-pyridine- 3-yl-thiazol-2-ylamino) -benzamide, 4-methyl-N- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -3 -(4-Pyridin-4-yl-thiazol-2-ylamino) -benzamide, 4-methyl-N- {4- [1- (4-methyl-piperazin-1-yl) -ethyl]- Phenyl} -3- (4-pyridin-3-yl-thiazol-2-ylamino) -benzamide, N- (3-dimethylamino-phenyl) -4-methyl-3- (4-pyridine-4- Yl-thiazol-2-ylamino) -benzamide, N- (3-dimethylamino-phenyl) -4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -benz Compound selected from amides. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8. A pharmaceutical composition according to claim 9 suitable for oral administration. A dermatological composition or cosmetic composition for topical administration of a compound according to any one of claims 1 to 8. A veterinary composition comprising a compound according to any one of claims 1 to 8. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament. Autoimmune diseases, allergic diseases, bone loss; Cancer including leukemia and GIST; The method of claim 13 for the manufacture of a medicament for the treatment of a disease selected from tumor angiogenesis, inflammatory diseases such as arthritis, inflammatory bowel disease (IBD), interstitial cystitis, mastocytosis, infectious disease, metabolic disorders, fibrosis, diabetes and CNS disorders. Use of the compound according to the invention.