WO2025083280A1 - Sorafenib analogs for use in the treatment of cancer - Google Patents

Abstract

The present invention provides a compound of formula (I), or a salt, solvate or stereoisomer thereof for use in the treatment and/or prevention of cancer, wherein: R₁ is selected from the group consisting of: halogen, (C₁-C₅)alkyl optionally substituted with one or more Z substituents, (C₂-C₅)alkenyl optionally substituted with one or more Z substituents, (C₂- C₅)alkynyl optionally substituted with one or more Z substituents, C(O)R_x1, NR_X2R_X3, CN, C=NOH, C(=N-OH)(C₁-C₅)alkyl, and NO₂; and R₂ and R₃ are independently selected from the group consisting of: H, halogen, (C₁-C₅)alkyl optionally substituted with one or more Z substituents, (C₂-C₅)alkenyl optionally substituted with one or more Z substituents, (C₂- C₅)alkynyl optionally substituted with one or more Z substituents, C(O)R_X4, NR_x5R_X6, CN, C=NOH, C(=N-OH)(C₁-C₅)alkyl, and NO₂.

Description

SORAFENIB ANALOGS FOR USE IN THE TREATMENT OF CANCER

FIELD OF THE INVENTION

The present invention refers to new compounds which are potent inhibitors of cancer cells, as well as to pharmaceutical compositions comprising these compounds and uses thereof in the treatment or prevention of this disease.

BACKGROUND

Osteosarcoma (OS) is the most common primary malignant bone neoplasm in children and young adults characterized by high local aggressiveness and distant organic metastases. For patients with metastases at diagnosis or who relapse, the 5-year survival rate is less than 30% (cf. P. S. Meltzer et al., 2021)

Established treatment regimens, consisting of intensive therapy with drug combinations and surgical resection, cause significant short- and long-term toxicities and morbidities. The intensification of chemotherapy, for high-risk groups could not demonstrate a greater survival. The prognosis of this disease is often complicated, possibly due to its high rate of tumor mutations, which leads to widespread dysregulation in cell signalling pathways and genomic instability.

Due to the lack of tumor selectivity or metastasis problems or the complex etiology of these bone tumors, currently used drugs to treat osteosarcoma have a narrow therapeutic index and have not led to increased survival rates in recent years, decades (cf. D. J. Harrison, 2018), which shows that therapeutic strategies must be reviewed. In addition, 30% to 40% of patients with osteosarcoma develop lung metastases and relapse, leading to a significantly poor prognosis with a very low overall 5-year survival rate (cf. N. M. Marina, 2016). The development of new therapeutic strategies for the treatment of osteosarcoma remains an important unmet clinical need, underscoring a critical need for new treatment strategies.

As previously indicated, the treatment of patients diagnosed with osteosarcoma has not changed in the last four decades. First-line therapy for current osteosarcoma includes courses of high-dose cisplatin, doxorubicin, and methotrexate. Second-line therapy may integrate some tyrosine kinase inhibitors, such as sorafenib and everolimus, plus antineoplastic agents such as etoposide, topotecan, and cyclophosphamide (cf. R. Rathore, 2021). Neoadjuvant chemotherapy is generally administered over a 10-week period, followed by surgical resection of the involved tumor area and radiation therapy. If 90% or more of the tumor area shows necrosis, additional cycles of post-operative therapy are applied to combat micrometastasis.

In addition, currently there are not many treatment alternatives. In fact, the existing ones can create resistance or lack of specificity, which prevents the cure of the affected person and the use of surgical treatment followed by chemotherapy against osteosarcoma in patients with recurrent or metastatic cancer has not shown satisfactory improvement (cf. Z. D. Prudowsky, 2021).

For this reason, the development of new effective drugs with high cell selectivity is essential.

SUMMARY OF THE INVENTION

The present inventors have designed new compounds of formula (I) with efficient inhibitory effect on the proliferation of tumoral cells.

As it is shown below, the compounds of the invention were remarkable efficient in inhibiting the proliferation of two different osteosarcoma cell lines representing two stages of the disease: the cell line SaOS-2, which is a model of the disease with low aggressiveness (i.e. early stages); and the cell line MNNG/HOS, which is highly aggressive, being a model of the worst prognosis. In both cases, the compounds of the invention not only showed to be highly potent, with IC50 values in the range of micro- or nanomolar, but that they remarkably improved the efficacy of treatments of reference such as cisplatin or sorafenib (see Table 1 below).

Remarkably, this potent effect was highly selective of tumoral cells: the IC50 value was substantially higher when the compounds of the invention were tested in non-tumoral cell lines (HFF-1 or hOB cells). That is, healthy cells remain intact at the doses at which the compounds provide an anti-tumoral effect. And, therefore, this is indicative of their safety.

Altogether, the data provided herein support that the compounds of the invention can mean a therapeutic advance in the medical management of this disease.

Thus, in a first aspect the present invention provides a compound of formula (I), a salt, solvate or stereoisomer thereof:

for use in the treatment and/or prevention of cancer, wherein:

R1 is selected from the group consisting of: halogen; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; (C2-Cs)alkenyl optionally substituted with one or more Z substituents; (C2-Cs)alkynyl optionally substituted with one or more Z substituents; C(O)R_xi; NR_X2RX₃; CN; C=NOH; C(=N-OH)(Ci-C₅)alkyl; and NO₂;

R2 and R3 are independently selected from the group consisting of: H; halogen; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; (C2-Cs)alkenyl optionally substituted with one or more Z substituents; (C2-Cs)alkynyl optionally substituted with one or more Z substituents; C(O)R_X4; NRxsRxe; CN; C=NOH; C(=N-OH)(Ci-Cs)alkyl; and NO2;

R_xi and R_X4 are selected from H; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; (C2-Cs)alkenyl optionally substituted with one or more Z substituents; (C2- Cs)alkynyl optionally substituted with one or more Z substituents; -O-(Ci-Cs)alkyl; or NR_x?Rx8;

RX2, RX3, RXS, RX6, RX7 and Rxs are the same or different and are selected from: H, (Ci-Cs)alkyl optionally substituted with one or more Z substituents, (C2-Cs)alkenyl optionally substituted with one or more Z substituents; (C2-Cs)alkynyl optionally substituted with one or more Z substituents; or C(O)R_xg;

R_xg are independently selected from H; (Ci-Cs)alkyl optionally substituted by one or more Z substituents; -O-(Ci-Cs)alkyl optionally substituted by one or more Z substituents; (C2- Cs)alkenyl optionally substituted with one or more Z substituents; (C2-Cs)alkynyl optionally substituted with one or more Z substituents; -O-ring, wherein “ring” means an aromatic ring having 5 or 6 members optionally substituted with one or more Z substituents;

Z substituent is selected from halogen, OH, NH2, NO2, CN, C(O)H, or C(O)R_x ; being R_x selected from H, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, -O-(Ci-C₅)alkyl, -O-(Ci-C₅) haloalkyl, NH₂, NH- (Ci-Cs)alkyl. This aspect can also be formulated as the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of cancer. This aspect can also be formulated as a method for the treatment or prevention of cancer, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) as defined above to a subject in need thereof.

In a second aspect the invention provides a compound of formula (Ibis'!), (Ibis2), (Ibis3), (I bis4) , (I bis5), a salt, solvate or a stereoisomer thereof:

wherein: Ribis is selected from the group consisting of: halogen; (Ci-Cs)alkyl substituted with one or more Z’ substituents; C(O)R_xn; C(O)NH(Ci-C₅)alkyl; C(O)O(Ci-C₅)alkyl; NH₂, NHC(O)R_XI₂;

NHC(O)OR_XI₃; CN; and C(=N-OH)(Ci-C₅)alkyl;

R₂bis and R₃bis are independently selected from the group consisting of: H; halogen; (Ci-Cs)alkyl substituted with one or more Z’ substituents; NH₂; and NO₂;

R_xii represents H or (Ci-Cs)alkyl;

R_XI₂ and R_XI₃ are independently selected from (Ci-Cs)alkyl or 5- or 6-membered aromatic ring, particularly a benzyl ring;

Z’ substituent is selected from halogen, OH, and NH₂; provided that when Ribis is CN, then R₂bis and R₃bis are independently selected from H and NH₂; when Ribis is C(O)O(Ci-Cs)alkyl, then R₂bis and R₃bis are independently selected from H or NO₂; and when one of R₂bis and R₃bis is halogen and the other (Ci-Cs)alkyl substituted by one or more halogen groups, then the compound is of formula (Ibis'!) or (Ibis3), as defined above.

In a third aspect the present invention provides a pharmaceutical composition comprising a compound as defined in the second aspect of the invention, and one or more pharmaceutically acceptable excipients and/or carriers.

In a fourth aspect the present invention provides a compound as defined in the second aspect of the invention, for use in therapy.

DETAILED DESCRIPTION OF THE INVENTION

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

Throughout the present specification and the accompanying clauses, the words "comprise" and variations such as "comprises", "comprising" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. The word “comprise” also includes the term “consists of”. For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range.

In a first aspect the present invention refers to compounds useful in the treatment or prevention of cancer.

In the context of the invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e. g., methyl, ethyl, n-propyl, /-propyl, n-butyl, f-butyl, n-pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl. If substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl or phenethyl. If substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" radical.

In the context of the invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one C=C double bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.

In the context of the invention, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical containing one or more C=C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

In the context of the invention, the term "halogen" refers to bromo, chloro, iodo or fluoro.

In the context of the invention, the term “haloalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen. Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.

In the context of the present invention, the term "salt" must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions. The definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".

In the context of the present invention, the term "pharmaceutically acceptable salts" means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and/or mammals. Salts with alkali and alkali earth metals are preferred particularly, as well as those formed with ammonium cations (NH₄ ⁺). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e., salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

In the context of the present invention, the term "solvate" should be understood as meaning any form a compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, like for example, methanolate. A preferred solvate is the hydrate.

The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Preferably, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.

Prodrugs can typically be prepared using well-known methods.

Any compound of formula (I) referred to herein is intended to represent such specific compound as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus, any given compound of formula (I) referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same as, or different to, the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.

Furthermore, any compound of formula (I) referred to herein may exist as tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another.

In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, the compound is any of formula (la) to (le), or any salt, solvate or stereoisomer thereof:

wherein R1 to R3 are as defined above or below.

In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, R2 and R3 are independently selected from the group consisting of: H; halogen; (C1-C5) alkyl substituted with one or more Z substituents; NR_X2Rx3; and NO2.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, R2 and R3 are independently selected from H; halogen; (Ci-Cs)alkyl substituted with one or more halogen atoms, particularly trifluoromethyl; NO2 or NH₂.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, R2 and R3 are different.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, the compound is of formula (la) or (lb), R2 and R3 are different and are selected from halogen; halogen; or (Ci-Cs)alkyl substituted with one or more halogen atoms, particularly trifluoromethyl.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, the compound is one of formula (Ic) or (Id), R2 and R3 are different and are selected from H; NO2; halogen; (Ci-Cs)alkyl substituted with one or more halogen atoms, particularly trifluoromethyl; or NH2.

In an alternative embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, the compound is one wherein R2 and R3 are the same; particularly R2 and R3 represent H. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, Ri is selected from (Ci-Cs)alkyl substituted with one or more Z substituents; COR_xi; NR_X2Rx3; CN; C(=N-OH)(Ci-Cs)alkyl; and NO2.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, R1 is selected from (Ci-Cs)alkyl substituted with one or more Z substituents; C(O)H; C(O)(Ci-C₅)alkyl; C(O)-O-(Ci-C₅)alkyl; NH₂; C(=N-OH)(Ci- C₅)alkyl; NH-C(O)-(Ci-C₅)alkyl; NH-C(O)-O-benzyl; C(O)-NH-(Ci-C₅)alkyl; or CN.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, Z is selected from halogen, OH, or NH2.

In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, the compound is selected from the group consisting of:

(i) N-(4-(acetamidophenyl)-4-phenoxy)-N'-phenylurea;

(ii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(3-nitrophenyl)urea;

(iii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl)urea;

(iv)N-((4-methoxycarbonylphenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl) urea;

(v) N-(4-(2-(bromomethyl)phenoxy)phenyl)-N'-(3-nitrophenyl)urea;

(vi) 1-(4-(4-Acetylphenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

(vii)N-[4-((4-(1-hydroxyamino)ethyl)phenoxy)phenyl]-N’-[(2-fluoro-4-trifluoro)phenyl] urea;

(viii)N-[4-(4-(acetamidophenyloxy)phenyl)]-N’-[(2-fluoro-5-trifluoromethy)phenyl]urea;

(ix) Methyl 4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenoxy}-benzoate;

(x) N-(3-(4-Cyanophenoxy)phenyl)-N’-(3-nitrophenyl)urea;

(xi) N-(3-(4-Cyanophenoxy)phenyl)-N’-(3-aminophenyl)urea;

(xii) Methyl 3-(4-(3-(3-nitrophenyl)ureido)phenoxy)benzoate;

(xiii) Methyl 4-(4-(-3-(3-nitrophenyl)ureido)phenoxy)benzoate;

(xiv) 1-(4-(4-Cyanophenoxy)phenyl)-3-(2-fluoro-5(trifluoromethyl)phenyl)urea;

(xv)1-(4-(4-(Aminomethyl)phenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea; (Cccx ✓ z zv II II IIi) 1-(4-(4-(Aminophenoxy)phenyl)-3-phenylurea;

(xvii) Phenyl (4-(4-(3-phenylureido)phenoxy)phenyl)phenyl)carbamate;

(xviii) 1-(2-Fluoro-5-(trifluoromethyl)phenyl-3-(4-(-4-formylphenoxy)phenyl)urea;

(xix) Methyl 3-(4-(3-(2-fluoro-5-(trifluoromethyl))phenyl)ureido)phenoxy)benzoate;

(xx)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-hydroxymethyl)phenoxy)phenyl)urea;

(xxi)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-hydroxymethyl)phenoxy)phenyl)urea;

(xxii) Methyl 3-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)benzoate; and any salt, solvate or stereoisomer thereof.

Please note that a preferred compound is (iv)N-((4-methoxycarbonylphenyl)-4-phenoxy)-N'-(4- chloro-3-(trifluoromethyl)phenyl) urea. In particular, this compound can have the following general structure: alkyl (C1 untill C4, linear or ramified)

Phenyl, and mono- and disubstituted Phenyl)

-CH₂-Ar; -CH₂-CH₂-Ar; Ar: Phenyl, thiophene, pyrrole, furane, pyridine, quinoline

R= CH₂-CH₂-OH; CH₂-CH₂-NH₂; CH₂-CH₂-NHCH₃; CH₂-CH₂-NHCH₃;

Please further note that if R = H, then this compound will have an acid in position R1 as shown in the examples.

In the context of the invention, the compounds herein provided are suitable in the treatment and/or prevention of cancer.

The term "cancer" as used herein refers to a malignant neoplasm characterized by deregulated or unregulated cell growth. In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the cancer is a sarcoma, particularly an osteosarcoma.

The terms "treat" and "treatment" encompass both the therapeutic treatment of an already developed disease or condition, such as the therapy of an already developed cancer, as well as prophylactic or preventive measures, wherein the aim is to prevent or lessen the chances of incidence of an undesired affliction, such as to prevent occurrence, development and progression of cancer. Beneficial or desired clinical results may include, without limitation, a reduction in tumor burden or a decrease in the number of size of metastases, a diminishment of extent of disease, stabilised (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and the like. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. “Amelioration” refers to the reduction in the number or severity of signs or symptoms of cancer.

As used in the present invention, the term "prevention" or “preventing” refers to inhibiting the full development of a disease.

The uses and methods provided by the invention allow to administer a therapeutically effective amount of the compound of formula (I), and of any of the embodiments provided above or below, as taught herein in subjects having cancer, which will benefit from such treatment.

The term "therapeutically effective amount" as used in the context of the invention refers to an amount of active compound that elicits the biological or medicinal response in a subject that is being sought by a surgeon, researcher, veterinarian, medical doctor or other clinician, which may include inter alia alleviation of the symptoms of the disease or condition being treated. Methods are known in the art for determining therapeutically effective doses of the compound. In one embodiment, a therapeutically effective amount is the amount necessary to eliminate, reduce the size, or prevent metastasis of a tumor.

Appropriate therapeutically effective doses of the compound as taught herein may be determined by a qualified physician with due regard to the nature of the compound, the disease condition and severity, and the age, size and condition of the patient.

The compounds of the invention can be obtained by a simple process just requiring the use of cheap and easy-to-obtain reagents. An illustrative, non-limitative way for their obtaining is provided below. In one embodiment, the process comprises the step of reacting an isocyanate of formula (II) with an aniline of formula (III):

wherein Ri, R2, and R3 are as defined in the first aspect of the invention.

The compounds may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration.

Optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art. Synthesis of the compounds of the invention can be accomplished by methods analogous to the one described in the synthetic scheme hereinabove and in specific examples provided below.

Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described scheme or the procedures described in the synthetic examples section.

When an optically active form of a compound of the invention is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). Similarly, when a pure geometric isomer of a compound of the invention is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

In a second aspect the present invention provides compounds of formula (Ibisl) to (Ibis4) as defined above.

In one embodiment of the second aspect, the compound is of formula (Ibisl), a salt, solvate or stereoisomer thereof, wherein:

Ribis is C(O)(Ci-C₅)alkyl, NHC(O)(Ci-C₅)alkyl, C(=N-OH)(Ci-C₅)alkyl, C(O)O(C Cs)alkyl, CN, (Ci-Cs)alkyl substituted by one or more Z groups (particularly NH2 group(s)), or C(O)H; and

R2bis and Rabis are the same or different and are selected from halogen or (Ci-Cs)alkyl substituted with one or more Z groups (particularly halogen group(s)).

In another embodiment of the second aspect, the compound is of formula (Ibis2), a salt, solvate or stereoisomer thereof, wherein:

Ri bis is selected from C(O)NH(Ci-C₅)alkyl, C(O)O(Ci-C₅)alkyl, CN, NH₂, NHC(O)OR_XI₃, or (Ci-Cs)alkyl substituted by one or more Z groups (particularly OH group(s)); and

R2bis and R₃bis are the same or different and are selected from H, halogen, NH2, NO2, (Ci-Cs)alkyl substituted by one or more halogen atoms.

In another embodiment of the second aspect, the compound is of formula (Ibis3), a salt, solvate or stereoisomer thereof, wherein:

Ri bis is C(O)O(Ci-Cs)alkyl; and

R2bis and R₃bis are the same or different and are selected from halogen or (Ci-Cs)alkyl substituted by one or more halogen atoms.

In another embodiment of the fourth aspect, the compound is of formula (I bis4) , a salt, solvate or stereoisomer thereof, wherein:

Ri bis is (Ci-Cs)alkyl substituted by one or more Z groups (particularly OH group(s)); and

R2bis and R₃bis are the same or different and are selected from H, NO2, halogen or (C1- Cs)alkyl substituted by one or more Z groups; or, alternatively,

Ri bis is C(O)O(Ci-Cs)alkyl; and R2bis and Rabis are the same or different and are selected from H or NO2.

In another embodiment of the fourth aspect, the compound is of formula (Ibis5), a salt, solvate or stereoisomer thereof, wherein:

Ri bis is (Ci-Cs)alkyl substituted by one or more Z groups (particularly halogen group(s)); and

R2bis and Rabis are the same or different and are selected from H or NO2.

In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds (Ibis'!) to (Ibis-4), as well as salts, solvates, salts or stereoisomers thereof, as defined above. All the embodiments provided above, under the first or second aspect of the invention, are also embodiments of the pharmaceutical composition of the invention.

The pharmaceutical compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such.

These compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.

Pharmaceutically acceptable adjuvants, vehicles or excipients which may be used in such compositions are adjuvants, vehicles or excipients known to those skilled in the art or commonly used in the preparation of therapeutic compositions, which may be selected, for example, from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders.

The term "pharmaceutically acceptable" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio in animals and, particularly, in humans.

As used herein, the term “animal” or “subject” or “patient” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and non-domestic animals such as wildlife. In one embodiment, the animal is a vertebrate. In a particular embodiment the animal is a domestic mammal or a human.

The selection of physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic. Preparations in the form of tablets, dragees, capsules, granules, pills, drops, in particular otic drops, juices or syrups are preferably suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations or also sprays are preferably suitable for parenteral, topical or inhalation administration. The compounds in accordance with the invention used in the pharmaceutical composition in accordance with the invention in a depot, in a dissolved form or in a dressing, or if appropriate having added other agents favoring penetration into the skin, are preparations suitable for percutaneous administration. The preparation forms administrable orally or percutaneously can also release the respective compound according to the invention in a delayed form.

For instance, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.

The dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient; nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but is preferably a human.

To those skilled in the art, other objects, advantages or features of the invention will be apparent in part from the description or in part from the practice of the invention. The following examples are provided by way of illustration or are not intended to be limiting of the present invention.

EXAMPLES

Melting points were determined with a Gallenkamp model MFB.595.010M device with an internal thermometer and were adjusted with an external thermometer.

Proton and carbon nuclear magnetic spectroscopy (¹H and ¹³C NMR, respectively) spectrums were performed with a Mercury-400 spectrophotometer (400 and 100.6 MHz, respectively) using CDCh, acetone, DMSO-d6 or other deuterated solvents with TMS as a reference. Chemical shifts were expressed as parts per million (ppm).

IR spectrums were performed with FT-IR Perkin Elmer model Spectrum RX I and Thermo Nicolet model avatar 320 FT-IR spectrophotometers. It is noteworthy that only relevant frequencies (expressed in cm^-1) have been highlighted.

ESI Mass spectrums were carried out with Agilent LC/MSD-ToF mass spectrophotometer (Chemical Faculty, University of Barcelona).

Column chromatography was performed manually on silica gel Merck 60 (40-60 cm) eluting with mixtures of different solvents or through an automatic CombiFlash® Rf system. TLC plate 60 F254 Merck was used as thin layer chromatography.

Microdistillations were performed in a Buchi GKR-50 Glass Tube Oven.

All reagents and organic solvents used have recognized analytical grade or were purified before their use. Commercial products were obtained from Sigma-Aldrich. L Preparation of diarylethers

General procedure A

A 50 mL round-bottomed flask specially equipped with a screw cap for coupling reactions and a magnetic stirring bar, previously flame-dried under argon, was charged with 4-bromoaryl (5.043 mmol, 1 equiv.), the substituted phenol (5.043 mmol, 1 equiv.), caesium carbonate (1.643 g, 5.043 mmol, 1 equiv.) and ACHN (1 ,T-azob/s(cyclohexanecarbonitrile)) and CuBr in catalytic quantities in 10 mL of DMF. The reaction was heated at 130 ± 10 °C under stirring.

The reaction mixture was cooled down to room temperature, 20 mL of water were then added to the mixture and the crude reaction was extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SO4, filtered under vacuum and the solvent was removed under reduced pressure.

The crude reaction was purified by column chromatography using a Combi-Flash Rf provided with a UV-vis detector. The eluent used was hexane and ethyl acetate with increasing polarity. The desired product eluted with a polarity of hexane/ethyl acetate (30:70).

General procedure B

A 50 mL round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser was charged with NaH 60% purity (0.15 g, 3.70 mmol, 1.5 equiv.) and washed out with 10 mL of hexane in order to eliminate the paraffin. Once dry, substituted phenol (2.46 mmol, 1 equiv.) was added in 10 mL of DMF and stirred under argon at room temperature for 30 minutes. After that time, 1-bromo-4-nitrobenzene (0.50 g, 2.46 mmol, 1 equiv.) was added. The resulting mixture was heated up to 120 ± 10 °C under stirring for 24 hours.

The reaction mixture was cooled down to room temperature and was then diluted with water (20 mL) and extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SO4, filtered under vacuum and the solvent was evaporated under reduced pressure. The crude reaction obtained was purified by column chromatography using a Combi-Flash Rf provided with a UV-v/s detector. The eluent used was hexane and ethyl acetate with increasing polarity. The desired product eluted with a polarity of hexane/ethyl acetate (80:20).

General procedure C

A 50 mL round-bottomed flask specially equipped with a screw cap for coupling reactions and a magnetic stirring bar, previously flame-dried under argon, was charged with substituted phenol (1.98 mmol, 1 equiv.), 1-bromo-4-nitrobenzene (0.401 g, 1.98 mmol, 1 equiv.), caesium carbonate (0.647 g, 2,38 mmol, 1.2 equiv.) and (±)-BINAP and palladium complex (II) in catalytic quantities in 10 mL of toluene. The reaction was heated at 140 ± 10 °C under stirring for 24 hours. The reaction mixture was cooled down to room temperature and HCI 2N was then added to the mixture in order to obtain a slightly acid p/7 (5-6). Ethyl acetate (3 x 20 mL) was used to extract the crude reaction. The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SO₄, filtered under vacuum and the solvent was removed under reduced pressure.

The crude reaction obtained was purified by column chromatography using a Combi-Flash Rf provided with a UV-v/s detector. The eluent used was hexane and ethyl acetate with increasing polarity. The desired product eluted with a polarity of hexane/ethyl acetate (54:46).

Methyl 4-(4-Nitro)phenoxybenzoate

152,15 g/mol 202,01 g/mol 273,24 g/mol

Following general procedure B

Theoretical mass: 0.673 g, Obtained mass: 0.398 g, Yield: 59%, Rt (Hexano/EtOAc 8:2): 0,45

IR (film) v (cm’¹): 1712 (C=O); 1584 (NO₂); 1526 (C=C); 1344 (NO₂); 1289 (Ar-O); 1239 (Ar- OAr); 1160 (C-O).

Mp: 104-106 °C (AcOEt). RMN ¹H (CDCh, 300 MHz) 5 (ppm): 3.93 (s, 3H, -OCH₃); 7.09 (d, J = 9.0 Hz, 2H, H-3, H-5); 7.11 (d, J = 8.9 Hz, 2H, H-2’, H-6’); 8.09 (d, J = 9.0 Hz, 2H, H-2, H-6); 8.24 (d, J = 8,9 Hz, 2H, H-3’, H-5’).

RMN ¹³C (CDCh, 75.4 MHz) 5 (ppm): 52.3 (CH₃, -OCH₃); 118.4 (CH, C-2’, C-6’); 119.5 (CH, C-3, C-5); 126.1 (CH, C-3’, C-5’); 126.9 (C, C-1); 132.1 (CH, C-2, C-6); 143.5 (C, C-4’); 159.1 (C, C-4); 161.9 (C, C-1’); 166.2 (C, C=O).

A/-(4-(4-nitrophenoxy)phenyl)acetamide

toluene, 150 °C

Following general procedure C

Aspect: brown oil, Yield: 32%, Rt (hexane/ethyl acetate (1 :1)): 0.28

NMR ¹H (CDCh, 400 MHz) <5(ppm): 2.20 (s, 3H, -CH₃); 6.99 (d, J= 9.3 Hz, 2H, H-2’, H-6’); 7.05 (d, J = 8.9 Hz, 2H, H-3, H-5); 7.27 (s, 1 H, -NH-); 7.57 (d, J = 8.9 Hz, 2H, H-2, H-6); 8.19 (d, J = 9.3 Hz, 2H, H-3’, H-5’).

NMR ¹³C (CDCh, 100.6 MHz) <5(ppm): 24.3 (CH₃); 116.7 (CH, C-3, C-5); 121.0 (CH, C-2’, C- 6’); 121.9 (CH, C-2, C-6); 125.9 (CH, C-3’, C-5’); 135.4 (C, C-1); 142.4 (C, C-4’); 150.6 (C, C- 4); 163.5 (C, C-1’); 168.9 (C, CO).

Methyl 3-(4-nitrophenoxy)benzoate

Pd[p(o-tolyl)₃]₂CI₂

Following general procedure B

Aspect: Yellow Solid, Yield: 100%, Rt (hexane/ethyl acetate (1 :1)): 0.43

Mp: 173-175 °C (ethyl acetate) NMR-¹H (CDCI₃, 400 MHz) c(ppm): 3.92 (s, 3H, CH3-O); 7.02 (d, J = 9.2 Hz, 2H, H-2', H-6'); 7.31 (dd, Ji = 2.1 Hz, J₂ = 6.8 Hz, 1 H, H-4); 7.57 (t, J = 6.8 Hz, 1 H, H-5); 7.75 (t, J = 2.1 Hz,

I H, H-2); 7.93 (dd, Ji = 2.1 Hz, J₂ = 6.8 Hz, 1 H, H-6); 8.09 (d, J = 9.2 Hz, 2H, H-3', H-5').

NMR-¹³C (CDCI3, 100.6 MHz) c(ppm): 52.4 (CH3-O); 116.4 (CH, C-2', C-6'); 117.4 (CH, C-2); 121.3 (CH, C-6); 123.4 (CH, C-4); 124.9 (CH, C-3', C-5'); 126.4 (CH, C-5); 129.3 (C, C-1); 143.0 (C, C-4'); 156.6 (C, C-3); 162.7 (C, C-1 '); 166.0 (C, C=O ester).

II. Reduction of nitroderivatives. General procedure D

A specific 100 mL round-bottomed flask for catalytic hydrogenations was charged with nitro compound (0.776 mmol, 1 equiv.) in 30 mL of methanol and ethyl acetate (5:1). The catalyst Pd-C 10% (10% p/p) was then added. Finally, hydrochloric acid was added to the solution in order to catalyze the reaction (3 drops). The reaction mixture was stirred at room temperature for 36 hours, under hydrogen at atmospheric pressure. The theoretical volume required for the reaction was 35 mL. Given that the hydrogenation apparatus was not hermetical and may leak, the consumed volume was of 70 mL, higher than expected.

The crude reaction was filtered by means of a pleated filter and washed with 20 mL of methanol. Finally, the solvent was removed under reduced pressure. Then, 20 mL of water with an excess of K2CO3 were added to the reaction mixture to reach a p/7 7-8. The crude reaction was then extracted with ethyl acetate (3 X 20 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered under vacuum and the solvent was removed under reduced pressure.

Methyl 4-(4-aminophenoxy)benzoate

Following general procedure D

Aspect: brown solid, Yield: 97%, Rt (hexane/ethyl acetate 5:5): 0.31

Mp: 122-124 °C (ethyl acetate)

IR (film) v(cm’¹): 3439 (NH); 3358 (NH); 1706 (C=O); 1498 (C=C); 1279 (Ar-O); 1236 (Ar-O- Ar); 1163 (C-O). NMR ¹H (CDCh, 400 MHz) <5(ppm): 3.65 (bs, 2H, -NH₂); 3.88 (s, 3H, CH₃); 6.70 (d, J = 9 Hz, 2H, H-3', H-5'); 6.89 (d, J = 9 Hz, 2H, H-2', H-6'); 6.91 (d, J = 9 Hz, 2H, H-3, H-5); 7.96 (d J = 9 Hz, 2H, H-2, H-6).

NMR ¹³C (CDCh, 100.6 MHz) <5(ppm): 51.9 (CH₃, OCH₃); 116.1 (CH, C-2’, C-6’); 116.3 (CH, C-3, C-5); 121.8 (CH, C-3’, C-5’); 123.6 (C, C-1); 131.6 (CH, C-2, C-6); 143.7 (C, C-1’); 147.1 (C, C-4’); 163.2 (C, C-4); 166.7 (C, CO).

4-(2-(Bromomethyl)phenoxy)aniline

From methyl 4-(4-nitrophenoxy)benzoate and following the general procedure.

Aspect: brown crystals, Yield: 86%, Rt (hexane/ethyl acetate (4:6)): 0.72

Mp: 126-128 °C (dichloromethane)

NMR ¹H (CDCh, 400 MHz) <5(ppm): 5.06 (s, 2H, -CH₂-); 6.65 (d, J = 9.0 Hz, 2H, H-3’, H-5’);

6.83 (d, J = 9.0 Hz, 2H, H-2’, H-6’); 7.09 (bs, 2H, -NH₂); 7.18 (dd, Ji = 7.8, J₂ = 1.5 Hz, 1 H, H-6); 7.32 (dt, Ji = 7.8, J₂ = 1 .5 Hz, 1 H, H-4); 7.54 (dd, Ji = 7.8, J₂ = 1 .5 Hz, 1 H, H-3); 7.56

/V-(4-(4-aminophenoxy)phenyl)acetamide

Following the general reduction procedure D, the desired aniline was obtained.

Aspect: brown oil, Yield: 96%, Rt (hexane/ethyl acetate (1 :1)): 0.25

¹H NMR (CDCh, 400 MHz) <5(ppm): 2.15 (s, 3H, -CH₃); 3.58 (bs, 2H, -NH₂); 6.66 (d, J = 8.7 Hz, 2H, H-3’, H-5’); 6.84 (d, J = 8.7 Hz, 2H, H-2’, H-6’); 6.88 (d, J = 9.0 Hz, 2H, H-3, H-5); 7.28 (bs, 1 H, -NH-); 7.38 (d, J = 9.0 Hz, 2H, H-2, H-6). ¹³C NMR (CDCI₃, 100.6 MHz) <5(ppm): 24.0 (CH₃); 116.2 (CH, C-3’, C-5’); 117.6 (CH, C-2’, C- 6); 120.6 (CH, C-3, C-5); 121.9 (CH, C-2, C-6); 132.4 (C, C-1); 142.5 (C, C-4’); 148.8 (C, C-

T); 155.1 (C, C-4); 168.8 (C, CO).

Methyl 3-(4-amino)phenoxybenzoate

Following general procedure D

Aspect: Brown-yellow solid, Yield: 90%, Rt (hexane/ethyl acetate (1 :1)): 0.3

Mp: 141-143 °C (ethyl acetate)

NMR-¹H (CDCI₃, 400 MHz) o(ppm): 3.88 (s, 3H, CH₃-O); 6.69 (d, J = 6.5 Hz, 2H, H-3', H-5');

6.86 (d, J = 6.5 Hz, 2H, H-2', H-6'); 7.12 (dd, Ji = 1.5 Hz, J₂ = Q.2 Hz, 1 H, H-4); 7.34 (t, J = 7.7 Hz, 1 H, H-5); 7.56 (t, J = 1.5 Hz, 1 H, H-2); 7.70 (dd, Ji = 1.5 Hz, J₂ = 7.7 Hz, 1 H, H-6).

III. Preparation of ureas General procedure E

A 50 mL round-bottomed flask equipped with a magnetic stirring bar was charged with the corresponding aniline compound (1.30 mmol, 1 equiv.) and the substituted isocyanate (1.30 mmol, 1 equiv.) dissolved in 10 mL of THF. The reaction mixture was stirred at room temperature for 24 h. THF was evaporated under vacuum.

Purification

The crude reaction was purified by column chromatography using a Combi-Flash Rf provided with a UV-v/s detector. The eluent used was hexane and ethyl acetate with increasing polarity. The desired products eluted with a polarity of hexane/ethyl acetate (55:45).

A/-(4-(acetamidophenyl)-4-phenoxy)-A/'-phenylurea (Compound 1)

Following general procedure E.

Aspect: grey solid, Yield: 67%, Rf (hexane/ethyl acetate (3:7): 0.22)

Mp: 155-157 °C (dichloromethane)

NMR ¹H (DMSO-d₆, 400 MHz) <5(ppm): 2.02 (s, 3H, CH₃); 6.92 (d, J = 9.0 Hz, 2H, H-3, H-5); 6.93 (d, J = 8.9 Hz, 2H, , H-2’, H-6’); 6.96 (t, J = 7.5 Hz, 1 H, H-4”); 7.27 (t, J = 7.5 Hz, 2H, H- 3”, H-5”); 7.43 (d, J = 9.0 Hz, 2H, H-2, H-6); 7.44 (d, J = 7.5 Hz, 2H, H-2”, H-6”); 7.55 (d, J = 8.9 Hz, 2H, H-3’, H-5’); 8.61 (s, 1 H, -NH-C-4’); 8.63 (s, 1 H, -NH-C-1”); 9.91 (s, 1 H, -NH-C-1).

NMR ¹³C (DMSO-d₆, 100.6 MHz) <5(ppm): 23.9 (CH₃); 118.2 (CH, C-2’, C-6’); 118.4 (CH, C-3, C-5); 119.0 (CH, C-2, C-6); 119.9 (CH, C-3’, C-5’); 120.6 (CH, C-2”, C-6”); 121.8 (CH, C-4”); 128.8 (CH, C-3”, C-5”); 134.7 (C, C-1); 135.3 (C, C-1”); 139.8 (C, C-4’); 151.6 (C, C-4); 152.62 (C, C-1'); 152.63 (C, -NH-CO-NH-); 168.0 (C, CO).

HRMS (ESI+): Calculated for C₂IH₂₀N₃O₃ [M+H]⁺: 362.1499, found 362.1481. Calculated for C₂iHi₈N₃O₃Na [M+Na]⁺: 384.1319, found 384.1297. A/-(4-(acetamidophenyl)-4-phenoxy)-A/'-(3-nitrophenyl)urea (Compound 2)

Following general procedure E.

Aspect: grey solid, Yield: 63%, Rt (hexane/ethyl acetate (3:7)): 0.25

Mp: 159-161 °C (ethyl acetate)

IR (KBr) v(cm’¹): 3293 (NH); 1698 (C=O); 1650 (C=O); 1611 (NH-C=O); 1562 (NO); 1276 (Ar- NH); 1218 (Ar-O-Ar).

¹H NMR (DMSO-d₆, 400 MHz) <5(ppm): 2.02 (s, 3H, -CH₃); 6.93 (d, J = 8.8 Hz, 2H, H-3, H-5); 6.94 (d, J = 8.8 Hz, 2H, H-2’, H-6’); 7.47 (d, J = 8.8 Hz, 2H, H-2, H-6); 7.52-7.56 (m, 1 H, H-5”); 7.57 (d, J = 8.8 Hz, 2H, H-3’, H-5’); 7.71 (dd, Ji = 8.0, J₂ = 0.6 Hz, 1 H, H-6”); 7.80 (dd, Ji = 8.0, ₂ = 2.1 Hz, 1 H, H-4”); 8.56 (s, 1 H, H-2”); 8.82 (s, 1 H, -NH-C-4’); 9.19 (s, 1 H, -NH-C-1”); 9.91 (s, 1 H, -NH-C-1).

¹³C NMR (DMSO-d₆, 100.6 MHz) <5(ppm): 23.9 (CH₃); 112.1 (CH, C-2”); 116.2 (CH, C-4”); 118.5 (CH, C-3, C-5); 118.9 (C, C-2’, C-6’); 120.4 (CH, C-2, C-6); 120.6 (C, C-3’, C-5’); 124.2 (CH, C-6”); 130.0 (CH, C-5”); 134.7 (C, C-1); 134.8 (C, C-1”); 141.1 (C, C-4’); 148.1 (C, C-3”); 152.0 (C, C-4); 152.5 (C, C-1’); 152.5 (C, -NH-CO-NH-); 168.0 (C, CO).

HRMS (ESI+): Calculated for C21H19N4O5 [M+H]⁺: 407.1350, found 407.1342. Calculated for C2iHi₈N₄NaO5 [M+Na]⁺: 429.1169, found 429.1163.

A/-(4-(acetamidophenyl)-4-phenoxy)-A/'-(4-chloro-3-(trifluoromethyl)phenyl)urea

(Compound 3)

Following general procedure E.

Aspect: white crystals, Yield: 62%, Rt (hexane/ethyl acetate 3:7): 0.24

Mp: 168-170 °C (acetone) IR (KBr) v(cm’¹): 3292 (NH); 1697 (C=O); 1650 (C=O); 1601 (NH-C=O); 1281 (Ar-O-Ar); 822 (CF₃).

NMR ¹H (acetone-d₆, 400 MHz) <5(ppm): 2.87 (s, 3H, CH₃); 6.91 (d, J = 9.0 Hz, 2H, H-3, H-5); 6.93 (d, J = 8.9 Hz, 2H, H-2’, H-6’); 7.50 (d, J = 9.0 Hz, 2H, H-2, H-6), 7.52 (d, J = 8.8 Hz, 1 H, H-5”); 7.61 (d, J = 9.0 Hz, 2H, H-3’, H-5’); 7.73 (dd, Ji = 8.8 Hz, J₂ = 2.6 Hz, 1 H, H-6”), 8.13 (d, J = 2.6 Hz, 1 H, H-2”); 8.28 (s, 1 H, -NH-C-4’); 8.57 (s, 1 H, -NH-C-1”); 9.18 (s, 1 H, -NH-C- 1).

NMR ¹³C (acetone-d₆, 100.6 MHz) <5(ppm): 24.1 (C, CH₃); 118.0 (CH, J = 9 Hz, C-2”); 119.5 (CH, C-2’, C-6’); 119.8 (CH, C-3, C-5); 121.5 (CH, C-2, C-6); 121.6 (CH, C-3’, C-5’); 123.7 (CH, J = 9 Hz, C-6”); 124.0 (C, J = 272 Hz, CF₃); 124.1 (C, C-4”); 128.5 (C, J = 31 Hz, C-3”); 132.7 (C, C-5”); 135.7 (C, C-1); 135.9 (C, C-1”); 140.5 (C, C-4’); 153.3 (C, C-4); 153.7 (C, C- T); 154.1 (C, NH-CO-NH); 169.0 (C, -NH-CO-CH₃).

HRMS (ESI+): Calculated for C₂2HI₈CIF₃N₃O₃ [M+H]⁺: 464.0983, found 464.1002. Calculated for C₂₂H₂ICIF₃N₄O₃ [M+NH₄]⁺: 481.1249, found 481.1270.

A/-((4-methoxycarbonylphenyl)-4-phenoxy)-A/'-(4-chloro-3-(trifluoromethyl)phenyl)urea

(Compound 4)

Following general procedure E.

Aspect: white crystals, Yield: 100%, Rt: 0.48 (hexane/ethyl acetate 5:5)

Mp: 179-181 °C (acetone)

¹H NMR (acetone-d₆, 400 MHz) <5(ppm): 3.85 (s, 3H, CH₃); 7.00 (d, J = 8.8 Hz, 2H, H-2’, H-6’); 7.06 (d, J = 8.8 Hz, 2H, H-3, H-5); 7.53 (d, J = 8.7 Hz, 1 H, H-5”); 7.61 (d, J = 8.8 Hz, 2H, H-3’, H-5’); 7.75 (dd, Ji = 8.7 Hz, J₂ = 2.0 Hz, 1 H, H-6”); 7.98 (d, J = 8.8 Hz, 2H, H-2, H-6); 8.13 (d, J = 2.0 Hz, 1 H, H-2”); 8.40 (s, 1 H, -NH-C-4’); 8.61 (s, 1 H, -NH-C-1”).

¹³C NMR (acetone-d₆, 100.6 MHz) <5(ppm): 52.2 (CH₃); 117.5 (CH, C-2’, C-6’); 118.2 (CH, J = 11 Hz, 1 H, C-2”); 121.6 (CH, C-3, C-5, C-3’, C-5’); 123.85 (CH, C-6”); 123.90 (C, J = 272 Hz, CF₃); 124.2 (C, J = 2 Hz, C-4”); 125.1 (C, C-1); 128.5 (C, J = 31 Hz, C-3”); 132.4 (CH, C-2, C- 6); 132.7 (CH, C-5”); 137.2 (C, C-4’); 140.3 (C, C-1”); 151.3 (C, C-1’); 153.3 (C, -NH-CO-NH- ); 163.3 (C, C-4); 166.7 (C, -CO-OCH3).

HRMS (ESI+): Calculated for C22H17CIF3N2O4 [M+H]⁺: 465.0823, found 465.0824.

4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)benzoic acid (acid form of compound 4)

General procedure

A 50 mL round-bottomed flask was charged with compound 4 (0.159 g, 0.341 mmol, 1 equiv.) and dissolved in NaOH 2N (8 mL) and ethanol (2 mL). The reaction mixture was stirred at room temperature for 22 h.

Work-up

The solvent was removed under reduced pressure. Then, HCI 2N was added (10 mL) and the crude of reaction was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered under vacuum and the solvent was removed under reduced pressure.

Purification

Recrystallized from ethanol

Aspect: white crystals, Yield: 94%, Rt: 0.23 (hexane/ethyl acetate 3:7)

Mp: 166-168 °C (ethanol)

¹H NMR (acetone-d₆, 400 MHz) <5(ppm): 7.05 (d, J = 8.8 Hz, 2H, H-2’, H-6’); 7.04 (d, J = 8.8 Hz, 2H, H-3, H-5); 7.54 (d, J = 8.7 Hz, 1 H, H-5”); 7.68 (d, J = 8.8 Hz, 2H, H-3’, H-5’); 7.77 (dd, Ji = 8.7 Hz, J₂ = 2.0 Hz, 1 H, H-2”); 7.97 (d, J = 8.8 Hz, 2H, H-2, H-6); 8.40 (d, J = 2.0 Hz, 1 H, H-2”); 8.60 (s, 1 H, -NH-C-4’); 8.75 (s, 1 H, -NH-C-1”).

HRMS (ESI+): Calculated for C22H16CIF3N2O4 [M-H]’: 449.0516, found 449.0442.

A/-(4-(2-(bromomethyl)phenoxy)phenyl)-A/'-(3-nitrophenyl)urea (Compound 5)

Aspect: yellow solid, Yield: 32%; Rt: 0.53 (hexane/ethyl acetate (1 :1))

Mp: 205-207 °C (hexane/ethyl acetate)

¹H NMR (DMSO-d₆, 400 MHz) <5(ppm): 5.09 (s, 2H, -CH₂-); 6.98 (d, J = 9.0 Hz, 2H, H-2’, H-6’); 7.31 (td, Ji = 7.6, J₂ = 1.6 Hz, 1 H, H-4); 7.40 (d, J = 9.0 Hz, 2H, H-3’, H-5’); 7.43 (td, Ji = 7.6, J₂ = 1 .0 Hz, 1 H, H-5); 7.56 (t, J = 8.2 Hz, 1 H, H-5”); 7.57 (td, Ji = 7.6, J₂ = 1.6 Hz, 1 H, H-6); 7.68 (dd, Ji = 8.2, J₂ = 1.0 Hz, 1 H, H-6”); 7.70 (dd, Ji = 7.6, J₂ = 1.0 Hz, 1 H, H-3); 7.80 (ddd, Ji = 8.2, J₂ = 2.2 Hz, J₃ = 1 .0 Hz, 1 H, H-4”); 8.55 (t, J = 2.2 Hz, 1 H, H-2”); 8.68 (s, 1 H, -NH-C- 4’); 9.15 (s, 1 H, -NH-C-1”).

¹³C NMR (DMSO-d₆, 100.6 MHz) <5(ppm): 69.3 (CH₂, -CH₂-Br); 112.0 (CH, C-2”); 115.0 (CH, C-2’, C-6’); 116.1 (CH, C-6); 120.5 (CH, C-3’, C-5’); 122.7 (C, C-2); 124.2 (CH, C-4”); 127.9 (CH, C-4); 130.01 (CH, C-6”); 130.02 (CH, C-5); 130.1 (CH, C-3); 132.6 (CH, C-5”); 132.7 (C, C-4’); 136.0 (C, C-1”); 141.2 (C, C-3”); 148.1 (C, C-1’); 152.6 (C, C-1); 153.6 (C, CO).

HRMS (ESI+): Calculated for C₂oHi?BrN304 [M+formic acid]⁺, for isotope ⁷⁹Br: 442.0397, found 442.0413. Calculated for C₂oHieBrN3Na04 [M+Na]⁺, for isotope ⁷⁹Br: 464.0216, found 464.0226. Calculated for C₂oHi?BrN304 [M+formic acid]⁺, for isotope ⁸¹ Br: 444.0376, found 444.0393. Calculated for C₂oHieBrN3Na04 [M+Na]⁺, for isotope ⁷⁹Br: 466.0216, found 466.0217.

1 -(4-(4-Acetylphenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea (Compound 6)

C₁₄H₁₃NO₂ C₈H₃F₄NO

227.26 g/mol 205.11 g/mol 432.37 g/mol

Following general procedure E.

Aspect: pink powder, Theoretical mass: 0.357 g. Obtained mass: 0.321 g. Yield: 90%. Rt (Hexane/EtOAc 4:6): 0.65

IR (film) v (cm’¹): 3290 (NH); 1721 (C=O); 1654 (C=O _urea); 1560 (NH _urea); 1500 (C=C); 1279 (Ar-O); 1161 (C-N); 1118 (Ar-O-Ar); 1072 (C-F). Mp: 156-158 °C (AcOEt).

NMR ¹H ((CD₃)₂CO, 300 MHz) 5 (ppm): 2.54 (s, 3H, -CH₃); 7.00 (d, J = 9 Hz, 2H, H-3’, H-5’); 7.07 (d, J = 9 Hz, 2H, H-2”, H-6”); 7.37 (m, 2H, NH (x2)); 7.63 (d, J = 9 Hz, 2H, H-2’, H-6’); 7.98 (d, J = 9 Hz, H-3”, H-5”); 8.34 (ba, 1 H, H-3); 8.69 (s, 1 H, H-4); 8.78 (d, J = 9 Hz, H-6).

NMR ¹³C ((CD₃)₂CO, 75.4 MHz) 5 (ppm): 26.25 (CH₃, -CH₃); 113.6 (CH, J = 20.6 Hz, C-3); 116.0 (CH, C-3’, C-5’); 116.3 (CH, C-6); 117.1 (CH, J = 7.8 Hz, C-4); 117.8 (CH, C-2”, C-6”); 119.8 (CH, C-2’, C-6’); 121.0 (C, J = 270.4 Hz, CF₃); 121.4 (C, C-4”); 131.1 (C, J = 32.5 Hz, C-5); 132.5 (C, J = 11.1 Hz, C-1); 136.8 (CH, C-3”, C-5”); 151.0 (C, C-4’); 152.7 (C, C-1’); 156.2 (C, C=O urea); 158.1 (C, J = 246.7 Hz, C-2); 162.9 (C, C-1”); 196.1 (C, C=O).

HRMS (ESI): Calculated for C2₂Hi6F₄N₂O₃Na [M+Na]⁺: 455.3574, found 455.3512.

/V-[4-((4-(1 -hvdroxyamino)ethyl)phenoxy)phenyl1-/V'-r(2-fluoro-4-trifluoro)phenyl1urea

(Compound 7)

432.37 g/mol 447.38 g/mol

To a 50 mL capacity flask, add the starting urea (0.0783 g, 0.182 mmol) dissolved in 10 mL of EtOH. Next, 1.2 equivalents (0.220 mmol) of hydroxylamine hydrochloride are added, a septum was introduced into the mouth of the flask with gas outlet and the flask is left under magnetic stirring. Finally, a previously prepared Na₂CO₃ solution (0.5 eq/5 mL H2O) was added. And the resulting mixture was left, under magnetic stirring, at reflux temperature for 24 hours.

After 24 hours and by CCF control, it was verified that there is no starting product left. The reaction was then considered complete and once the solution has reached room temperature, the EtOH is carefully evaporated in a rotary evaporator, so that only the water remains in the flask. Finally, the crude reaction was extracted with EtOAc (3 x 20 mL). The combined organic fractions are dried over anhydrous Na₂SO4, filtered and the solvent is evaporated to dryness.

The reaction crude is purified in a Combi-Flash Rf system equipped with a UV-vis detector and a 12 g silica gel column. Mixtures of hexane and ethyl acetate of increasing polarity are used as eluents. The desired product eluted with a polarity of 25% AcOEt. Aspect: grayish solid, Theoretical mass: 0.081 g, Obtained mass: 0.080 g, Yield: 99%, Rt (Hexane/EtOAc 4:6): 0.45

IR (film) v (cm’¹): 3293 (NH); 1719 (C=O); 1653 (C=O _urea); 1558 (NH _urea); 1498 (C=C); 1338 (CN); 1160 (C-O); 1118 (C-F).

Mp: 178- 180 °C (AcOEt).

NMR ¹H ((CD₃)₂CO, 300 MHz) 5 (ppm): 2.21 (s, 3H, -CH₃); 6,94 (d, J = 9 Hz, 2H, H-3’, H-5’); 7.01 (d, J = 9 Hz, 2H, H-2”, H-6”); 7.36 - 7.39 (m, 2H, (-NH (x2)); 7.57 (d, J = 9 Hz, 2H, H-2’, H-6’); 7.67 (d, J = 9 Hz, 2H, H-3”, H-5”); 8.32 (ba, 1 H, H-3); 8.63 (ba, 1 H, H-4); 8.78 (d, J = 9 Hz, 1 H, H-6); 10.21 (bs, 1 H, OH).

NMR ¹³C ((CD₃)₂CO, 75,4 MHz) 5 (ppm): 11.5 (CH₃, -OCH₃); 116.3 (CH, J = 19.6 Hz, C-3); 116.7 (CH, J = 6.8 Hz, C-6); 118.3 (CH, C-3’, C-5’); 120.1 (C, J = 10.1 Hz, C-1); 120.9 (CH, C- 2”, C-6”); 121.3 (CH, C-2’, C-6’); 123.7 (CH, J = 22,5 Hz, C-4); 128.2 (CH, C-3”, C-5”); 129.9 (C, J = 260.4 Hz, -CF₃); 132.9 (C, C-5); 136.3 (C, C-1’); 152.5 (C, C-4’); 152.9 (C, C=O); 153.7 (C, C=N); 156.2 (C_q, C-1”); 159.5 (C-F; J = 236.7 Hz, C-2).

HRMS (ESI): calculated for C₂2Hi₇F₄N₃O₃Na [M+Na]⁺: 470.3721 , found 4703879.

A/-r4-(4-(acetamidophenyloxy)phenyl)1-A/'-f(2-fluoro-5-trifluoromethv)phenyl1urea

(Compound 8)

447.38 g/mol 447.38 g/mol

To a 25 mL flask, oxime (0.083 g, 0.185 mmol) was added and dissolved in 10 mL of 40% acetic acid solution. It was left under magnetic stirring, as soon as the oxime has finished dissolving, Zn (0.097 g, 1.48 mmol) was added. Finally, the resulting mixture was left under constant stirring, at room temperature and under an argon atmosphere for 72 hours.

Once the reaction time has elapsed and it has been confirmed that there was no starting product left by CCF, the flask containing the reaction crude was taken and placed in an ice bath, a little ice was introduced inside, it was alkalinized until p/7 = 10 with 5N NaOH. The crude was then extracted with dichloromethane and water (3 x 15 mL). The combined organic fractions are dried over anhydrous Na2SO4, filtered and the CH2CI2 was evaporated to dryness. The obtained residue was purified by silica gel column chromatography using a constant polarity of 20% ethyl acetate and 80% hexane as eluent.

Aspect: grayish powder, Theoretical mass: 0.0829 g, Obtained mass: 0.0336 g, Yield: 41%, Rt (Hexane/EtOAc 8:2): 0,13

IR (film) v (cm-1): 3456 (NH); 1258 (NH); 2924 (=CH); 1672 (C=O); 1440 (C=C); 1312 (C-N); 1068 (C-F).

Mp: 222-224 °C (AcOEt).

NMR ¹H ((CD₃)₂CO, 300 MHz) 5 (ppm): 2.54 (s, 3H, -CH₃); 7.00 (d, J = 9 Hz, 2H, H-2”, H-6”); 7.07 (d, J = 9 Hz, 2H, H-3’, H-5’); 7.37 (bs, 1 H, H-3); 7.63 (d, J = 9 Hz, 2H, H-3”, H-5”); 7.98 (d, J = 9 Hz, 2H, H-2’, H-6’); 8.75 (bs, 1H, H-4); 8.78 (d, J = 9 Hz, 1H, H-6).

NMR ¹³C ((CD₃)₂CO, 75.4 MHz) 5 (ppm): 26.5 (CH₃, -CH₃); 116.2 (CH, J = 21.1 Hz, C-6); 117.4 (CH, C-3’, C-5’); 118.6 (CH, J = 7.1 Hz, C-3); 120.2 (CH, J = 8.2, Hz, C-6); 121.3 (CH, C-2’, C-6’); 121.6 (CH, C-3”, C-5”); 123.9 (C, J = 35.5 Hz, C-5); 128.8 (C, J = 43.1 Hz, -CF₃); 129.9 (C, J = 11.1 Hz, C-1); 131.4 (CH, C-2”, C-6”); 13.9 (C, C-4”); 132.7 (C, C-1’); 151.3 (C, C=O); 156.1 (C, C-4’); 157.1 (C, C-1”); 163.1 (C, J = 122.1 Hz, C-F); 190.4 (C, -NCO-).

HRMS (ESI): Calculated C₂₂Hi₇F₄N₃O₃Na [M+Na]⁺: 470,3721 , found 470,3517.

Methyl

:-fluoro-5-tri

(Compound 9)

Following the general procedure E.

Aspect: fine light brown solid, Theoretical mass: 0.977 g, Obtained mass: 0.869 g, Yield:

89%, R_f (Hexane/EtOAc 6:4): 0.49

IR (film) v(crrr¹): 3290 (NH); 1721 (C=O); 1654 (C=O _urea); 1560 (NH _urea); 1500 (C=C); 1279 (Ar-O); 1161 (C-N); 1118 (Ar-O-Ar); 1072 (C-F).

Mp: 156-158 °C (AcOEt) NMR ¹H (CDCI3, 300 MHz) 5 (ppm): 3.93 (s, 3H, -OCH₃); 6.97 (d, J = 9,0 Hz, 2H, H-2’, H-6’); 7.04 (d, J = 8.9 Hz, 2H, H-3’, H-5’); 7.06 (bs, 1 H, NH); 7.15 (d, J = 1.7 Hz, 1 H, H-3”); 7.16 (d, J = 7.5 Hz, 1 H, H-4”); 7.39 (d, J = 8.9 Hz, 2H, H-2’, H-6’); 8.00 (d, J = 9.0 Hz, 2H, H-2, H-6); 8.59 (dd, Ji = 7.5 Hz, J₂ = 1 .7 Hz, 1 H, H-6”).

NMR ¹³C (CDCI3, 75,4 MHz) 5 (ppm): 52.3 (CH₃, -OCH₃); 115.3 (CH, J= 20.6 Hz, C-3”); 116.9 (CH, C-2’, C-6’); 118.9 (CH, C-6”); 120.5 (CH, J = 7.8 Hz, C-4”); 120.9 (CH, C-3, C-5); 122.5 (CH, C-3’, C-5’); 123.7 (C, J = 270.4 Hz, CF₃); 124.1 (C, C-1); 127.1 (C, J = 32.5 Hz, C-5”); 127.6 (C, J = 11.1 Hz, C-1”); 131.8 (CH, C-2, C-6); 134.4 (C, C-4’); 151.6 (C, C-1’); 153.6 (C, C=O urea); 154.3 (C, J = 246.7 Hz, C-2”); 162.3 (C, C-4); 167.4 (C, C=O).

HRMS (ESI): Calculated for C22Hi6F₄N₂O4Na [M+Na]⁺: 471.3568, found 471.3376.

A/-(3-(4-Cyanophenoxy)phenyl)-A/'-(3-nitrophenyl)urea (Compound 10)

C13H10N2O C20H14N4O4

210.23 g/mol 374.35 g/mol

Following general procedure E.

Aspect: yellowish solid, Theoretical mass: 0.231 g, Obtained mass: 0.119 g, Yield: 52%, Rt (Hexane/EtOAc 7:3): 0.20

IR (film) v(crrr¹): 1725 (C=O); 1596 (NO₂); 1538 (C=C); 1356 (NO₂); 1292 (Ar-O); 1242 (Ar- OAr); 1173 (C-O).

Mp: 104-106 °C

NMR ¹H (CDCI3, 300 MHz) 5 (ppm): 6.73 (dd, i = 3 Hz, J₂ = 9 Hz, 1 H, H-4); 6.99 (d, J = 9 Hz, 2H, H-2”, H-6”); 7.14 (d, J = 9 Hz, 1 H, H-6’); 7.25 (s, 1 H, H-2’); 7.41 (t, J = 9 Hz, 1 H, H- 5’); 7.58 (d, J = 9 Hz, 2H, H-5”, H-3”); 7.82 (d, J = 9 Hz, 1 H, H-6); 7.83 (bs, 2H, NH); 8.02 (s, 1 H, H-2); 8.12-8.14 (m, 2H, H-4, H-5).

NMR ¹³C (CDCI3, 75.4 MHz) 8 (ppm): 105.8 (C_q, C-4); 111.4 (CH, C-2); 113.5 (CH, C-6); 114.7 (CH, C-4’); 115.7 (CH, C-2’); 117.3 (CH, C-2”, C-6”); 118.1 (CH, C-4’); 124.7 (CH, C-6’); 129.9 (CH, C-5); 130.5 (CH, C-5’); 134.2 (CH, C-3”, C-5”); 140.3 (C_q, C-3’); 140.8 (C_q, C-1”); 148.6 (C_q, C-3); 155.4 (C_q, C=O); 156.2 (C_q, C-1’); 162.9 (C_q, C-1). HRMS (ESI): Calculated for C₂oHi4N₄04Na [M+Na]⁺: 397.3323, found 397.3478.

/V-(3-(4-Cvanophenoxy)phenyl)-Ar-(3-aminophenyl)urea (Compound 11 )

374.35 g/mol 344.37 g/mol

Following general procedure D.

Aspect: brownish solid, Theoretical mass: 0.110 g, Obtained mass: 0.086 g, Yield: 78%, Rt (EtOAc 100%): 0.60

IR (film) v(cm’¹): 3364 (NH); 1604 (C=O); 1521 (NO₂); 1403 (C=C); 1348 (NO₂); 1208 (C-N); 1191 (C-O).

MP: 142-144 °C (EtOAc).

NMR ¹H (CDCh, 300 MHz) 5 (ppm): 6.70 (d, J = 8 Hz, 1H, H-4); 6.96 (d, J = 8 Hz, 2H, H-2”, H-6”); 7.12 (d, J = 8 Hz, 1 H, H-2); 7.25 (d, J = 8 Hz, 2H, H-4’, H-5’); 7.35 (t, J = 8 Hz, 1 H, H- 5); 7.54 (d, J = 8 Hz, 2H, H-3”, H-5”); 7.78 (t, J = 8 Hz, 1 H, H-6); 7.80 (d, J = 8 Hz, 1 H, H-6’); 8.10 (d, J = 8 Hz, 1 H, H-2’); 8,17 (bs, 1H, NH-); 8.28 (bs, 1H, NH-).

NMR ¹³C (CDCh, 75.4 MHz) 5 (ppm): 103.9 (C_q, C-4”); 110.1 (CH, C-2); 112.2 (CH, C-6);

110.4 (CH, C-4); 113.7 (CH, C-2’); 114.1 (CH, C-2”, C-6”); 117.6 (CH, C-4’); 118.6 (Cq, CN);

122.5 (CH, C-6’); 128.2 (CH, C-5’); 129.5 (CH, C-5); 133.6 (CH, C-3”, C-5”); 136.3 (C_q, C-3); 137.8 (C_q, C-1”); 146.6 (C_q, C-3’); 152.6 (C_q, C=O); 154.7 (C_q, C-1); 160.7 (C_q, C-1’).

HRMS (ESI): Calculated for C2oHi6N₄0₂Na [M+Na]⁺: 367.3574, found 367.3737.

Methyl 3-(4-(3-(3-nitrophenyl)ureido)phenoxy)benzoate (Compound 12)

Starting from 3-nitrophenylisocyanate purchased from Sigma Aldrich and methyl 3-(4- aminophenoxy)benzoate and following general procedure E.

Aspect: Grey-black solid. Yield: 98%, Rt (EtOAc/Hexane 1.1): 0.49 IR (film) v(cm’¹): 3345 (NH); 1612 (C=0); 1565 (N0₂); 1421 (C=C); 1355 (N0₂); 1212 (C-N); 1178 (C-0).

Mp: 173-175 °C (Dichloromethane).

NMR ¹H (CDCh, 300 MHz) 5 (ppm): 3.86 (s, 3H, CH3O-); 6.60 (d, J = 8.7 Hz, 2H, H-2’, H-6’); 6.68 (d, J = 8.7 Hz, 2H, H-3’, H-5’); 6.73 (dd, J = 1.3, J = 8.9 Hz, 1 H, H-4); 6.98 (d, J = 1.3 Hz, 1 H, H-2); 7.19 (t, J = 8.9 Hz, 1 H, H-5); 7.47 (t, J = 8 Hz, 1 H, H-5”); 7.62 (dd, J = 1.3, J = 8.9 Hz, 1 H, H-6); 7.71 (d, J = 8.9 Hz, 1 H, H-4”); 7.91 (d, J = 8 Hz, 1 H, H-6”); 8,02 (bs, 1 H, NH-); 8.23 (s, 1 H, H-2); 8.97 (bs, 1 H, NH-).

HRMS (ESI): Calculated for C₂IHI₈N₃O₆ [M+H]⁺: 408.1196, found 408.1191.

Methyl 4-(4-(-3-(3-nitrophenyl)ureido)phenoxy)benzoate (Compound 13)

Starting from 3-nitrophenylisocyanate purchased from Sigma Aldrich and methyl 4-(4- aminophenoxy)benzoate and following general procedure E.

Aspect: Grey solid, Yield: 98%, Rt (hexane/ethyl acetate (1 :1)): 0.49

Mp: 173-175 °C (ethyl acetate)

IR (KBr) v(cm-¹): 3289 (NH); 1695 (C=O); 1654 (C=O); 1609 (NH-C=O); 1571 (NO); 1280 (Ar- NH); 1209 (Ar-O-Ar).

¹H NMR (CDCh, 400 MHz) <5(ppm): 3.86 (s, 3H, -CH₃); 6.60 (d, J= 8.7 Hz, 2H, H-2’, H-6’); 6.65 (d, J = 8.7 Hz, 2H, H-3, H-5); 6.72 (d, J = 8.7 Hz, 2H, H-3’, H-5’); 7.17 (dt, J = 1.2, J = 8Hz, 1 H, H-2”); 7.47 (d, J = 8 Hz, 1 H, H-5”); 7.62 (dd, Ji = 8.0, J₂ = 1.2 Hz, 1 H, H-4”); 7.70 (d, Ji = 8.0, Hz, 2H, H-2, H-6); 7.90 (d, J = 4.6 Hz,1 H, H-2”); 8.23 (s, 1 H, -NH); 8.97 (s, 1 H, -NH).

HRMS (ESI+): Calculated for C₂iHi₇NaN₃O₆ [M+Na]⁺: 430.1015, found 430.1089.

1-(4-(4-Cvanophenoxy)phenyl)-3-(2-fluoro-5(trifluoromethyl)phenyl)urea (Compound 14)

Starting from 2-fluoro-3-trifluoromethylphenylisocyanate purchased from Sigma Aldrich and 4- (4-aminophenoxy)benzonitrile and following general procedure E.

Aspect: brown semisolid, Yield: 99%, Rt (hexane/ethyl acetate (1 :1)): 0.53

IR (KBr) v(cm-¹): 3278 (NH); 2220 (CN); 1695 (C=O); 1654 (C=O); 1609 (NH-C=O); 1571 (NO); 1280 (Ar-NH); 1198 (Ar-O-Ar).

¹H NMR (CDCI₃, 400 MHz) <5(ppm): 6.71 (d, J = 7.8 Hz, 2H, H-2’, H-6’); 6.91 (d, J = 8.6 Hz, 2H, H-3”, H-5”); 7.11 (d, J = 7.4 Hz, 1 H, H-3); 7.34 (dd, J = 1.2, J = 7.4 Hz, 1 H, H-4); 7.47 (dd, J = 1.2, J = 7.4 Hz, 2H, H-3’, H-5’); 7.52 (d, J= 8.6 Hz, 2H, H-2”, H-6”); 7.72 (s, 1 H, -NH); 8.46 (s, 1 H, -NH); 8.52 (dd, J = 1.6, J = 7.4 Hz, 1 H, H-6).

HRMS (ESI+): Calculated for C21H14F4N3O6 [M+H]⁺: 416.1022, found 416.1054.

1-(4-(4-(Aminomethyl)phenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea (Compound 15)

Starting from 2-fluoro-5-trifluoromethylphenylisocyanate purchased from Sigma Aldrich and 4- (4-(aminomethyl)phenoxy)aniline and following general procedure E.

Aspect: brown semisolid, Yield: 100%, Rt (hexane/ethyl acetate (1 :1)): 0.47

IR (KBr) v(cm-¹): 3267 (NH); 1609 (NH-C=O); 1282 (Ar-NH); 1211 (Ar-O-Ar).

¹H NMR (CDCI3, 400 MHz) <5(ppm): 4.08 (s, 2H, CH₂OH); 6.82 (d, J = 8.4 Hz, 2H, H-3’, H-5’); 6.98 (d, J = 8.7 Hz, 1 H, H-3); 7.10 (t, J = 9 Hz, 1 H, H-4); 7.13 (d, , J = 7 Hz, 2H, H-2”; H-6”); 7.89 (d, J = 7 Hz, 2H, H-3”, H-5”); 7.97 (d, J= 7.7 Hz, 1 H, H-6); 8.51 (s, 1 H, -NH); 8.58 (d, J = 5 Hz, 2H, H-2’; H-6’); 9.02 (bs, 1 H, -NH)

HRMS (ESI+): Calculated for C21H18F4N3O2 [M+H]⁺: 420.1335, found 420.1339.

1-(4-(4-(Aminophenoxy)phenyl)-3-phenylurea (Compound 16)

Starting from phenylisocyanate purchased from Sigma Aldrich and 4,4'-oxydianiline and following general procedure E.

Aspect: brown semisolid, Yield: 60%, Rt (hexane/ethyl acetate (1 :1)): 0.44

IR (KBr) v(cm’¹): 3301 (NH); 1611 (NH-C=O); 1275 (Ar-NH); 1209 (Ar-O-Ar).

¹H NMR (aceton-d₆, 400 MHz) <5(ppm): 5.10 (s, 2H, NH₂); 6.62 (d, J = 8.7 Hz, 2H, H-2’, H-6’); 7.10-7.13 (m, 4H, H-2’, H-3’, H-5’, H-6’); 7.33 (d, J = 8.2 Hz, 2H, H-3, H-5); 7.42 (dd, J = 2, J = 8.2 Hz, 2H, H-1 , H-6); 7.59 (bs, 1H, -NH); 7.62 (s, 1H, -NH)

HRMS (ESI+): Calculated for C19H18N3O2 [M+H]⁺: 320.1399, found 320.1400.

Phenyl (4-(4-(3-phenylureido)phenoxy)phenyl)phenyl)carbamate (Compound 17)

Starting from phenylisocyanate purchased from Sigma Aldrich and phenyl (4-(4- aminophenoxy)phenyl)carbamate and following general procedure E.

Aspect: brown semisolid, Yield: 80%, Rt (hexane/ethyl acetate (1 :1)): 0.48

IR (KBr) v(cm-¹): 3300 (NH); 1678 (O-CO-N); 1609 (NH-C=O); 1260 (Ar-NH); 1198 (Ar-O-Ar).

¹H NMR (aceton-d₆, 400 MHz) <5(ppm): 6.70 (d, J = 8.6 Hz, 2H, H-3, H-5); 6.77 (d, J = 8.6 Hz, 1 H, H-2); 6.84 (d, J = 8.6 Hz, 1 H, H-6); 6.91-6.99 (m, 3H, H-4, H-2’”, H-6’”); 7.31 (d, J = 7.3 Hz, 2H, H-3’, H-5’); 7.35 (d, J = 7.3 Hz, 2H, H-3”, H-5”); 7.45 (d, J = 7.3 Hz, 2H, H-2’, H-6’); 7.49 (d, J = 7.3 Hz, 2H, H-2”, H-6”); 7.52-7.55 (m, 3H, H-3’”, H-4’”, H-5’”)7.59 (bs, 1 H, -NH); 7.61 (s, 1 H, -NH).

¹³C NMR (aceton-d₆, 400 MHz) <5(ppm): 121.1 (CH, ortho (x 6)); 126.3 (CH, metha (x 4)); 128.3 (CH, para (x 2)); 128.7 (C, C-N); 139.9 (C, C-N); 140.0 (C, C-N); 148.0 (C, C-N carbamate); 151.2 (C, Ar-0 (x 3)); 152.0 (C, CO carbamate); 152.5 (C, CO urea).

HRMS (ESI+): Calculated for C26H22N3O4 [M+H]⁺: 440.1610, found 440.1608.

1-(2-Fluoro-5-(trifluoromethyl)phenyl-3-(4-(-4-formylphenoxy)phenyl)urea (Compound 18}

Following general procedure E.

Aspect: white-yellow solid, Yield: 75%, Rt (hexane/ethyl acetate (1 :1)): 0.31

Mp: 178-180 °C (toluene)

IR (KBr) v(cm-¹): 3240 (NH); 1599 (NH-C=O); 1245 (Ar-NH); 1210 (Ar-O-Ar).

¹H NMR (CDCh, 400 MHz) <5(ppm): 6.87 (d, J = 7 Hz, 2H, H-3’, H-5’); 7.14 (d, J = 7 Hz, 2H, H- 2’, H-6’); 7.31 (dd, J = 1.6, J = 7 Hz, 2H, H-3’, H-4’); 7.42 (d, J = 7 Hz, 2H, H-3, H-5); 7.46 (s, 1 H, H-5”); 7.96 (d, J = 7 Hz, 2H, H-2, H-6); 9.89 (s, 1 H, CHO).

HRMS (ESI+): Calculated for C21H15F4N2O3 [M+H]⁺: 419.1019, found 419.1009.

Methyl 3-(4-(3-(2-fluoro-5-(trifluoromethyl))phenyl)ureido)phenoxy)benzoate

(Compound 19)

Following general procedure E.

Aspect: white solid, Yield: 90%, Rt (hexane/ethyl acetate (1 :1)): 0.49

Mp: 205-207 °C (toluene)

IR (KBr) v(cm’¹): 3298 (NH); 1602 (NH-C=O); 1269 (Ar-NH); 1214 (Ar-O-Ar).

¹H NMR (CDCI₃, 400 MHz) <5(ppm): 3.90 (s, 3H, CH₃); 6.90 (d, J = 6.8 Hz, 2H, H-3’, H-5’); 7.14 (d, J = 7 Hz, 1 H, H-3”); 7.18 (dd, J = 1.6, J = 5 Hz, 1 H, H-4”); 7.24 (d, J = 7 Hz, 1 H, H-4); 7.31 (d, J = 6.8 Hz, 2H, H-2’, H-6’); 7.42 (d, J = 7.8 Hz, 1 H, H-5); 7.62 (d, J = 1.6 Hz, 1 H, H-2); 8.52 (bs, 1 H, -NH); 8.54 (d, J = 7.4, 1 H, H-6”). HRMS (ESI+): Calculated for C₂₂HI₇N₂O₄ [M+H]⁺: 449.1124, found 449.1127.

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-hvdroxymethyl)phenoxy)phenyl) urea

(Compound 20)

Following general procedure E.

Aspect: dark semisolid, Yield: 100%, Rt (hexane/ethyl acetate (1 :1)): 0.58

IR (KBr) v(crrr¹): 3400 (NH); 1612 (NH-C=O); 1276 (Ar-NH); 1211 (Ar-O-Ar).

¹H NMR (CDCI₃, 400 MHz) <5(ppm): 3.90 (s, 2H, CH₂); 6.82 (dd, J = 2.5, J = 8.9 Hz, 2H, H-3’, H-5’); 7.08 (d, J = 2.5, J = 8.9 Hz, 2H, H-2’, H-6’); 7.23-1.26 (m, 2H, H-4, H-6); 7.36 (t, J = 8.5 Hz, 1H, H-5); 7.52 (bs, 1 H, OH), 7.56 (d, J = 2.5 Hz, 1 H, H-2); 7.76 (d, J = 7.2 Hz, 1 H, H-6”); 7.97 (bs, 1 H, NH); 8.00 (d, J = 7.2 Hz, 2H, H-5”); 8.12 (bs, 1H, -NH); 8.05 (s, 1H, H-2”).

¹³C NMR (Acetone-d₆, 100.6 MHz) <5(ppm): 52.4 (CH₂, CH₂OH); 118.0 (CH, J = 9 Hz, C-2”); 119.1 (CH, C-2’, C-6’); 121.1 (CH, C-4); 123.4 (CH, C-6); 123.5 (CH, C-2); 123.7 (CH, J = 9 Hz, C-6”); 124.1 (C, J = 272 Hz, CF₃); 124.1 (C, C-4”); 128.5 (C, J = 31 Hz, C-3”); 126.5 (C, J = 16.6 Hz, C-5”); 128.5 (C, J = 26 Hz, C-4”); 131.0 (CH, C-5); 131.6 (C, C-1); 131.8 (CH, C- 3’, C-5’); 132.6 (C, C-1”); 136.7 (CH, C-5”); 140.5 (C, C-3); 153.3 (C, C-4); 153.5 (C, C-1’); 154.4 (C, NH-CO-NH).

HRMS (ESI+): Calculated for C₂IHI₇CIF₃N₂O₃ [M+H]⁺: 437.0880, found 437.0878.

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-hvdroxymethyl)phenoxy)phenyl)urea

(Compound 21)

Following general procedure E.

Aspect: dark solid, Yield: 100%, Rt (hexane/ethyl acetate (1 :1)): 0.56

Mp: 147-149 °C (dichloromethane)

IR (KBr) v(cm-¹): 3310 (NH); 1599 (NH-C=O); 1256 (Ar-NH); 1218 (Ar-O-Ar). ¹H NMR (CDCI3, 400 MHz) <5(ppm): 1.70 (bs, 1 H, OH); 3.88 (s, 2H, CH₂); 6.91 (d, J = 7 Hz, 2H, H-3, H-5); 6.97 (d, J = 7 Hz, 2H, H-2’, H-6’); 7.27 (d, J = 7 Hz, 2H, H-2, H-6); 7.33 (d, J = 7 Hz, 1 H, H-6”); 7.47 (d, J = 7 Hz, 1 H, H-5”); 7.48 (bs, 1 H, NH); 7.59 (d, J = 2.5 Hz, 1 H, H-2”); 7.68 (bs, 1 H, NH); 7.98 (d, J = 7 Hz, 2H, H-3’, H-5’); 8.52 (bs, 1 H, -NH); 8.54 (d, J = 7.4, 1 H, H-6”).

HRMS (ESI+): Calculated for C21H17CIF3N2O3 [M+H]⁺: 437.0880, found 436.0882.

Methyl 3-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)benzoate

(Compound 22)

Aspect: orange-yellow oil, Yield: 100%, Rt (hexane/ethyl acetate (1 :1)): 0.57

NMR-¹H (CDCI₃, 400 MHz) o(ppm): 3.98 (s, 3H, CH3-O); 6.89 (d, J = 8.8 Hz, 2H, H-2', H-6'); 7.19 (d, J = 8.8 Hz, 2H, H-3', H-5'); 7.30 (d, J = 8.6 Hz, 1 H, H-4); 7.39 (d, J = 8.6 Hz, 1 H, H- 6); 7.43 (t, J = 8.6 Hz, 1 H, H-5); 7.44 (s, 1 H, H-2); 7.50 (d, J = 8 Hz, 1 H, H-6”); 7.68 (s, 1 H. H- 2”); 7.75 (dd, Ji = 1.3 Hz, J₂ = 8 Hz, 1 H, H-5”); 8.14 (bs, 2H, NH).

PHARMACOLOGICAL PROCEDURES

In vitro test

The biological activity was measured using the MTT test ((3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide)), which consisted of a colorimetric test that allowed evaluating the metabolic activity of cells, and therefore quantify cell viability. Cells with active metabolism transform MTT (yellow) into another product called formazan (purple); if the cells are not viable they lose the ability to carry out this reaction.

This test allows determining the inhibitory capacity of a compound on cell growth and can give a slight idea about the type of mechanism of action of the compound (cytotoxic or cytostatic). In these tests, cell viability is compared in percentage as a function of the control, with the different tested concentrations of the compound. In order to be able to compare the effectiveness of different compounds, it is most common to determine the IC50 value (concentration at which 50% of cell growth is inhibited compared to the control test).

Biological activity on cancer cells The compounds were incubated at increasing concentrations for 24 and 48 hours in two different human osteosarcoma cell lines from the American Type Culture Collection (ATCC): SaOS-2 (HTB-85) and MNNG/HOS (TE 85, clone F-5) [R-1059-D], These two cell lines were used as they have different degrees of cell differentiation: SaOS-2 cells are quite differentiated cells that would be equivalent to a healthy cell type - they are considered a cell model similar to osteoblasts (HOS-CRL-1543)- and MNNG/HOS cells show a lower degree of differentiation similar to the typical profile of tumor cells. In addition, the replication rate of both cells also diverges, with MNNG/HOS being the fastest growing with a doubling of cell number within 24 hours of incubation, while SaOS-2 they double in approximately 43 hours. Cancer originating in MNNG cells is more aggressive.

Each MTT assay required 4 or 5 steps depending on the time point assessed (24 or 48 hours) (A. Spreafico et al., 2006):

- Day 1 : SaOS-2, MNNG/HOS and the control non-tumoral cell line (either hOB cells (ATCC, CRL-1427) or HFF-1 (ATCC, SCRC-1041)) were seeded with a multichannel pipette in a 96-well plate at a density of 9- 10³, 4 10³ and 7- 10³ cells/well, respectively, using a Scepter™ 2.0 Cell Counter (Merck Millipore). The cells were allowed to attach for 30 hours incubated at 37 °C in a humidified atmosphere with 5% CO2 (Thermo Scientific Incubator).

- Day 2: After that time, complete medium was replaced by 200 pL 0.5% FBS DMEM medium/well for overnight starvation incubated under the same conditions described above.

- Day 3: The next day, the starved medium was replaced by 200 pL of different concentrations of each product. Control cell cultures were treated with the highest concentration of DMSO used for the treatment (0.1% v/v). Cells were incubated for 24 hours under the same conditions.

- Day 4: After 24 hours of treatment addition, culture medium was removed and cells were incubated with 1 :5 diluted MTT (final concentration of 1 mg/mL) with white DMEM (without phenol red) for 3 hours and 30 min. After incubation time, the DMEM/MTT solution was carefully removed, and formazan salts were dissolved in 100 pg/mL of DMSO. Finally, absorbance was read at a wavelength of 550 nm using a microplate reader VersaMax TM, Molecular Devices.

- Day 5: After 48 hours of treatment addition, the MTT assay described above was repeated. For the non-tumoral cell line, this time point was not evaluated. Determination of IC50

Cell viability was expressed as percentage of cell growth compared with DMSO control. Cell viability at each concentration was tested in quadruplicate in order to obtain a representative average with its corresponding standard deviation. Average absorbance values and standard deviation were determined by Microsoft® Excel® version 14.7.3. IC50 values were determined using GraphPad Prism software version 6.0.1.298.

The results are provided in Table 1 below:

Table 1. Synthetized compounds

It could be concluded that the compounds of formula (I) were potent and selective anti-cancer compounds.

BIBLIOGRAPHIC REFERENCES

[1], P. S. Meltzer et al., “New horizons in the treatment of osteosarcoma”, N. Engl. J. Med., 2021, 385, 2066-2076. [2], D. J. Harrison et al., “Current and future therapeutic approaches for osteosarcoma”, Expert Rev. Anticancer Then, 2018, 18, 39-50.

[3], N. M. Marina, et al., “Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (Ell RAMOS-1): an open-label, international, randomised controlled trial”, Lancet Oncol., 2016, 17, 1396-1408.

[4], R. Rathore et al., “Pathogenesis and current treatment of osteosarcoma: perspectives for future therapies”, J. Clin. Med., 2021, 10, 1182.

[5], Z. D. Prudowsky etal., “Recent insights into therapy resistance in osteosarcoma”, Cancers, 2021, 13, 83. [6], Spreafico A. et al., “A proteomic study on human osteoblastic cells proliferation and differentiation”, Proteomics, 2006, 6(12), 3520-3532.

Claims

1. A compound of formula (I), or a salt, solvate or stereoisomer thereof, for use in the treatment and/or prevention of cancer:

wherein:

Ri is selected from the group consisting of: halogen; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; C(O)R_xi; NR_X2Rxs; CN; C(=N-OH)(Ci-C5)alkyl; and NO2;

R2 and R3 are independently selected from the group consisting of: H; halogen; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; C(0)R_X4; CN; and NO2;

R_xi and R_X4 are selected from H; (Ci-Cs)alkyl optionally substituted with one or more Z substituents; -O-(Ci-Cs)alkyl; or NR_X7 _xs; X2, _X3, _X5, _X6, _X7 and R_X8 are the same or different and are selected from: H or C(O)R_xg;

R_X9 are independently selected from H; (Ci-Cs)alkyl optionally substituted by one or more Z substituents; -O-ring, wherein “ring” means an aromatic ring having 5 or 6 members optionally substituted with one or more Z substituents;

Z substituent is selected from halogen, OH, NH2, and wherein the compound is selected from the group consisting of:

(iv)N-((4-methoxycarbonylphenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl) urea;

(i) N-(4-(acetamidophenyl)-4-phenoxy)-N'-phenylurea;

(ii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(3-nitrophenyl)urea;

(iii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl)urea;

(v) N-(4-(2-(bromomethyl)phenoxy)phenyl)-N'-(3-nitrophenyl)urea;

(vi) 1-(4-(4-Acetylphenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

(vii)N-[4-((4-(1-hydroxyamino)ethyl)phenoxy)phenyl]-N’-[(2-fluoro-4-trifluoro)phenyl] urea;

(viii)N-[4-(4-(acetamidophenyloxy)phenyl)]-N’-[(2-fluoro-5-trifluoromethy)phenyl]urea;

(ix) Methyl 4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenoxy}-benzoate;

(x) N-(3-(4-Cyanophenoxy)phenyl)-N’-(3-nitrophenyl)urea; (xi) N-(3-(4-Cyanophenoxy)phenyl)-N’-(3-aminophenyl)urea;

(xii) Methyl 3-(4-(3-(3-nitrophenyl)ureido)phenoxy)benzoate;

(xiii) Methyl 4-(4-(-3-(3-nitrophenyl)ureido)phenoxy)benzoate;

(xiv) 1-(4-(4-Cyanophenoxy)phenyl)-3-(2-fluoro-5(trifluoromethyl)phenyl)urea;

(xv)1-(4-(4-(Aminomethyl)phenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

(xvi) 1-(4-(4-(Aminophenoxy)phenyl)-3-phenylurea;

(xvii) Phenyl (4-(4-(3-phenylureido)phenoxy)phenyl)phenyl)carbamate;

(xviii) 1-(2-Fluoro-5-(trifluoromethyl)phenyl-3-(4-(-4-formylphenoxy)phenyl)urea;

(xix) Methyl 3-(4-(3-(2-fluoro-5-(trifluoromethyl))phenyl)ureido)phenoxy)benzoate;

(xx)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-hydroxymethyl)phenoxy)phenyl)urea;

(xxi)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-hydroxymethyl)phenoxy)phenyl)urea;

(xxii)Methyl 3-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)benzoate; and any salt, solvate or stereoisomer thereof.

2. The compound for use according to the preceding claim, wherein the compound is selected from the group consisting of:

(i) N-(4-(acetamidophenyl)-4-phenoxy)-N'-phenylurea;

(ii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(3-nitrophenyl)urea;

(iii) N-(4-(acetamidophenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl)urea;

(iv)N-((4-methoxycarbonylphenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl) urea;

(v) N-(4-(2-(bromomethyl)phenoxy)phenyl)-N'-(3-nitrophenyl)urea;

(vi) 1-(4-(4-Acetylphenoxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

(vii)N-[4-((4-(1-hydroxyamino)ethyl)phenoxy)phenyl]-N’-[(2-fluoro-4-trifluoro)phenyl] urea;

(xix) Methyl 3-(4-(3-(2-fluoro-5-(trifluoromethyl))phenyl)ureido)phenoxy)benzoate;

(xxii)Methyl 3-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)benzoate; and any salt, solvate or stereoisomer thereof.

3. The compound for use according to the preceding claim, wherein the compound is N-((4- methoxycarbonylphenyl)-4-phenoxy)-N'-(4-chloro-3-(trifluoromethyl)phenyl) urea; or any salt, solvate or stereoisomer thereof.

4. The compound for use according to any one of the preceding claims, wherein the cancer is selected a sarcoma, particularly an osteosarcoma.

5. A compound of formula I, a salt, solvate or stereoisomer thereof, wherein the compound is as defined in claim 1.

6. The compound of claim 5, wherein the compound is as defined in claim 2.

7. The compound according to the preceding claim, wherein the compound is as defined in claim 3.

8. A pharmaceutical composition comprising a compound as defined in any one of the claims 5 to 7, and one or more pharmaceutically acceptable excipients and/or carriers.

9. A compound as defined in any one of the claims 5 to 8, for use in therapy.